Clinical trial NCT02075840
Conditions: Non-Small Cell Lung Cancer
Sponsor: Hoffmann-La Roche
Start date: 2014-08-19; Completion date: 2025-04-28
Enrollment: 303 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized, active controlled, multicenter phase III open-label study is designed to evaluate the efficacy and safety of alectinib compared with crizotinib treatment in participants with treatment-naive anaplastic lymphoma kinase-positive (ALK-positive) advanced non-small cell lung cancer (NSCLC). Participants will be randomized in a 1:1 ratio to receive either alectinib, 600 milligrams (mg) orally twice daily (BID), or crizotinib, 250 mg orally BID. Participants will receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, or death. The study is expected to last approximately 144 months.

Detailed description:

Arms: arm 1: Participants will receive alectinib from Visit 0 (baseline) until disease progression, unacceptable toxicity, withdrawal of consent or death. arm 2: Participants will receive crizotinib from Visit 0 (baseline) until disease progression, unacceptable toxicity, withdrawal of consent or death.
Interventions: intervention 1: Alectinib intervention 2: Crizotinib
Intervention descriptions: intervention 1: Participants will receive alectinib 600 mg orally (four 150 mg capsules) BID from Visit 0 (baseline) until disease progression, unacceptable toxicity, withdrawal of consent or death. intervention 2: Participants will receive crizotinib 250 mg capsules orally BID from Visit 0 (baseline) until disease progression, unacceptable toxicity, withdrawal of consent or death.

Protocol documents:
Prot_001.pdf: 
 
Document Type: 
Protocol and amendments 
Official Title: 
RANDOMIZED, MULTICENTER, PHASE III, OPEN-LABEL 
STUDY OF ALECTINIB VERSUS CRIZOTINIB IN 
TREATMENT-NAIVE ANAPLASTIC LYMPHOMA KINASE-
POSITIVE ADVANCED NON－SMALL CELL LUNG CANCER 
NCT Number: 
NCT02075840 
Document Date(s): 
Protocol version 5: 10-Feb-2017 
Protocol version 4: 15 April 2016 
Protocol version 3: 14 May 2015 
Protocol version 2: 8 October 2014 
Protocol version 1: 10 Feb 2014 
 
 


Clinical Study Report: RO5424802 - F. Hoffmann-La Roche Ltd
Protocol BO28984     Report Number 1078196
1956
 
Title
10-Feb-2017 00:53:50
Date and Time (UTC)
Company Signatory
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 5 (Canada) 
PROTOCOL 
TITLE: 
RANDOMIZED, MULTICENTER, PHASE III, 
OPEN-LABEL STUDY OF ALECTINIB VERSUS 
CRIZOTINIB IN TREATMENT-NAIVE ANAPLASTIC 
LYMPHOMA KINASE-POSITIVE ADVANCED 
NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: BO28984 
VERSION NUMBER: 
5 (Canada) 
EUDRACT NUMBER: 
2013-004133-33 
IND NUMBER: 
111723 
UTN NUMBER: 
 
TEST PRODUCT: 
Alectinib (RO5424802) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  10 February 2014 
DATE AMENDED: 
Version 2:  8 October 2014 
Version 3:  14 May 2015 
Version 4:  15 April 2016 
Version 5 (Canada): See electronic date stamp below.


Clinical Study Report: RO5424802 - F. Hoffmann-La Roche Ltd
Protocol BO28984     Report Number 1078196
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2/Protocol BO28984, Version 5 (Canada) 
PROTOCOL AMENDMENT, VERSION 5 (CANADA): 
RATIONALE 
Protocol BO28984 has been amended to include information related to gastrointestinal 
perforation in order to be aligned with the approved Canadian product monograph 
(Section 5.1.2.4).  The guideline for the management of specific adverse events has also 
been updated to include gastrointestinal perforation (Section 5.1.3). 
 


Clinical Study Report: RO5424802 - F. Hoffmann-La Roche Ltd
Protocol BO28984     Report Number 1078196
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PROTOCOL AMENDMENT, VERSION 5 (CANADA): 
SUMMARY OF CHANGES 
SECTION 5.1.2.4:  Gastrointestinal Disorders 
In pivotal clinical trials, one case of GI perforation (0.4%) occurred and had a fatal 
outcome. In the post-market setting, cases of GI perforation were also reported with 
alectinib. 
TABLE 2:  Guidelines for Management of Specific Adverse Events with 
Alectinib 
Table 2 has been updated to include guidelines around GI perforation.  
 
 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11 
PROTOCOL SYNOPSIS .................................................................................... 12 
1. 
BACKGROUND .......................................................................................... 23 
1.1 
Background on Anaplastic Lymphoma 
Kinase−Positive Non−Small Cell Lung Cancer...................... 23 
1.2 
Background on Alectinib........................................................ 25 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 30 
2. 
OBJECTIVES.............................................................................................. 32 
2.1 
Efficacy Objectives ................................................................ 32 
2.2 
Safety Objectives................................................................... 33 
2.3 
Pharmacokinetic Objectives .................................................. 33 
2.4 
Patient-Reported Outcome Objectives .................................. 33 
2.5 
Exploratory Objectives........................................................... 33 
3. 
STUDY DESIGN ......................................................................................... 34 
3.1 
Description of Study .............................................................. 34 
3.2 
End of Study.......................................................................... 36 
3.3 
Rationale for Study Design.................................................... 37 
3.3.1 
Rationale for Alectinib Dosage .............................................. 37 
3.3.2 
Rationale for Patient Population ............................................ 38 
3.3.3 
Rationale for Control Group................................................... 38 
3.3.4 
Rationale for Open-Label Design .......................................... 39 
3.3.5 
Rationale for Primary Endpoint Selection .............................. 40 
3.3.6 
Rationale for Secondary Endpoint of Time to 
CNS Progression................................................................... 41 
3.3.7 
Rationale for PK Sample Collection Schedule....................... 42 
3.3.8 
Rationale for Biomarker Assessments................................... 42 
3.3.9 
Rationale for PRO Assessments ........................................... 43 
3.4 
Outcome Measures ............................................................... 44 
3.4.1 
Efficacy Outcome Measures.................................................. 44 
3.4.2 
Safety Outcome Measures .................................................... 44 
3.4.3 
Pharmacokinetic Outcome Measures.................................... 45 


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3.4.4 
Patient-Reported Outcome Measures ................................... 45 
3.4.5 
Exploratory Outcome Measures ............................................ 46 
4. 
MATERIALS AND METHODS .................................................................... 46 
4.1 
Patients.................................................................................. 46 
4.1.1 
Inclusion Criteria.................................................................... 46 
4.1.2 
Exclusion Criteria................................................................... 48 
4.2 
Method of Treatment Assignment and Blinding..................... 49 
4.3 
Study Treatment.................................................................... 49 
4.3.1 
Formulation, Packaging, and Handling.................................. 49 
4.3.1.1 
Alectinib................................................................................. 49 
4.3.1.2 
Crizotinib................................................................................ 50 
4.3.2 
Dosage, Administration, and Compliance.............................. 50 
4.3.2.1 
Alectinib................................................................................. 50 
4.3.2.2 
Crizotinib................................................................................ 50 
4.3.3 
Investigational Medicinal Product Accountability ................... 51 
4.3.4 
Post-Trial Access to Alectinib ................................................ 51 
4.4 
Concomitant Therapy ............................................................ 52 
4.4.1 
Permitted Therapy ................................................................. 52 
4.4.2 
Prohibited Therapy ................................................................ 53 
4.4.3 
Prohibited Food ..................................................................... 54 
4.5 
Study Assessments ............................................................... 54 
4.5.1 
Informed Consent Forms and Screening Log........................ 54 
4.5.2 
Medical History and Demographic Data ................................ 55 
4.5.3 
Corticosteroid Use for CNS Metastases ................................ 55 
4.5.4 
Physical Examinations........................................................... 55 
4.5.5 
Vital Signs.............................................................................. 55 
4.5.6 
ECOG Performance Status ................................................... 56 
4.5.7 
Tumor and Response Evaluations......................................... 56 
4.5.8 
Laboratory, Biomarker, and Other Biological 
Sample .................................................................................. 57 
4.5.8.1 
Laboratory Assessments ....................................................... 57 
4.5.8.2 
Pre-Treatment Tumor Samples (Mandatory)......................... 57 


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4.5.8.3 
Pre- and Fresh Post-Treatment Tumor Biopsies 
(Optional)............................................................................... 58 
4.5.8.4 
Blood and Plasma Samples................................................... 59 
4.5.8.5 
Samples for Pharmacokinetic Assessments.......................... 60 
4.5.9 
Electrocardiograms................................................................ 61 
4.5.10 
Patient-Reported Outcomes .................................................. 61 
4.5.11 
Samples for Roche Clinical Repository.................................. 62 
4.5.11.1 
Overview of the Roche Clinical Repository............................ 62 
4.5.11.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 62 
4.5.11.3 
Sample Collection.................................................................. 62 
4.5.11.4 
Confidentiality........................................................................ 63 
4.5.11.5 
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 63 
4.5.11.6 
Withdrawal from the Roche Clinical Repository..................... 64 
4.5.11.7 
Monitoring and Oversight....................................................... 64 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 64 
4.6.1 
Patient Discontinuation.......................................................... 64 
4.6.2 
Study Treatment Discontinuation........................................... 65 
4.6.3 
Study and Site Discontinuation.............................................. 65 
5. 
ASSESSMENT OF SAFETY....................................................................... 66 
5.1 
Safety Plan ............................................................................ 66 
5.1.1 
Adverse Events Collection..................................................... 66 
5.1.2 
Adverse Events Relating to ALK Inhibitors and/or 
the Tyrosine Kinase Inhibitor Class and Alectinib 
Data....................................................................................... 66 
5.1.2.1 
Interstitial Lung Disease ........................................................ 66 
5.1.2.2 
Hepatotoxicity........................................................................ 66 
5.1.2.3 
Anemia .................................................................................. 67 
5.1.2.4 
Gastrointestinal Disorders ..................................................... 67 
5.1.2.5 
Skin Disorders ....................................................................... 67 
5.1.2.6 
Vision Disorders .................................................................... 68 
5.1.2.7 
Edema ................................................................................... 68 


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5.1.2.8 
Bradycardia ........................................................................... 68 
5.1.2.9 
Abnormal Renal Function ...................................................... 69 
5.1.2.10 
Severe Myalgia and CPK Elevations ..................................... 69 
5.1.3 
Management of Specific Adverse Events with 
Alectinib................................................................................. 70 
5.1.4 
Safety of Crizotinib and Management of Adverse 
Events.................................................................................... 73 
5.2 
Safety Parameters and Definitions ........................................ 76 
5.2.1 
Adverse Events ..................................................................... 76 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 77 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 77 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 78 
5.3.1 
Adverse Event Reporting Period ........................................... 78 
5.3.2 
Eliciting Adverse Event Information ....................................... 78 
5.3.3 
Assessment of Severity of Adverse Events ........................... 78 
5.3.4 
Assessment of Causality of Adverse Events ......................... 79 
5.3.5 
Procedures for Recording Adverse Events............................ 80 
5.3.5.1 
Diagnosis Versus Signs and Symptoms................................ 80 
5.3.5.2 
Adverse Events that are Secondary to Other 
Events.................................................................................... 80 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 80 
5.3.5.4 
Abnormal Laboratory Values ................................................. 81 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 82 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 82 
5.3.5.7 
Deaths ................................................................................... 82 
5.3.5.8 
Preexisting Medical Conditions.............................................. 83 
5.3.5.9 
Lack of Efficacy or Worsening of Non-Small Cell 
Lung Cancer.......................................................................... 83 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 83 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 84 
5.3.5.12 
Patient-Reported Outcome Data ........................................... 84 


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5.3.5.13 
Adverse Events in Individuals Not Enrolled in the 
Study ..................................................................................... 84 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 84 
5.4.1 
Emergency Medical Contacts................................................ 85 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 85 
5.4.2.1 
Events That Occur Prior to Study Drug Initiation ................... 85 
5.4.2.2 
Events That Occur After Study Drug Initiation ....................... 85 
5.4.3 
Reporting Requirements for Pregnancies.............................. 86 
5.4.3.1 
Pregnancies in Female Patients............................................ 86 
5.4.3.2 
Pregnancies in Female Partners of Male Patients................. 86 
5.4.3.3 
Abortions ............................................................................... 87 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 87 
5.5 
Follow-Up of Patients After Adverse Events.......................... 87 
5.5.1 
Investigator Follow-Up........................................................... 87 
5.5.2 
Sponsor Follow-Up ................................................................ 87 
5.6 
Post-study Adverse Events.................................................... 88 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 88 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 88 
6.1 
Determination of Sample Size ............................................... 89 
6.2 
Summaries of Conduct of Study............................................ 90 
6.3 
Summaries of Treatment Group Comparability ..................... 90 
6.4 
Efficacy Analyses .................................................................. 91 
6.4.1 
Primary Efficacy Endpoint...................................................... 91 
6.4.2 
Secondary Efficacy Endpoints............................................... 92 
6.4.2.1 
Sensitivity Analyses............................................................... 94 
6.4.2.2 
Subgroup Analyses ............................................................... 94 
6.5 
Safety Analyses..................................................................... 94 
6.6 
Pharmacokinetic Analyses..................................................... 95 
6.7 
Patient-Reported Outcome Analyses .................................... 96 


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6.7.1 
Time to Deterioration of Patient-Reported Lung 
Cancer Symptoms................................................................. 96 
6.7.2 
Additional Patient-Reported Outcomes ................................. 97 
6.8 
Exploratory Analyses............................................................. 97 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 98 
7.1 
Data Quality Assurance......................................................... 98 
7.2 
Electronic Case Report Forms............................................... 98 
7.3 
Electronic Patient-Reported Outcome Data........................... 99 
7.4 
Source Data Documentation.................................................. 99 
7.5 
Use of Computerized Systems ............................................ 100 
7.6 
Retention of Records........................................................... 100 
8. 
ETHICAL CONSIDERATIONS.................................................................. 100 
8.1 
Compliance with Laws and Regulations .............................. 100 
8.2 
Informed Consent ................................................................ 100 
8.3 
Institutional Review Board or Ethics Committee.................. 102 
8.4 
Confidentiality...................................................................... 102 
8.5 
Financial Disclosure ............................................................ 102 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 103 
9.1 
Study Documentation .......................................................... 103 
9.2 
Protocol deviations .............................................................. 103 
9.3 
Site Inspections ................................................................... 103 
9.4 
Administrative Structure....................................................... 103 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 104 
9.6 
Protocol Amendments ......................................................... 105 
10.  REFERENCES ......................................................................................... 106 


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LIST OF TABLES 
Table 1 
Overall Response Rates and Time to Response in Patients 
in Part 2 of Study AF-001JP........................................................ 27 
Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib ...................................................................................... 70 
Table 3 
Crizotinib Dose Modification-Hematologic Toxicities (Except 
Lymphopenia) ............................................................................. 74 
Table 4 
Crizotinib Dose Modification-Non-Hematologic Toxicities........... 75 
Table 5 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in the NCI CTCAE ......................................... 79 
 
 
LIST OF FIGURES 
Figure 1 
Change in Size of Target Lesions as Assessed by the 
Independent Review Committee in Part 2 of Study AF-001JP 
Using RECIST v1.1 (Data Cutoff Date: 18 April 2013)................ 26 
Figure 2 
Duration of Dosing by Cohort in Patients in Part 1 of 
Study NP28761/AF-002JG (Data Cutoff Date: 
12 September 2013) ................................................................... 28 
Figure 3 
Best Percent Change in Size of Target Lesions from 
Baseline as Assessed by the Investigator in Patients in 
Part 1 of Study NP28761/AF-002JG (Data Cutoff Date: 
12 September 2013) ................................................................... 29 
Figure 4 
Summary of Study Design .......................................................... 36 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 111 
Appendix 2 
Schedule of Alectinib Pharmacokinetic Assessments............... 119 
Appendix 3 
List of Substrates, Inhibitors, and Inducers of Drug-
Metabolizing Enzymes and Transporters.................................. 120 
Appendix 4 
Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1: Excerpt from Original Publication.......................... 122 
Appendix 5 
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 134 
Appendix 6 
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires .......... 135 
Appendix 7 
Modification of Diet in Renal Disease (MDRD) Formula ........... 143 
Appendix 8 
Anaplastic Lymphoma Kinase (ALK) Immunohistochemistry.... 144 
Appendix 9 
Drug Metabolism Enzymes, Transporters (DMET), and Liver 
Injury Polymorphisms................................................................ 145 
Appendix 10 Formulae for the Calculation of QTcF and RR.......................... 147 


Clinical Study Report: RO5424802 - F. Hoffmann-La Roche Ltd
Protocol BO28984     Report Number 1078196
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
RANDOMIZED, MULTICENTER, PHASE III, 
OPEN-LABEL STUDY OF ALECTINIB VERSUS 
CRIZOTINIB IN TREATMENT-NAIVE ANAPLASTIC 
LYMPHOMA KINASE-POSITIVE ADVANCED 
NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: BO28984 
VERSION NUMBER: 
5 (Canada) 
EUDRACT NUMBER: 
2013-004133-33 
IND NUMBER: 
111723 
UTN NUMBER: 
 
TEST PRODUCT: 
Alectinib (RO5424802) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy to 
your local study monitor. 
 


Clinical Study Report: RO5424802 - F. Hoffmann-La Roche Ltd
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PROTOCOL SYNOPSIS 
TITLE: 
RANDOMIZED, MULTICENTER, PHASE III, OPEN-LABEL STUDY 
OF ALECTINIB VERSUS CRIZOTINIB IN TREATMENT-NAIVE 
ANAPLASTIC LYMPHOMA KINASE-POSITIVE ADVANCED 
NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: 
BO28984 
VERSION NUMBER: 
5 (Canada) 
EUDRACT NUMBER: 
2013-004133-33 
IND NUMBER: 
111723 
UTN NUMBER: 
 
TEST PRODUCT: 
Alectinib (RO5424802) 
PHASE: 
Phase III 
INDICATION: 
Anaplastic lymphoma kinase−positive (ALK-positive) non−small cell 
lung cancer (NSCLC) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Efficacy Objectives 
The primary efficacy objective for this study is as follows: 
• 
To evaluate and compare the efficacy of alectinib compared to crizotinib in patients with 
treatment-naive anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung 
cancer (NSCLC), as measured by investigator-assessed progression-free survival (PFS) 
The secondary efficacy objectives for this study are as follows: 
• 
To evaluate and compare the Objective Response Rate (ORR) and Duration of Response 
(DOR) 
• 
To evaluate and compare the time to progression in the CNS on the basis of Independent 
Review Committee (IRC) review of radiographs by Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 and Revised Assessment in Neuro Oncology (RANO) criteria, as 
well as: 
To evaluate CNS objective response rate (C-ORR) in patients with CNS metastases 
who have measurable disease in the CNS at baseline  
To assess CNS duration of response (C-DOR) in patients who have a CNS Objective 
Response  
To assess CNS progression rates (C-PR) at 6, 12, 18, and 24 months on the basis of 
cumulative incidence  
• 
To evaluate and compare the PFS assessment by the IRC 
• 
To evaluate and compare the overall survival (OS) 
 
Safety Objective 
The safety objective for this study is as follows: 
• 
To evaluate the safety and tolerability of alectinib compared to crizotinib 
 


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Pharmacokinetic Objective 
The secondary pharmacokinetic (PK) objective for this study is as follows: 
• 
To characterize the pharmacokinetics of alectinib and metabolite(s) 
 
Patient-Reported Outcome Objectives 
The secondary patient-reported outcome (PRO) objectives for this study are as follows: 
• 
To evaluate and compare time to deterioration (TTD) in patient-reported lung cancer 
symptoms of cough, dyspnea (single item and multi-item subscales), chest pain, arm and 
shoulder pain, and fatigue as measured by the European Organization for the Research 
and Treatment of Cancer (EORTC) Quality of Life Questionnaire − Core (QLQ-C30) and the 
supplemental lung cancer module (QLQ-LC13) as well as a composite of three symptoms 
(cough, dyspnea, chest pain) 
• 
To evaluate and compare PROs of health-related quality of life (HRQoL), patient functioning, 
and side effects of treatment as measured by the EORTC QLQ-C30 and EORTC 
QLQ-LC13 
 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To evaluate and compare patient's health status as assessed by the EuroQoL 5 Dimension 
(EQ-5D-3L) questionnaire to generate utility scores for use in economic models for 
reimbursement 
• 
To evaluate and compare an onset of hypogonadism in adult men by measuring total 
testosterone and free testosterone (either by direct measurement or by calculation using 
albumin and sex hormone-binding globulin [SHBG]), follicle-stimulating hormone (FSH), and 
luteinizing hormone (LH) levels in blood 
• 
To evaluate and compare efficacy in patients with treatment-naive ALK-positive NSCLC as 
assessed by the FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott). 
• 
To evaluate and compare efficacy and safety in patients having treatment-naive ALK 
positive NSCLC as assessed by plasma ALK assays (polymerase chain reaction [PCR] 
and/or sequencing)  
• 
To determine the correlation between ALK status as assessed by plasma ALK PCR and/or 
plasma ALK sequencing tests, with ALK status obtained using the Ventana ALK IHC and 
FISH Vysis ALK Break Apart FISH Probe Kit (Abbott) 
• 
To investigate molecular mechanisms of resistance to ALK inhibitors 
• 
To investigate detection of ALK mutations/fusions in plasma  
 
Study Design 
Description of Study 
This is a randomized, active controlled, multicenter Phase III open-label study in patients with 
treatment-naive ALK-positive advanced NSCLC.  All patients are required to provide 
pretreatment tumor tissue to confirm the presence of ALK rearrangement (by Ventana 
immunohistochemistry [IHC] testing).  Patients will be randomized 1:1 into one of the two 
treatment arms to receive either alectinib or crizotinib. 
This study will comprise approximately 180 centers, in around 30 countries worldwide. 
The primary endpoint of the study is investigator-assessed PFS. 
Central randomization will be performed via an interactive voice or web-based response system 
(IxRS) using the following stratification factors:  Eastern Cooperative Oncology Group 
Performance Status (ECOG PS) (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at 
baseline (yes vs. no).  An IxRS manual containing relevant information will be provided to each 
study site. 
The experimental arm will receive alectinib at 600 mg orally twice daily (BID), taken with food.  
The control arm will receive crizotinib at 250 mg orally BID, taken with or without food.  The first 


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dose of the study drug should be administered as soon as possible after randomization, 
preferably within 24 hours, and no later than 48 hours after randomization. 
Patients will be treated until disease progression, unacceptable toxicity, withdrawal of consent, 
or death.  After disease progression (as per RECIST v1.1), patients should discontinue the 
study medication. After disease progression, patients will be treated at the discretion of the 
investigator according to local practice.  Information regarding the nature and the duration of 
subsequent therapies will be collected. 
In case of isolated asymptomatic CNS progression (e.g., new CNS oligometastases), a local 
therapy can be given (e.g., stereotactic radiotherapy or surgery) followed by continuation of 
either alectinib (in alectinib arm) or crizotinib (in crizotinib arm) until systemic disease 
progression and/or symptomatic CNS progression.  The decision to continue the treatment 
beyond isolated, asymptomatic CNS progression is at the investigator’s discretion for patients 
who can continue to benefit from respective treatment. 
Patients who discontinue treatment prior to disease progression (e.g., due to unacceptable 
toxicity or withdrawal of consent) will continue to be followed until disease progression and for 
OS regardless of whether they subsequently receive non-study anti-cancer therapy.  Data for 
subsequent therapy will be collected for the analysis of OS. 
Number of Patients 
Approximately 286 patients will be randomly assigned in a 1:1 allocation ratio to the two 
treatment arms via a block stratified randomization procedure and over a planned recruitment 
period of 24 months. 
Randomization will guard against systematic selection bias and should ensure the comparability 
of treatment groups.  To assist balance in important prognostic factors, randomization will be 
stratified by ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at baseline 
(yes vs. no). 
Target Population  
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not 
amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive 
as assessed by the Ventana IHC test.  Sufficient tumor tissue to perform ALK IHC and ALK 
FISH is required.  Both tests will be performed at designated central laboratories. 
• 
Age ≥ 18 years old 
• 
Life expectancy of at least 12 weeks 
• 
ECOG PS of 0−2 
• 
No prior systemic treatment for advanced or recurrent NSCLC (Stage IIIB not amenable for 
multimodality treatment) or metastatic (Stage IV) NSCLC 
• 
Adequate hematologic function: 
Platelet count ≥ 100 × 109/L 
ANC ≥ 1500 cells/μL 
Hemoglobin ≥ 9.0 g/dL 
• 
Adequate renal function: 
An estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet 
in Renal Disease equation of at least 45 mL/min/1.73 m2 
• 
Patients must have recovered from effects of any major surgery or significant traumatic 
injury at least 28 days before the first dose of study treatment. 
• 
Measurable disease (by RECIST v1.1) prior to the administration of study treatment 


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• 
Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed 
incidentally at study baseline).  Asymptomatic CNS lesions might be treated at the 
discretion of the investigator as per local clinical practice.  If patients have neurological 
symptoms or signs due to CNS metastasis, patients need to complete whole brain radiation 
or gamma knife irradiation treatment.  In all cases, radiation treatment must be completed at 
least 14 days before enrollment and patients must be clinically stable. 
• 
For all females of childbearing potential, a negative pregnancy test must be obtained within 
3 days before starting study treatment. 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus), agreement to remain abstinent or 
use single or combined contraceptive methods that result in a failure rate of  < 1% per year 
during the treatment period and for at least 3 months after the last dose of study drug.  
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  Examples of 
contraceptive methods with a failure rate of < 1% per year include tubal ligation, male 
sterilization, hormonal implants, established and proper use of combined oral or injected 
hormonal contraceptives, and certain intrauterine devices.  Alternatively, two methods 
(e.g., two barrier methods such as condom and cervical cap use) may be combined to 
achieve a failure rate < 1% per year.  Barrier methods must always be supplemented with 
the use of a spermicide.  
• 
For men, agreement to remain abstinent or use a condom plus an additional contraceptive 
method that together result in a failure rate of  < 1% per year during the treatment period 
and for at least 3 months after the last dose of study drug.  Abstinence is only acceptable if 
it is in line with the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.   
• 
Able and willing to provide written informed consent prior to performing any study-related 
procedures and to comply with the study protocol, including patients must be willing and 
able to use the electronic patient-reported outcome (ePRO) device. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients with a previous malignancy within the past 3 years are excluded (other than 
curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by 
endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered 
to have no impact in PFS and OS for the current NSCLC). 
• 
Any GI disorder that may affect absorption of oral medications, such as mal-absorption 
syndrome or status post-major bowel resection 
• 
Liver disease characterized by: 
ALT or AST > 3 × ULN (≥ 5 × ULN for patients with concurrent liver metastasis) 
confirmed on two consecutive measurements 
OR 
Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or other 
conditions of decompensated liver disease such as coagulopathy, hepatic 
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices 
OR 
Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis 
• 
National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) 
Grade 3 or higher toxicities due to any prior therapy such as radiotherapy (excluding 
alopecia), which have not shown improvement and are strictly considered to interfere with 
current study medication 
• 
History of organ transplant 


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• 
Co-administration of anti-cancer therapies other than those administered in this study 
• 
Patients with baseline QTc > 470 ms or symptomatic bradycardia 
• 
Administration of strong/potent cytochrome P450 (CYP) 3A inhibitors or inducers within 
14 days prior to the first dose of study treatment and while on treatment with alectinib or 
crizotinib 
• 
Administration of agents with potential QT interval prolonging effects within 14 days prior to 
the first administration of study drug for all patients and while on treatment through the end 
of the study for crizotinib-treated patients only (see protocol for details) 
• 
History of hypersensitivity to any of the additives in the alectinib drug formulation 
(see protocol for details)   
• 
History of hypersensitivity to any of the additives in the crizotinib drug formulation 
(see protocol for details) 
• 
Pregnant or lactating women  
• 
Known HIV positivity or AIDS-related illness 
• 
Any clinically significant concomitant disease or condition that could interfere with, or for 
which the treatment might interfere with, the conduct of the study or the absorption of oral 
medications or that would, in the opinion of the Principal Investigator, pose an unacceptable 
risk to the patient in this study 
• 
Any psychological, familial, sociological, or geographical condition potentially hampering 
compliance with the study protocol requirements and/or follow-up procedures; those 
conditions should be discussed with the patient before trial entry 
 
Length of Study 
The time from first patient screened to end of study, defined below, will be approximately 
43 months. 
End of Study 
This study is event driven, with a recruitment period of approximately 24 months.  The required 
number of events for the final analysis of the primary endpoint is expected approximately 
33 months after the first patient has been enrolled.  Patients are to be treated until disease 
progression, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.  
Follow-up for survival will continue until the survival follow-up analysis or the Sponsor decides to 
end the trial, whichever occurs first.  The study will formally end once the survival follow-up 
analysis is complete. 
A survival follow-up analysis will be performed once approximately 50% of patients 
(i.e., 143 patients) have died, which is estimated to occur approximately 42 months after the first 
patient has been enrolled. 
Outcome Measures 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
• 
PFS, which is defined as the time from randomization to the first documented disease 
progression, as determined by the investigators (primary endpoint) or IRC (secondary 
endpoint) using RECIST v1.1 or death from any cause, whichever occurs first.  Patients 
without an event will be censored at the last tumor assessment either during follow-up or 
during study treatment.  Patients with no post-baseline assessments will be censored at the 
date of randomization. 
• 
ORR, which is defined as the percentage of patients who attain complete response (CR) or 
partial response (PR); response, as determined by the investigators using RECIST v1.1.  
Patients without any assessments will be regarded as non-responders. 


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• 
Time to CNS progression, which is defined as the time from randomization to the first 
occurrence of disease progression in the CNS as determined by IRC using RECIST 
v1.1 and RANO (separate assessments and analyses), as well as C-ORR in patients with 
CNS metastases who have measurable disease in the CNS at baseline, C-DOR in patients 
who have a CNS Objective Response, and C-PR at 6, 12, 18, and 24 months 
• 
DOR, which is defined as the time from when response (CR or PR) was first documented to 
first documented disease progression or death (whichever occurs first).  This will only be 
calculated for patients who have a best overall response of CR or PR.  Patients who do not 
progress or die after they have had a response are censored at the date of their last tumor 
measurement. 
• 
OS, which is defined as the time from randomization to death from any cause.  Patients 
without an event will be censored at the last date known to be alive.  Patients without any 
follow-up information will be censored at the date of randomization. 
 
Safety Outcome Measures 
The secondary safety outcome measures for this study are as follows: 
• 
Serious and non-serious adverse events 
• 
Safety laboratory tests values 
• 
Vital signs (blood pressure, heart rate), ECG 
• 
Physical examination 
 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Sparse (pre-dose) PK samples for measurement of alectinib and its major metabolite(s) will 
be collected in all study patients receiving alectinib treatment 
• 
Serial/intensive PK sampling will be collected in a subset of consenting patients enrolled to 
receive alectinib treatment (approximately 10%−15%, at least approximately n = 20) 
• 
PK parameters will be determined as appropriate and where data allow: 
The pharmacokinetics of alectinib (and metabolite[s], if appropriate) will be described, 
and the between-patient variability will be estimated using a population PK approach.  
The potential influence of covariates that contribute significantly to the between-patient 
differences in PK parameters of alectinib will also be explored and quantified. 
Non-compartmental analysis may be conducted in patients undergoing serial/intensive 
PK sample collection, as appropriate and where data allow. 
 
Patient-Reported Outcome Measures 
The PRO measures for this study are as follows: 
• 
EORTC QLQ-C30 and the EORTC QLQ-LC13 to determine the impact of alectinib 
compared with crizotinib as measured by TTD in patient-reported lung cancer symptoms 
(e.g., cough, dyspnea [single item and multi-item scales], pain in chest, pain in 
arm/shoulder, fatigue) 
• 
The EORTC QLQ-C30 and EORTC QLQ-LC13 to measure PROs of HRQoL, patient 
functioning, and side effects of therapy compared between patients treated with alectinib 
and those treated with crizotinib 
 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
EQ-5D-3L to generate utility scores for use in economic models for the purpose of 
reimbursement 
• 
Total testosterone and free testosterone levels (either by direct measurement or by 
calculation using albumin and SHBG), FSH, and LH in blood to measure an onset of 
hypogonadism in adult men 


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• 
Results from the FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) to evaluate and 
compare efficacy in patients with treatment-naive NSCLC that is ALK-positive by FISH test 
• 
ALK fusion status in circulating tumor nucleic acids from plasma to evaluate and compare 
efficacy and safety in patients with treatment-naive NSCLC that is ALK-positive by plasma 
ALK tests (PCR and/or sequencing) for diagnostic purposes  
• 
Post-progression tumor mutation status to study molecular mechanisms of resistance to 
ALK inhibitors 
• 
ALK mutation status in plasma DNA to monitor efficacy and disease progression 
 
Investigational Medicinal Products 
Test Product 
Alectinib comes in a capsule dosage form containing the following active ingredient: 
[Chemical name] 9-Ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-6, 
11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride 
Each capsule contains 150 mg of alectinib (as free base) along with lactose monohydrate, 
carmellose calcium, hydroxypropyl cellulose, SLS, and magnesium stearate. 
Alectinib capsules should be stored in accordance with the storage instructions on the label. 
Alectinib capsules should be administered orally BID with food in the morning and evening. 
Comparator 
Crizotinib comes in a hard capsule dosage form.  Each capsule contains 250 mg or 200 mg 
crizotinib.  Crizotinib hard capsules should be stored in accordance with the storage instructions 
on the label.  Crizotinib capsules should be administered orally BID. 
For further details, see the local prescribing information for crizotinib (Xalkori®). 
Non-Investigational Medicinal Products 
Standard-of-care therapy administered to all patients in addition to test product or comparator. 
Statistical Methods 
Primary Analysis 
PFS is defined as the time from date of randomization to the date of first documented disease 
progression or death, whichever occurs first.  The primary endpoint of PFS will be determined 
on the basis of investigator assessment of progression using RECIST v1.1.  Patients who have 
not experienced disease progression or death at the time of analysis will be censored at the last 
tumor assessment date either during study treatment or during follow-up.  Patients with no 
post-baseline tumor assessment will be censored at the date of randomization. 
Patients who discontinue treatment prior to disease progression (e.g., due to toxicity) will 
continue on study and will be followed until disease progression and for OS regardless of 
whether they subsequently receive anti-cancer therapy. 
The treatment comparison of PFS will be based on a stratified log-rank test at the 5% level of 
significance (two-sided).  The stratification factors are the randomization stratification factors:  
ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at baseline (yes vs. no), 
as recorded on the eCRF.  Results from an unstratified log-rank test will also be presented. 
The Kaplan-Meier method will be used to estimate the median PFS for each treatment arm with 
95% confidence limits, and a Kaplan-Meier curve will be constructed to provide a visual 
description of the difference between the treatment arms.  A stratified Cox proportional 
regression model will be used including treatment in order to provide an estimate of the 
treatment effect expressed as a hazard ratio (HR) (alectinib vs. crizotinib), as well as a 95% CI. 
The difference between the two treatment groups will be assessed and tested for the following 
hypothesis:  the survival distribution function (SDF) of the alectinib treatment group is the same 
as for the crizotinib treatment group versus the alternative that the two distributions are different:  
H0:  SDF (alectinib) = SDF (crizotinib) 
versus 
H1:  SDF (alectinib) ≠ SDF (crizotinib) 
where SDF denotes the survival distribution function of the parameter PFS. 


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Determination of Sample Size   
The focus of this clinical trial is hypothesis testing, and the primary endpoint of PFS was used to 
determine the sample size of the study. 
At the time of initially writing the protocol, there were no Phase III data available on crizotinib in 
the first-line setting in ALK-positive patients.  The median PFS for crizotinib administered as 
second-line therapy from the global randomized Phase III PROFILE 1007 study was 7.7 months 
(95% CI: 6.0%, 8.8%).  From the Phase II single arm study of patients who had received ≥ 1 line 
of chemotherapy (with 85% patients having received ≥ 2 prior chemotherapy regimens), the 
median PFS was 8.5 months (95% CI: 6.2%, 9.9%).  The Phase III PROFILE 1014 study of 
crizotinib versus standard pemetrexed−platinum-based chemotherapy in previously untreated 
patients with ALK-positive non-squamous NSCLC reported a median PFS of 10.9 months for 
crizotinib. 
Thus, an initial assumption of median PFS of 9.8 months for the crizotinib arm has been 
reassessed based on data from the Phase III study PROFILE 1014 to 10.9 months.  An HR 
of 0.65 for alectinib versus crizotinib (i.e., an increase from 10.9 months median PFS to 
16.8 months) will be targeted. 
In this study, 286 patients will be enrolled in a 1:1 randomization allocation.  Enrollment will take 
approximately 24 months on the basis of an assumption of non-linear recruitment as follows: 
• 
Month 1:  1 patient per month 
• 
Month 2:  2 patients per month 
• 
Month 3:  4 patients per month 
• 
Month 4:  6 patients per month 
• 
Month 5:  8 patients per month 
• 
Month 6:  10 patients per month 
• 
Month 7:  12 patients per month 
• 
Months 8−12:  13 patients per month 
• 
Months 13−14:  14 patients per month 
• 
Month 15 onwards:  15 patients per month 
 
A total of 170 PFS events are required to achieve 80% power at a two-sided alpha level of 5%.  
This number of PFS events is estimated to occur approximately 33 months after the first patient 
has been enrolled. 
Interim Analyses 
No interim analysis for efficacy or futility is planned. 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
AUC 
area under the concentration−time curve 
BID 
twice daily 
Cmax 
maximum concentration 
C-DOR 
CNS duration of response 
C-ORR 
CNS objective response rate 
C-PR 
CNS progression rate 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DOT 
duration of treatment 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EGFR 
epidermal growth factor receptor 
EML4 
echinoderm microtubule-associated protein-like 4 
EORTC  
European Organization for the Research and Treatment of Cancer  
ePRO 
electronic patient-reported outcome 
EQ-5D-3L 
EuroQoL 5 Dimension 
FDA 
U.S. Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FSH 
follicle-stimulating hormone 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
HRQoL 
health-related quality of life 


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Abbreviation 
Definition 
ICH 
International Conference on Harmonisation 
iDMC 
independent Data Monitoring Committee 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITT 
intent-to-treat 
IxRS 
interactive voice or web-based response system 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
LH 
luteinizing hormone 
MET 
mesenchymal-epithelial transition factor 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCA 
non-compartmental analysis 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
not evaluable 
NSCLC 
non−small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
P-gp 
P-glycoprotein 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PRO 
patient-reported outcome 
PS 
Performance Status 
QLQ-C30 
Quality of Life Questionnaire−Core 
QLQ-LC13 
Quality of Life Questionnaire lung cancer module 
QTcF 
QT interval corrected using Fridericia’s formula 
RANO 
Revised Assessment in Neuro Oncology 
RCR 
Roche Clinical Repository 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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Abbreviation 
Definition 
RON 
recepteur d’origine nantais 
ROS1 
c-ros oncogene 1 
SAE 
serious adverse event 
SAP 
Safety Analysis Population 
SD 
stable disease 
SDF 
survival distribution function 
SHBG 
sex hormone-binding globulin  
SLS 
sodium lauryl sulfate 
TKI 
tyrosine kinase inhibitor 
TTD 
time to deterioration 
UGT 
uridine 5'-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 


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1. 
BACKGROUND 
1.1 
BACKGROUND ON ANAPLASTIC LYMPHOMA 
KINASE−POSITIVE NON−SMALL CELL LUNG CANCER 
Non−small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality 
worldwide.  Lung cancer was estimated to cause 160,340 deaths in the United States 
in 2012, accounting for 28% of all cancer-related deaths according to the report from the 
American Lung Association (Lung Cancer Fact Sheet).  There is an annual incidence of 
310,000 cases of NSCLC in men in Europe with a mortality of 276,000 deaths 
(GLOBOCAN 2008).  Among women in Europe, there is an annual incidence of 107,000 
cases and a mortality of 91,000 deaths.  In total, there are 417,000 cases of NSCLC and 
367,000 deaths in Europe each year, which represents a major health problem.  Survival 
rates for lung cancer tend to be much lower than other common cancers because of its 
late diagnosis and limited effective therapy in the advanced stage.  The expected 5-year 
survival rate for all patients in whom lung cancer is diagnosed is 16.3% compared with 
65.2% for colon cancer, 90.0% for breast cancer, and 99.9% for prostate cancer 
(Siegel et al. 2012).  Conventional anti-cancer therapies are far from satisfactory, and 
there is an unmet medical need for the development of new therapies for NSCLC. 
Recent progress in the identification of genetic mutations or chromosomal 
rearrangements in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral 
oncogene homolog (KRAS), mesenchymal-epithelial transition factor (MET), and other 
genes has provided new opportunities to use targeted therapeutic agents for the 
treatment of NSCLC, when the tumor is identified as having these mutations 
(Katayama et al. 2011; Doebele et al. 2012). 
Approximately 5% of NSCLC cases have been shown to harbor the echinoderm 
microtubule-associated protein-like 4 (EML4)−anaplastic lymphoma kinase (ALK) fusion 
gene as a result of a chromosomal inversion at 2p21 and 2p23 (Choi et al. 2010; 
Ou et al. 2012).  The formation of the resulting ALK fusion protein results in activation 
and dysregulation of the gene’s expression and signaling, which can contribute to 
increased cell proliferation and survival in tumors expressing these genes.  This is 
further supported by reports that the TFG and KIF5B genes can also serve as ALK 
fusion partners in some NSCLC patients.  Expression of these ALK fusion genes in 
mouse 3T3 fibroblasts causes their transformation and enhanced proliferation.  ALK 
gene alterations are generally in a mutually exclusive relationship with mutations in 
EGFR or KRAS (Soda et al. 2007; Inamura et al. 2008; Inamura et al. 2009; 
Wong et al. 2009), although EGFR mutations may develop as a resistance mechanism 
after treatment with crizotinib (Doebele et al. 2012).  Inhibition of ALK activity in Ba/F3 
cells transfected with the EML4-ALK fusion protein resulted in inhibition of cell growth 
(Ou et al. 2012), whereas a small molecule inhibitor of ALK demonstrated anti-tumor 
efficacy in two xenograft models in athymic mice, namely, the H3122 NSCLC and 
Karpas299 anaplastic large cell lymphoma models harboring the EML4-ALK and 


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nucleophosmin-ALK fusion proteins, respectively.  Hence, ALK appears to be a suitable 
therapeutic target for NSCLC with ALK gene rearrangements. 
Wild-type ALK is expressed at very low levels in most normal human tissues, but is 
expressed at higher levels in a few limited types of tissue such as developing and 
mature nervous system tissue (glial cells, neurons, endothelial cells, and pericytes) 
(Pulford et al. 1997).  By contrast, an aberrant ALK with constitutively active kinase 
results from the formation of the EML4-ALK fusion gene by chromosomal translocation. 
Currently, the only approved medicine for treatment-naive ALK-positive NSCLC is 
crizotinib (Xalkori®, Pfizer, Inc.), an inhibitor of receptor tyrosine kinases including ALK, 
hepatocyte growth factor receptor (HGFR, c-Met), recepteur d’origine nantais (RON), 
and c-ros oncogene 1 (ROS1) (Sahu et al. 2013).  
Crizotinib was first granted accelerated approval by the U.S. Food and Drug 
Administration (FDA) for the treatment of patients with locally advanced or metastatic 
NSCLC that is positive for ALK as detected by an FDA-approved test in August 2011. 
The approval was based on two single-arm trials.  The primary endpoint of both trials 
was objective response rate (ORR) as assessed by the investigator.  In one study, the 
ORR was 50% (95% CI: 42%, 59%) with a median response duration of 42 weeks, and, 
in the other study, the ORR was 61% (95% CI: 52%, 70%) with a median response 
duration of 48 weeks (Camidge et al. 2012; Kim et al. 2012).  In November 2013, the 
FDA granted regular approval for crizotinib on the basis of demonstrating superior 
progression-free survival (PFS) and ORR for crizotinib compared with chemotherapy in 
patients with ALK-positive NSCLC whose disease progressed after platinum-based 
doublet chemotherapy (PROFILE 1007 study).  An open-label active-controlled 
multinational randomized trial enrolled 347 patients with ALK-positive metastatic NSCLC.  
Patients were required to have disease progression following platinum-based 
chemotherapy.  The trial demonstrated significantly prolonged PFS with crizotinib 
treatment compared with chemotherapy (hazard ratio [HR] = 0.49 [95% CI: 0.37, 0.64], 
p < 0.0001).  Median PFS was 7.7 months for patients treated with crizotinib and 
3.0 months for patients treated with chemotherapy.  The ORR was significantly higher 
for patients treated with crizotinib (65% vs. 20%), with median response durations of 
7.4 months for patients treated with crizotinib and 5.6 months for patients treated with 
chemotherapy.  No difference in overall survival (OS) was noted between the two groups 
(HR = 1.02 [95% CI: 0.68%, 1.54%]) in a planned interim analysis (Shaw et al. 2013).  
Common adverse reactions in clinical trials with crizotinib, occurring at an incidence of 
25% or higher, included visual disorders, nausea, diarrhea, vomiting, constipation, 
edema, elevated transaminases, and fatigue (National Cancer Institute 2013).  These 
results showed that an ALK inhibitor is effective in patients with NSCLC harboring ALK 
fusion genes.  Crizotinib has subsequently been approved in other countries, such as 
Japan, Korea, Canada, and Switzerland.  In the European Union, crizotinib was 
conditionally approved in October 2012 for the treatment of adults with previously treated 
ALK positive NSCLC. 


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Although substantial benefit has been observed with crizotinib therapy, relapse remains 
the norm.  Studies with patients who had progression with crizotinib treatment revealed 
two main reasons for treatment failure: the development of resistance because of 
secondary (e.g., gatekeeper) mutations (predominantly in ALK or occasionally in other 
genes, such as EGFR, cKIT, or KRAS) (Katayama et al. 2011; Doebele et al. 2012; 
Kim et al. 2013) and CNS relapse (crizotinib has impaired control of brain metastases in 
comparison to other sites of systemic disease).  The CNS is the primary site of initial 
treatment failure in 46% of patients with ALK-positive NSCLC treated with crizotinib 
(Costa et al. 2011; Chun et al. 2012; Weickhardt et al. 2012).  Significant morbidity is 
associated with brain metastases as a function of brain involvement, and because of 
treatment (corticosteroids, surgery, and radiation) required for disease control. 
A new generation of ALK inhibitors will have the potential to overcome these two major 
limitations of crizotinib treatment and may offer patients a better chance of prolonged 
remission and minimize the development of CNS metastases and the attendant 
comorbidity. 
1.2 
BACKGROUND ON ALECTINIB 
Alectinib (also RO5424802 or CH5424802) is a newly developed small molecule, highly 
selective, and potent oral next-generation ALK inhibitor with a benzo[b]carbazole 
scaffold.  In enzyme inhibition assays performed in vitro, this compound has been shown 
to selectively inhibit ALK.  The compound also shows high antitumor activity both in vitro 
and in vivo against tumor cell lines with some types of ALK gene alteration, including 
NSCLC and anaplastic large cell lymphoma lines harboring an ALK translocation and a 
neuroblastoma line harboring amplified ALK gene. 
Nonclinical pharmacology studies showed that alectinib is efficacious in a model of 
tumors expressing an ALK fusion bearing the L1196M mutation, which is associated with 
resistance to crizotinib, and alectinib is effective in mouse NCI H2228 NSCLC xenografts 
that are already maximally suppressed by crizotinib.  Alectinib also prolongs survival in 
an intracerebral NCI H2228 implantation model, and it reduces tumor growth in an 
intracranial model monitored using bioluminescence. 
The clinical development program for alectinib, to date, comprises three ongoing 
Phase I/II studies in patients with ALK-positive NSCLC.  The ongoing Phase I/II studies 
are as follows:  Study AF-001JP, which is being conducted in Japan; 
Study NP28761/AF-002JG, which is being conducted in United States and Canada; and 
Study NP28673, which is being conducted globally. 
The first-in-human study AF-001JP is an open-label Phase I/II study being conducted in 
Japan.  This study is assessing the pharmacokinetics, safety, and efficacy of alectinib in 
patients with ALK-positive NSCLC who are crizotinib-naive and have disease 
progression after at least one line of chemotherapy.  This study has completed 
enrollment, but it is still ongoing.  A total of 70 patients were included (24 patients in the 


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Phase I portion and 46 patients in the Phase II portion of the study).  In the Phase I 
portion of the study, at the data cutoff date of 31 July 2012, 24 patients were treated at 
doses of 20−300 mg twice daily (BID).  No dose-limiting toxicities (DLTs) or adverse 
events of Grade 4 were noted up to the highest dose; thus, 300 mg BID was evaluated 
in the Phase II portion of the study without further escalating the dose.  In the Phase II 
portion of the study, 46 patients were treated with the highest evaluated dose of 300 mg 
BID, of whom 43 achieved an objective response (93.5%; 95% CI: 82.1%, 98.6%) and 
7 patients had a complete response (CR) on the basis of an independent radiological 
review in the 12-month follow-up analysis (data cutoff for response data: 18 April 2013).  
The median duration of treatment (DOT) in the study has not been achieved at that date 
because 86% of patients were still on treatment in the study, but the projected median 
DOT is more than 14 months as data mature. 
Figure 1 shows the waterfall plot of the best change from baseline in the size of target 
lesions by an independent radiological review.  Table 1 shows the ORR by time interval.  
The majority (86%) of patients had a time to response of within 6 weeks after 
administration of the first dose. 
Figure 1 Change in Size of Target Lesions as Assessed by the 
Independent Review Committee in Part 2 of Study AF-001JP 
Using RECIST v1.1 (Data Cutoff Date: 18 April 2013) 
 


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Two of 7 patients who were assessed as having a CR had lymph nodes as the target 
lesions.  Per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), 
the percent change from baseline for patients with CR can be less than 100% when 
lymph nodes are identified as the target lesions.  Therefore, they were assessed as 
having CR, although their tumor change from baseline was less than 100%. 
Table 1 
Overall Response Rates and Time to Response in Patients 
in Part 2 of Study AF-001JP 
Response (Data Cutoff Date: 18 April 2013) 
IRC Assessment (N = 46) 
Complete response 
7 
Partial response 
36 
Stable disease 
1 
Progressive disease 
0 
Not evaluable 
2 
Total response 
43 
Overall response rate (95% CI) 
93.5% (82.1%, 98.6%) 
Time to Response 
IRC Assessment (N = 43) 
0 to ≤ 3 weeks 
22 (51%) 
> 3 to ≤ 6 weeks 
15 (35%) 
> 6 to ≤ 9 weeks 
3 (7%) 
> 9 weeks 
3 (7%) 
IRC = Independent Review Committee. 
 
In Study NP28761/AF-002JG (crizotinib-failed ALK-positive NSCLC patients), the 
Phase I portion has completed enrollment.  Two ‘bridging’ cohorts of patients receiving 
alectinib using the 150-mg capsule at 600 and 900 mg BID were included in 
Study NP28761/AF-002JG to transition/facilitate the planned formulation for the Phase II 
trials.  A total of 47 patients were enrolled in Phase I (Part 1).  There does not appear to 
be any substantial difference in pharmacokinetics between the two formulations 
(20/40-mg capsule and the 150-mg capsule) at the 600-mg dose on the basis of 
available data. 
The radiological imaging analysis performed in 44 evaluable patients who had a baseline 
scan and at least one follow-up scan (data cutoff date: 12 September 2013) has shown 
that 2 of 7 patients in the 300-mg BID dosage cohort, 5 of 7 patients in the 460-mg BID 
dosage cohort, 4 of 10 patients in the 600-mg BID dosage cohort, and 4 of 13 patients 
(including 1 patient with CR) in the 900-mg BID dosage cohort have achieved a 
confirmed partial response (PR), as assessed by the investigator.  Three of 10 patients 
in the 600-mg BID dosage cohort, 2 of 7 patients in the 760-mg BID dosage cohort, and 
4 of 13 patients in the 900-mg BID dosage cohort have achieved a PR, as assessed by 
the investigator, which is still to be confirmed.  Three patients (all in the 600-mg BID 






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both systemic disease and CNS progression).  No patient discontinued because of CNS 
progression alone. 
In addition, 2 patients with leptomeningeal carcinomatosis received benefit from alectinib 
treatment.  One patient with leptomeningeal spread in Study NP28761/AF-002JG 
achieved PR after 6 weeks of treatment.  Another patient with leptomeningeal 
carcinomatosis but without systemic lesions was treated under a single-patient 
Investigational New Drug (IND) application because of ineligibility to enter either of the 
two Phase II alectinib studies (because of the high intake of dexamethasone for 
symptom control).  After 6 weeks of treatment, this patient achieved CR as 
demonstrated by complete disappearance of gadolinium enhancement on magnetic 
resonance imaging (MRI) and disappearance of positive CSF cytology.  This patient has 
been able to reduce corticosteroids to physiological replacement dose only. 
See the Alectinib Investigator's Brochure for additional details on nonclinical and clinical 
studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Over the past 10 years, the treatment of NSCLC has become increasingly focused on 
guiding treatment based on the presence or absence of an actionable mutation.  
Numerous oncogenes have now been identified in NSCLC, including mutations in the 
genes coding for EGFR, KRAS, phosphoinositide-3-kinase (specifically, the catalytic α 
polypeptide), and EGFR 2 (Pao and Girard 2011).  As described in previous sections, a 
translocation in the gene encoding the receptor tyrosine kinase ALK, leading to the 
expression of ALK fusion proteins, was identified as an oncogenic driver in a subset of 
patients with NSCLC (Soda et al. 2007).  ALK rearrangements are found in 
approximately 4.6% of unselected patients with NSCLC (Koivunen et al. 2008; 
Takeuchi et al. 2008; Boland et al. 2009; Wong et al. 2009; Bang 2011; Kim et al. 2011; 
Paik et al. 2011; Cardarella et al. 2012; Dai et al. 2012; Fukui et al. 2012;). 
Crizotinib is the first ALK inhibitor that has been approved and registered in multiple 
countries worldwide for the treatment of ALK-positive NSCLC.  Crizotinib is an oral 
small-molecule multitargeted tyrosine kinase inhibitor (TKI) targeting ALK, MET, RON, 
and ROS1 tyrosine kinases (Sahu et al. 2013, Shaw et al. 2013).  The previous clinical 
studies reported that the median PFS with crizotinib ranged from 7.7−9.7 months 
(Camidge et al. 2012, Kim et al. 2013, Shaw et al. 2013).  The PROFILE 1014 study, a 
Phase III study of crizotinib compared to standard pemetrexed-platinum-based 
chemotherapy, was presented at the ASCO 2014 congress (Mok et al. 2014).  The study 
met its primary objective of prolonging PFS in previously untreated patients with 
ALK-positive non-squamous NSCLC with median PFS of 10.9 and 7.0 months 
(HR: 0.454; 95% CI: 0.346, 0.596; p < 0.0001) for crizotinib and 
pemetrexed-platinum-based chemotherapy, respectively. 


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Although substantial benefit has been observed with crizotinib therapy, relapse 
eventually occurs.  Two major reasons for this are the development of resistance 
because of secondary (e.g., gatekeeper) mutations, or CNS relapse 
(Katayama et al. 2011; Doebele et al. 2012; Kim et al. 2013).  This could be due to the 
fact that crizotinib is a P-gp substrate and has a low penetration in the CNS.  Thus, 
ALK-positive NSCLC treated with crizotinib has impaired control of brain metastases 
relative to other sites of systemic disease, with 46% of progressions in patients treated 
with crizotinib involving the CNS (Costa et al. 2011; Weickhardt et al. 2012).  The CNS 
becomes a sanctuary site for ALK-positive NSCLC treated with crizotinib⎯a physiologic 
and anatomic mechanism of drug resistance. 
Alectinib is a highly selective and potent oral next generation ALK inhibitor.  Clinical data 
collection from the Phase II portion is still ongoing.  Study AF-001JP, assessing alectinib 
in patients with ALK-positive NSCLC who are crizotinib-naive and have disease 
progression after at least one line of chemotherapy, reported that the median treatment 
duration in the study had not been achieved as 86% of patients were still active on the 
study, but the projected median DOT is estimated to be at least 14 months at the final 
point of data collection (Inoue et al. 2013). 
Moreover, alectinib is a lipophilic drug and is not a P-glycoprotein (P-gp) substrate.  
Thus, it is able to penetrate the blood-brain barrier and has the potential to reach higher 
concentrations in the brain as compared to substrates of P-gp such as crizotinib.  This 
has been shown in the nonclinical setting on the basis of the prolongation of survival in a 
mouse model with implanted CNS lesions and in a tissue distribution study with a single 
oral dose of [14C]-alectinib at 1 mg/kg in albino rats (Ou et al. 2013).  Preliminary clinical 
data from the Phase I/II studies show consistent therapeutic efficacy of alectinib in brain 
metastases. 
The clinical efficacy data is compelling given the demonstrated activity for a longer 
progression-free interval with alectinib treatment and improved activity in the CNS.  This 
progression-free interval delays the impact of CNS metastases on neurologic function 
along with the morbidities associated with treatment like brain radiation, surgery and 
corticosteroid use required for disease control.  The currently available clinical safety 
data is supportive of an acceptable safety and tolerability profile with alectinib.  
Altogether, it would be important to compare alectinib to crizotinib as a therapeutic 
option for treatment-naive ALK-positive advanced NSCLC patients. 
Alectinib was granted approval in Japan on 04 July 2014 for treatment of ALK fusion 
gene-positive, unresectable, recurrent or advanced NSCLC. 
In this proposed Phase III study, treatment-naive patients with ALK-positive advanced 
NSCLC will be enrolled and will be randomized to receive either crizotinib or alectinib 
treatment.  The results of this study will determine whether alectinib treatment has 
superior efficacy compared to crizotinib. 


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The first Phase I dose-escalation study of alectinib (Study AF001-JP, conducted only in 
Japan) with a dose schedule of 20, 40, 80, 160, 240, and 300 mg BID orally showed that 
alectinib was generally well tolerated without major toxicities.  Of the 58 patients who 
received treatment with 300 mg BID alectinib in Study AF-001JP, 27 experienced 
Grade 3 adverse events and 9 experienced serious adverse events.  No deaths were 
reported during this study and up to 28 days after treatment discontinuation.  There were 
5 adverse events leading to treatment discontinuation in Part 2 (brain edema, sclerosing 
cholangitis, interstitial lung disease [ILD], ALT increased, and tumor hemorrhage).  
Alectinib was well tolerated at all doses investigated in this study.  Its adverse event 
profile was consistent with the one known to be associated with TKIs.  In the 
Phase II Study NP28761/AF-002JG, alectinib was well tolerated with no DLTs or 
treatment-related dose modifications up to 600 mg BID.  Two DLTs were reported at 
900 mg BID.  The recommended alectinib Phase II dosage of 600 mg BID was chosen 
as having the best balance between clinical safety, efficacy, and pharmacokinetic (PK) 
data as observed in the Phase I/II studies (see Section 3.3.1). 
On the basis of available preliminary data, the estimated benefits of alectinib treatment 
outweigh the risks.  Specifically: 
• 
Available nonclinical and clinical data demonstrate that alectinib is active in NSCLC 
in crizotinib-naive patients as well as after progression on prior crizotinib therapy. 
• 
Clinical safety data in humans up to 900 mg BID demonstrate that its safety profile 
is consistent to the one known to be associated with ALK inhibitors. 
 
Identified and potential risks associated with alectinib treatment will continue to be 
closely monitored throughout the clinical program.  Patient safety during the alectinib 
program is ensured by targeting the most appropriate patient population, stringent safety 
monitoring by the Sponsor and independent Data Monitoring Committee (iDMC), and by 
protocol-specified study drug interruption criteria. 
2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The primary efficacy objective for this study is: 
• 
To evaluate and compare the efficacy of alectinib compared to crizotinib in patients 
with treatment-naive ALK-positive advanced NSCLC, as measured by 
investigator-assessed PFS 
 
The secondary efficacy objectives for this study are: 
• 
To evaluate and compare the Objective Response Rate (ORR) and Duration of 
Response (DOR) 


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• 
To evaluate and compare the time to progression in the CNS on the basis of IRC 
review of radiographs by RECIST v1.1 and Revised Assessment in Neuro Oncology 
(RANO) criteria, as well as: 
To evaluate CNS objective response rate (C-ORR) in patients with CNS 
metastases who have measurable disease in the CNS at baseline  
To assess CNS duration of response (C-DOR) in patients who have a CNS 
Objective Response  
To assess CNS progression rates (C-PR) at 6, 12, 18, and 24 months on the 
basis of cumulative incidence  
• 
To evaluate and compare the PFS assessment by the IRC 
• 
To evaluate and compare the OS 
 
2.2 
SAFETY OBJECTIVES 
The secondary safety objective for this study is: 
• 
To evaluate the safety and tolerability of alectinib compared to crizotinib 
 
2.3 
PHARMACOKINETIC OBJECTIVES 
The secondary PK objective for this study is: 
• 
To characterize the pharmacokinetics of alectinib and metabolite(s) 
 
2.4 
PATIENT-REPORTED OUTCOME OBJECTIVES 
The secondary patient-reported outcome (PRO) objectives for this study are: 
• 
To evaluate and compare time to deterioration (TTD) in patient-reported lung cancer 
symptoms of cough, dyspnea (single item and multi-item subscales), chest pain, 
arm and shoulder pain, and fatigue as measured by the European Organization for 
the Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire−Core (QLQ-C30) and the supplemental lung cancer module 
(QLQ-LC13) as well as a composite of three symptoms (cough, dyspnea, chest pain) 
• 
To evaluate and compare PROs of health-related quality of life (HRQoL), patient 
functioning, and side effects of treatment as measured by the EORTC QLQ-C30 
and EORTC QLQ-LC13 
 
2.5 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are: 
• 
To evaluate and compare patient’s health status as assessed by the EuroQoL 5 
Dimension (EQ-5D-3L) questionnaire to generate utility scores for use in economic 
models for reimbursement 
• 
To evaluate and compare the onset of hypogonadism in adult men by measuring 
total testosterone and free testosterone (either by direct measurement or by 
calculation using albumin and sex hormone-binding globulin [SHBG]), 
follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels in blood 


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• 
To evaluate and compare efficacy in patients with treatment-naive ALK-positive 
NSCLC as assessed by the FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) 
• 
To evaluate and compare efficacy and safety in patients having treatment-naive 
ALK positive NSCLC as assessed by plasma ALK assays (polymerase chain 
reaction [PCR] and/or sequencing)  
• 
To determine the correlation between ALK status as assessed by plasma ALK PCR 
and/or plasma ALK sequencing tests, with ALK status obtained using the Ventana 
ALK IHC and FISH Vysis ALK Break Apart FISH Probe Kit (Abbott) 
• 
To investigate molecular mechanisms of resistance to ALK inhibitors. 
• 
To investigate detection of ALK mutations/fusions in plasma 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a randomized, active-controlled, multicenter Phase III open-label study in patients 
with treatment-naive ALK-positive advanced NSCLC.  All patients are required to provide 
pretreatment tumor tissue to confirm the presence of ALK rearrangement (by Ventana 
immunohistochemistry [IHC] test).  Patients will be randomized 1:1 into one of the two 
treatment arms to receive either alectinib or crizotinib. 
This study will comprise approximately 180 centers, in around 30 countries worldwide. 
The primary endpoint of the study is investigator-assessed PFS. 
Central randomization will be performed via an interactive voice or web-based response 
system (IxRS) using the following stratification factors:  Eastern Cooperative Oncology 
Group Performance Status (ECOG PS) (0/1 vs. 2), race (Asian vs. non-Asian), and CNS 
metastases at baseline (yes vs. no).  An IxRS manual containing relevant information 
will be provided to each study site. 
The experimental arm will receive alectinib at 600 mg orally BID, taken with food.  The 
control arm will receive crizotinib at 250 mg orally BID, taken with or without food.  The 
first dose of the study drug should be administered as soon as possible after 
randomization, preferably within 24 hours, and no later than 48 hours after 
randomization. 
Patients will be treated until disease progression, unacceptable toxicity, withdrawal of 
consent, or death.  After disease progression (as per RECIST v1.1), patients should 
discontinue the study medication.  After disease progression, patients will be treated at 
the discretion of the investigator according to local practice.  Information regarding the 
nature and the duration of subsequent therapies will be collected. 
In case of isolated asymptomatic CNS progression (e.g., new CNS oligometastases), 
local therapy can be given (e.g., stereotactic radiotherapy or surgery) followed by 


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continuation of either alectinib (in alectinib arm) or crizotinib (in crizotinib arm) until 
systemic disease progression and/or symptomatic CNS progression.  The decision to 
continue the treatment beyond isolated, asymptomatic CNS progression is at the 
investigator’s discretion for patients who can continue to benefit from their respective 
treatment. 
Patients who discontinue treatment prior to disease progression (e.g., due to 
unacceptable toxicity or withdrawal of consent) will continue to be followed until disease 
progression and for OS regardless of whether they subsequently receive non-study 
anti-cancer therapy.  Data for subsequent therapy will be collected for the analysis of OS. 
Approximately 286 patients (143 per treatment arm) will be enrolled into the study over a 
planned competitive recruitment period of 24 months.  Patients inappropriately 
randomized into the study will not be replaced.  The final analysis evaluating the primary 
endpoint of investigator-assessed PFS will occur when approximately 170 patients have 
progressed or died, which is expected to occur approximately 33 months after the first 
patient has been enrolled.  Data collection will continue for each patient until death or 
study closure, whichever occurs first. 
An iDMC will be established to monitor the progress of the study and ensure that the 
safety of patients enrolled in the study is not compromised as outlined in Section 9.4. 
A summary of the study design is shown in Figure 4. 
A schedule of assessments is provided in Appendix 1. 




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3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Alectinib Dosage 
Selection of the alectinib dose for the study is based on the clinical safety, efficacy, and 
PK data observed in the Phase I/II studies, AF-001JP and NP28761/AF-002JG, and the 
supportive nonclinical data for alectinib. 
The first-in-human study, AF-001JP evaluated escalating doses of alectinib in an 
accelerated titration scheme to rapidly identify the maximum tolerated dose (MTD).  All 
doses, including the highest evaluated dose in the study, 300 mg BID, were well 
tolerated with no DLTs observed at any dose.  The highest tested dose, 300 mg BID, 
was further evaluated in the Phase II portion of the study and demonstrated robust 
efficacy and good safety with an ORR by IRC of 93.5% (43/46 patients; 95% CI: 82.1%, 
98.6%). 
With no MTD determined in Study AF-001JP, dose escalation progressed in the North 
American Study NP28761/AF-002JG using a modified 3 + 3 design, where 3 patients 
were assessed for DLT evaluation whereas additional patients were enrolled for PK 
evaluation.  The starting dose in Study NP28761/AF-002JG was the highest dosage 
evaluated in Study AF-001JP, 300 mg BID.  Following multiple dosages of alectinib at 
300 mg BID in Study NP28761/AF-002JG, median alectinib exposure (area under the 
concentration-time curve [AUC] from 0 to 10 hours) appeared to be approximately 
two-fold lower compared with that in patients from Study AF-001JP, which demonstrated 
robust efficacy and safety.  Dose escalation progressed with evaluation of higher doses 
of alectinib up to 900 mg BID. 
In Study NP28761/AF-002JG, no DLTs were observed in the dose escalation cohorts up 
to dose-level of 900 mg BID.  However, 2 patients in the subsequent 900 mg BID 
bridging cohort experienced a DLT; 1 patient had Grade 3 headache and 1 patient had 
Grade 3 neutropenia, and both patients continued study treatment at a reduced dosage 
of 600 mg BID.  Overall, alectinib was well tolerated in the study population.   
Importantly, administration of 600 mg BID provides systemic exposures that meet or 
exceed exposures achieved in patients receiving 300 mg BID in Study AF-001JP, 
demonstrating its robust efficacy and safety in crizotinib-naive patients.  Furthermore, in 
Study NP28761/AF-002JG, the 600 mg BID regimen has demonstrated promising 
activity in crizotinib-resistant patients, including activity in patients with CNS metastases 
while being tolerated by patients.  On the basis of available preclinical data, 
administration of alectinib 600 mg BID provides systemic exposures within the expected 
range (on the basis of regression of available data) for tumor regression observed in 
mouse xenograft models. 
Thus, on the basis of nonclinical and clinical data, a dosing regimen of 600 mg BID of 
alectinib has been chosen as the optimal therapeutic dose level with the best balance 
between efficacy and safety. 


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Alectinib at 600 mg should be administered orally BID with food in the morning and 
evening. 
3.3.2 
Rationale for Patient Population 
The study population will comprise patients with non-resectable, locally advanced and 
metastatic NSCLC who have been shown to be ALK-positive by the Ventana IHC test 
performed at central laboratories specially designated for the study.  Patients should not 
have received any prior treatment for advanced NSCLC (treatment-naive). 
Both experimental (alectinib) and control (crizotinib) treatments are ALK-targeted 
therapies.  The clinical practice guidelines recommend targeted treatment for patients 
with metastatic, oncogene-driven disease as first-line systemic therapy 
(i.e., EGFR-inhibitors for EGFR-positive NSCLC and ALK-inhibitors for ALK-positive 
NSCLC) (NCCN 2014).  
To be eligible for the study, determination of ALK positivity will be performed centrally 
using the IHC assay (see Appendix 8) that is being developed by Ventana Medical 
Systems as a companion diagnostic to alectinib.  IHC may replace fluorescence in situ 
hybridization (FISH)-based identification of ALK rearrangement as the standard 
companion diagnostic in the future.  IHC is faster, easier to perform in local laboratories, 
and requires less equipment compared with the FISH assay.  In addition, IHC has high 
concordance with FISH and a lower false-negative rate (Kim et al. 2011). 
3.3.3 
Rationale for Control Group 
Targeted therapy (including ALK-targeted therapy) is likely to have a greater anti-tumor 
effect than standard chemotherapy, offering patients a higher response rate and longer 
durability of response with less toxicity compared with any potential chemotherapy 
options (Mok et al. 2009; Rosell et al. 2012; Sequist et al. 2013; Shaw et al. 2013). 
Crizotinib (Xalkori®) is an oral small-molecule multi-targeted TKI targeting ALK, MET, 
RON, and ROS1 tyrosine kinases (Sahu et al. 2013, Shaw et al. 2013).  It is the only 
first-generation ALK inhibitor that has been approved in multiple countries worldwide for 
the treatment of ALK-positive NSCLC. 
In the United States, in November 2013, crizotinib was granted a regular approval for the 
ALK-positive NSCLC setting regardless of treatment line (XALKORI® U.S. Package 
Insert), whereas in Europe, crizotinib is currently only approved conditionally for patients 
with previously treated ALK-positive NSCLC (Crizotinib SmPC). 
The National Comprehensive Cancer Network (NCCN) guidelines recommend crizotinib 
as a first-line therapy for patients with advanced ALK-positive NSCLC (NCCN 2014). 
The randomized Phase III PROFILE 1014 study was conducted to assess the efficacy of 
crizotinib versus standard platinum-based chemotherapy (pemetrexed plus cisplatin or 


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carboplatin) as first-line treatment for patients with ALK-positive, non-squamous NSCLC.  
The study met its primary objective of prolonging PFS in previously untreated patients 
with ALK-positive non-squamous NSCLC with median PFS of 10.9 and 7.0 months 
(HR: 0.454; 95% CI: 0.346, 0.596; p < 0.0001) for crizotinib and pemetrexed 
platinum-based chemotherapy, respectively (Mok et al. 2014).  The authors concluded 
that these findings support crizotinib as the standard of care for patients with previously 
untreated advanced ALK-positive non-squamous NSCLC (Mok et al. 2014). 
Crizotinib will be dosed as per standard dose recommendations from prescribing 
information; patients in the crizotinib arm will receive crizotinib at 250 mg orally BID with 
or without food until disease progression, unacceptable toxicity, withdrawal of consent, 
or death.  See Section 5.1.4 for criteria for dosing interruption and/or dose reduction for 
treatment with crizotinib.  
3.3.4 
Rationale for Open-Label Design 
An open-label study design is more appropriate for patients enrolled in this particular trial 
for a number of reasons described below, and with the ultimate goal to ensure patient 
compliance as much as possible. 
For a blinded study design, all enrolled patients would be required to take five large 
capsules twice per day.  This high pill count results from the difference in capsule size 
between crizotinib (size 0) and alectinib (size 1).  Each dose would comprise one 
250-mg capsule of crizotinib or matching placebo and four 150-mg capsules of alectinib 
or matching placebo.  In order to blind, crizotinib capsules must be over-encapsulated. 
That further increases the size of a capsule from size 0 to size 00.  Size 00 is usually the 
largest capsule size used orally for humans.  For some patients, size 00 capsules are 
too large to swallow.  This high pill count of large capsules is considered to be a 
significant burden to patients and increases the risk of non-compliance. 
Additionally, a blinded study would increase the complexity of standard dose reductions.  
Dose interruption or dose reduction may be required on the basis of individual safety and 
tolerability.  The standard dose reductions for crizotinib would be 200 mg BID (different 
capsule, size 1), followed by 250 mg QD.  Dose reductions for alectinib would occur in 
150-mg steps.  In a double-blind study, these multiple step dose reductions introduce a 
high level of complexity and potential for error. 
In order to avoid a significant burden to patients with high pill count, increased risk of 
non-compliance, and complexity of standard dose reductions, adequate steps have been 
taken to ensure the validity of the data in an open-label study design.  These include 
performing a supportive analysis of efficacy on the basis of determining progression by 
an IRC, performing sensitivity analyses to demonstrate the robustness of the primary 
endpoint, defining progression using established response evaluation criteria 
(RECIST v1.1), performing tumor assessment at the same frequency in both arms and 
adhering to protocol-defined schedules, and finalizing the strategy for the final analysis 


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of the primary endpoint before trial start, including developing predefined methods for 
handling missing data and censoring rules.  Efficacy analyses will only be performed at 
the pre-specified analysis timepoints in the protocol (final analysis once 170 PFS events 
have occurred and survival follow-up analysis at 143 events). 
3.3.5 
Rationale for Primary Endpoint Selection 
The investigator-assessed PFS (which will be supported by IRC-assessed PFS analysis, 
one of the secondary endpoints of the study) is the primary endpoint for this trial. 
PFS, as an endpoint, can reflect tumor growth and can be assessed before the 
determination of a survival benefit, and its determination is not generally confounded by 
subsequent therapies.  Whether an improvement in PFS represents a direct clinical 
benefit or a surrogate for clinical benefit depends on the magnitude of the effect and the 
risk-benefit of the new treatment compared to available therapies (Guidance for 
Industry 2007; European Medicines Agency 2012).  A PFS HR of 0.65 will be targeted, 
which constitutes a clinically meaningful benefit in this patient population as it will delay 
the use of platinum-based chemotherapy and will potentially reduce the frequency of 
CNS relapse and the morbidity associated with treating CNS metastases. 
The assumed median PFS of patients in the alectinib treatment arm is 16.8 months, and 
an OS of more than 30 months is expected, which equates to a post-progression 
survival of at least 13 months.  Patients with ALK-positive NSCLC treated with crizotinib 
in the second-line setting had a median PFS of 7.7 months and an interim median OS of 
20.3 months (Shaw et al. 2013), which equated to a post-progression survival of 
12.6 months.  This lengthy post-progression survival provides an opportunity for 
subsequent treatment with other ALK inhibitors, several additional lines of chemotherapy, 
or participation in additional clinical trials. 
Patients in both study arms who experience disease progression on study treatment will 
likely be treated with other subsequent treatment options, including ALK inhibitors.  
The availability of crizotinib on the market, as well as the likely availability of other 
next-generation ALK TKIs, and the availability of other investigational agents in clinical 
trials offer potential treatment options to patients in the study who will eventually have 
disease progression.  Subsequent therapies frequently confound the detection of an OS 
benefit, particularly in a setting with a long post-progression survival, such as 
ALK-positive NSCLC.  This has been observed in trials for EGFR TKIs, in which strong 
PFS benefits were observed without evidence of OS benefit (Rosell et al. 2009; 
Fukuoka et al. 2011). 
The long post-progression survival and the confounding effects of subsequent lines of 
therapy indicate that it would be difficult to detect an OS benefit in this setting.  
Nevertheless, OS is one of the study’s secondary endpoints.  The crossover from the 
crizotinib arm to alectinib will not be allowed in this study, with the aim of preserving the 
trial’s ability to potentially demonstrate some degree of treatment benefit of alectinib in 


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OS.  However, the study will not be powered to demonstrate any statistically significant 
difference in the secondary endpoint of OS. 
To ensure the validity of the PFS as the primary endpoint, a number of measures have 
been implemented: full IRC assessment to support the analysis of the primary endpoint, 
a substantial target magnitude of benefit (target HR = 0.65) and study assessments that 
will allow a robust evaluation of risk-benefit (standard RECIST criteria to define 
progression with fixed assessment intervals that are identical in both treatment arms and 
a robust definition of PFS and prospectively defined methods to assess, quantify, and 
analyze PFS, including censoring methods and sensitivity analyses). 
3.3.6 
Rationale for Secondary Endpoint of Time to CNS Progression 
Lung cancer is the most common type of cancer to spread to the brain, with at least 40% 
of people with lung cancer developing brain metastases at some point during their 
disease.  ALK-positive NSCLC has a propensity to metastasize to the brain, and 
crizotinib has impaired control of brain metastases in comparison to other sites of 
systemic disease (Chun et al. 2012). 
Delaying or preventing the development of CNS metastases would provide patients with 
clinically meaningful benefit by avoiding consequences of neurological deficits from brain 
metastasis or by delaying/preventing long-term side effects associated with steroid use 
and brain irradiation. 
Preliminary evidence of CNS benefit with alectinib has been observed in patients in the 
two ongoing Phase I/II studies.  See Section 1.2 and Alectinib Investigator's Brochure for 
additional details. 
Time to CNS progression is defined as the time from randomization until radiographic 
evidence of CNS progression is documented.  The aim of the pre-specified analysis will 
be to evaluate whether alectinib significantly delays or prevents the development of CNS 
metastases. 
Randomization of the Phase III study will be stratified by the presence or absence of 
CNS metastasis at baseline. 
Imaging analysis by consistently used uniform image acquisition technique (MRI scans) 
will be performed routinely at baseline and at subsequent follow-up assessments along 
with every systemic imaging tumor assessment or whenever clinically indicated 
(i.e., clinical suspicion of CNS metastasis) in order to achieve an accurate determination 
of time to CNS progression.  This ensures that early brain metastatic lesions are 
detected and that assessment bias between the two arms is avoided by having regularly 
scheduled scans. 


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An independent central radiological review will be performed for all patients and the 
analysis of time to CNS progression or response will be based on the data from the 
independent review.  The review will be based on the standard RECIST v1.1 criteria to 
assess the CNS lesions, and a second independent review on the basis of the RANO 
criteria, which are typically used to assess brain tumors (Wen et al. 2010), will be 
performed.  The assessment will be performed independently from the overall disease 
progression assessment. 
3.3.7 
Rationale for PK Sample Collection Schedule 
To date, the pharmacokinetics of alectinib have been characterized in 
chemotherapy-failed, crizotinib-naive patients with NSCLC in Study AF-001JP and in 
patients who have failed chemotherapy and crizotinib treatment in 
Study NP28761/AF-002JG and Study NP28673.  In order to better understand the 
pharmacokinetics of alectinib and to further support the development of a robust 
population PK model for alectinib in order to better understand, identify, and characterize 
variables which lead to changes in exposure, characterization of alectinib 
pharmacokinetics will be done in this study.  This study will include PK assessment of 
alectinib in ALK inhibitor treatment-naive patients with ALK-positive advanced NSCLC by 
collecting trough samples from all patients receiving alectinib.  Serial/intensive PK 
samples will be collected from a subset of patients (10%−15% [at least n = 20] of patients 
receiving alectinib) to facilitate the PK assessment.  The data that will be collected from 
this study will enable more robust understanding of alectinib pharmacokinetics in the 
global crizotinib-naive population including investigation and potential identification of 
sources of variability influencing alectinib pharmacokinetics and/or response to alectinib 
therapy.  Results from PK data collection in this study and analyses of PK data could 
help support optimal use of alectinib therapy. 
3.3.8 
Rationale for Biomarker Assessments 
Several molecular mechanisms of resistance to crizotinib have been reported in the 
literature: increased copy number of ALK gene, increased expression of ALK mRNA, 
secondary mutations in ALK (e.g., gatekeeper mutation), and changes (e.g., increased 
copy number, increased phosphorylation, or point mutations) in escape genes such as 
EGFR, cKIT, or KRAS (Katayama et al. 2011; Doebele et al. 2012; Kim et al. 2013).  In 
order to investigate molecular mechanisms of resistance to ALK inhibitors and ALK 
mutation status, tumor samples will be collected before treatment and at the time of 
disease progression with the goal of sequencing nucleic acids.  Two types of 
approaches will be used: 1) targeted sequencing of a panel of genes known to be 
involved in cancer and 2) unbiased genomic sequencing.  
Mutations in cancer genes appearing from drug resistance can be monitored in 
circulating nucleic acids in plasma (Forshew et al. 2012).  Tumor nucleic acids are shed 
into circulation in amounts that allow direct amplification by PCR and sequencing.  
Plasma samples will be collected before treatment and at certain timepoints during 


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treatment to monitor mutations in ALK and other genes involved in resistance to ALK 
inhibitors.  Information from mutated genes in the tumor will be correlated with mutations 
in plasma DNA. 
Determination of ALK positivity will be initially performed by Ventana IHC 
(see Appendix 8).  In addition, the Abbott Vysis FISH test will be used as an exploratory 
assay, after patients have been enrolled in this study.  Results from these analyses will 
be used to quantify the degree of correlation between FISH and IHC for the detection of 
ALK-positive NSCLC.  For exploratory purposes, other methods to determine ALK 
positivity (e.g., reverse transcription-PCR) may also be used.  Currently, ALK positivity 
for fusions can only be determined in tissue samples using assays such as FISH, IHC or 
PCR.  As tissue sampling is difficult and tissue biopsy sample sizes from lung cancer 
patients are very small, testing of several important biomarkers is challenging.  Many 
NSCLC patients may not have enough tumor tissue available and therefore cannot be 
tested for some biomarkers such as ALK.  Plasma ALK assays analyzing circulating 
tumor nucleic acids will enable more NSCLC patients to be tested for ALK fusions.  
Information from plasma ALK assays will be used to investigate the use of circulating 
tumor nucleic acids from plasma as a surrogate for tumor tissue for diagnostic purposes. 
3.3.9 
Rationale for PRO Assessments 
In the treatment of lung cancer, it is important to both increase survival and palliate 
symptoms because disease symptoms have negative impacts on HRQoL 
(Hyde and Hyde 1974; Hopwood and Stephens 1995; Sarna et al. 2008).  This is 
especially true for trials that use PFS as a primary endpoint, where it is important to 
translate the delay in disease progression into an endpoint that is meaningful to patients. 
Pain (chest; arm and shoulder), dyspnea, cough, and fatigue have been regarded as the 
most frequent and clinically relevant disease-related symptoms experienced by patients 
with NSCLC.  The BR.21 study (erlotinib vs. chemotherapy in second- or third-line 
NSCLC) demonstrated that longer TTD in the pain, dyspnea, and cough scales of the 
EORTC QLQ-C30 and QLQ-LC13 was consistent with superior PFS, OS, and 
quality-of-life benefits in the erlotinib arm as compared with the placebo arm 
(Aaronson et al. 1993; Bergman et al. 1994; Bezjak et al. 2006).  Additionally, patients 
in the crizotinib PROFILE 1005 trial reported clinically significant improvements 
(by 10 points) in the pain, cough, dyspnea, and fatigue symptom scales seen as early 
as 2 weeks on treatment (Crinò et al. 2011). 
The EORTC QLQ-C30 and QLQ-LC13 were used in the Phase III PROFILE 1007 study 
(second-line crizotinib vs. chemotherapy).  The study reported significantly greater 
overall reduction from baseline in the symptoms of alopecia, cough, dyspnea, fatigue, 
chest pain, arm or shoulder pain, and pain in other parts of the body with crizotinib than 
with chemotherapy (p < 0.001 for all comparisons, without adjustment for multiple testing).  
Patients treated with crizotinib also had a significantly greater delay in the worsening of 
symptoms.  There was also a significantly greater overall improvement from baseline in 


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the global quality of life among patients who received crizotinib treatment than among 
those who received chemotherapy (p < 0.001).  In all domains measuring function, 
except for the domain measuring cognitive function, there was a significantly greater 
overall improvement from baseline among patients in the crizotinib group than among 
patients in the chemotherapy group (Shaw et al. 2013). 
Therefore, to assess the quality of life of patients in this trial, PRO data will be collected 
from patients enrolled in this study using the validated questionnaires EORTC 
QLQ-C30 and QLQ-LC13. 
3.4 
OUTCOME MEASURES 
3.4.1 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
• 
PFS, which is defined as the time from randomization to the first documented 
disease progression, as determined by the investigators (primary endpoint) or IRC 
(secondary endpoint) using RECIST v1.1 or death from any cause, whichever 
occurs first.  Patients without an event will be censored at the last tumor 
assessment either during follow-up or during study treatment.  Patients with no 
post-baseline assessments will be censored at the date of randomization. 
• 
ORR, which is defined as the percentage of patients who attain CR or PR; response, 
as determined by the investigators using RECIST v1.1.  Patients without any 
assessments will be regarded as non-responders. 
• 
Time to CNS progression, which is defined as the time from randomization to the 
first occurrence of disease progression in the CNS as determined by IRC using 
RECIST v1.1 and RANO (separate assessments and analyses), as well as C-ORR 
in patients with CNS metastases who have measurable disease in the CNS at 
baseline, C-DOR in patients who have a CNS Objective Response, and C-PR at 
6, 12, 18, and 24 months. 
• 
DOR, which is defined as the time from when response (CR or PR) was first 
documented to first documented disease progression or death (whichever occurs 
first).  This will only be calculated for patients who have a best overall response of 
CR or PR.  Patients who do not progress or die after they have had a response are 
censored at the date of their last tumor measurement. 
• 
OS, which is defined as the time from randomization to death from any cause.  
Patients without an event will be censored at the last date known to be alive.  
Patients without any follow-up information will be censored at the date of 
randomization. 
 
3.4.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Serious and non-serious adverse events 
• 
Safety laboratory tests values 


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• 
Vital signs (blood pressure, heart rate), ECG 
• 
Physical examination 
 
3.4.3 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Sparse (pre-dose) PK samples for measurement of alectinib and its major 
metabolite(s) will be collected in all study patients receiving alectinib treatment.  
See Appendix 1 and Appendix 2 for PK sampling times. 
• 
Serial/intensive PK sampling will be collected in a subset of consenting patients 
enrolled to receive alectinib treatment (approximately 10%−15%, at least 
approximately n = 20).  See Appendix 1 and Appendix 2 for PK sampling times. 
• 
PK parameters will be determined as appropriate and where data allow: 
The pharmacokinetics of alectinib (and metabolite[s], if appropriate) will be 
described, and the between-patient variability will be estimated using a 
population PK approach.  The potential influence of covariates that contribute 
significantly to the between-patient differences in PK parameters of alectinib will 
also be explored and quantified. 
Non-compartmental analysis (NCA) may be conducted in patients undergoing 
serial/intensive PK sample collection, as appropriate and where data allow. 
 
3.4.4 
Patient-Reported Outcome Measures 
The PRO measures included for this study are as follows and will be administered to 
patients every 4 weeks until disease progression and during post-progression on 
treatment in case of isolated, asymptomatic CNS progression; at the post-treatment visit 
(4 weeks after permanent treatment discontinuation); and every follow-up visit (every 
8 weeks) after post-treatment visit for 6 months: 
• 
The EORTC QLQ-C30 and EORTC QLQ-LC13 to determine the impact of alectinib 
compared with crizotinib as measured by TTD in patient-reported lung cancer 
symptoms (e.g., cough, dyspnea [single item and multi-item scales], pain in chest, 
pain in arm/shoulder, fatigue). 
• 
The EORTC QLQ-C30 and EORTC QLQ-LC13 to measure PROs of HRQoL, 
patient functioning, and side effects of therapy compared between patients treated 
with alectinib and those treated with crizotinib. 
 
For patients who discontinue treatment for reasons other than disease progression and 
who progress within the first 6 months of survival follow-up, PRO measures will be 
administered every 4 weeks until disease progression and then decreased to every 
8 weeks until 6 months post-treatment. 
For patients who discontinue treatment for reasons other than disease progression and 
have not yet progressed at 6 months post treatment, PRO measures will be 
administered every 4 weeks until disease progression and will no longer be required 
thereafter.  


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3.4.5 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
EQ-5D-3L to generate utility scores for use in economic models for the purpose of 
reimbursement 
• 
Total testosterone and free testosterone levels (either by direct measurement or by 
calculation using albumin and SHBG), FSH, and LH in blood to measure the onset 
of hypogonadism in adult men 
• 
Results from the FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) to evaluate 
and compare efficacy in patients with treatment-naive NSCLC that is ALK-positive 
by FISH test  
• 
ALK fusion status in circulating tumor nucleic acids from plasma to evaluate and 
compare efficacy and safety in patients with treatment-naive NSCLC that is 
ALK-positive by plasma ALK tests (PCR and/or sequencing) for diagnostic purposes  
• 
Post-progression tumor mutation status to study molecular mechanisms of 
resistance to ALK inhibitors 
• 
ALK mutation status in plasma DNA to monitor efficacy and disease progression 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
The target population is patients with treatment-naive, ALK-positive, non-resectable, 
locally advanced and metastatic NSCLC. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Histologically or cytologically confirmed diagnosis of advanced or recurrent 
(Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) 
NSCLC that is ALK-positive as assessed by the Ventana IHC test.  Sufficient tumor 
tissue to perform ALK IHC and ALK FISH is required.  Both tests will be performed 
at designated central laboratories. 
• 
Age ≥ 18 years old 
• 
Life expectancy of at least 12 weeks 
• 
ECOG PS of 0−2 
• 
No prior systemic treatment for advanced or recurrent NSCLC (Stage IIIB not 
amenable to multimodality treatment) or metastatic (Stage IV) NSCLC 
• 
Adequate hematologic function: 
Platelet count ≥ 100 × 109/L 
ANC ≥ 1500 cells/μL 
Hemoglobin ≥ 9.0 g/dL 


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• 
Adequate renal function: 
An estimated glomerular filtration rate (eGFR) calculated using the Modification 
of Diet in Renal Disease equation of at least 45 mL/min/1.73 m2 
• 
Patients must have recovered from effects of any major surgery or significant 
traumatic injury at least 28 days before the first dose of study treatment. 
• 
Measurable disease (by RECIST v1.1) prior to the administration of study treatment 
• 
Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed 
incidentally at study baseline).  Asymptomatic CNS lesions might be treated at the 
discretion of the investigator as per local clinical practice.  If patients have 
neurological symptoms or signs due to CNS metastasis, patients need to complete 
whole brain radiation or gamma knife irradiation treatment.  In all cases, radiation 
treatment must be completed at least 14 days before enrollment and patients must 
be clinically stable. 
• 
For all females of childbearing potential, a negative pregnancy test must be 
obtained within 3 days before starting study treatment. 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus), agreement to 
remain abstinent or use single or combined contraceptive methods that result in a 
failure rate of < 1% per year during the treatment period and for at least 3 months 
after the last dose of study drug.  Abstinence is only acceptable if it is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.  Examples of contraceptive methods with a 
failure rate of < 1% per year include tubal ligation, male sterilization, hormonal 
implants, established and proper use of combined oral or injected hormonal 
contraceptives, and certain intrauterine devices.  Alternatively, two methods 
(e.g., two barrier methods such as condom and cervical cap use) may be combined 
to achieve a failure rate of < 1% per year.  Barrier methods must always be 
supplemented with the use of a spermicide.  
• 
For men, agreement to remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of < 1% per year during the 
treatment period and for at least 3 months after the last dose of study drug.  
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception. 
• 
Able and willing to provide written informed consent prior to performing any 
study-related procedures and to comply with the study protocol, including patients 
must be willing and able to use the electronic patient-reported outcome (ePRO) 
device. 
 


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4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients with a previous malignancy within the past 3 years are excluded (other than 
curatively treated basal cell carcinoma of the skin, early gastrointestinal [GI] cancer 
by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is 
considered to have no impact in PFS and OS for the current NSCLC). 
• 
Any GI disorder that may affect absorption of oral medications, such as 
mal-absorption syndrome or status post-major bowel resection 
• 
Liver disease characterized by: 
ALT or AST > 3 × ULN (≥ 5 × ULN for patients with concurrent liver metastasis) 
confirmed on two consecutive measurements 
OR 
Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or 
other conditions of decompensated liver disease such as coagulopathy, hepatic 
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal 
varices 
OR 
Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis 
• 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy 
such as radiotherapy (excluding alopecia), which have not shown improvement and 
are strictly considered to interfere with current study medication 
• 
History of organ transplant 
• 
Co-administration of anti-cancer therapies other than those administered in this 
study 
• 
Patients with baseline QTc > 470 ms or symptomatic bradycardia 
• 
Administration of strong/potent cytochrome P450 (CYP)3A inhibitors or inducers 
within 14 days prior to the first dose of study treatment and while on treatment with 
alectinib or crizotinib (see Appendix 3)  
• 
Administration of agents with potential QT interval prolonging effects within 14 days 
prior to the first administration of study drug for all patients and while on treatment 
through the end of the study for crizotinib-treated patients only (see Section 4.4.2 for 
further details) 
• 
History of hypersensitivity to any of the additives in the alectinib drug formulation 
(see Section 4.3.1.1 for further details) 
• 
History of hypersensitivity to any of the additives in the crizotinib drug formulation 
(see Section 4.3.1.2 for further details) 
• 
Pregnant or lactating women 
• 
Known HIV positivity or AIDS-related illness 


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• 
Any clinically significant concomitant disease or condition that could interfere with, 
or for which the treatment might interfere with, the conduct of the study or the 
absorption of oral medications or that would, in the opinion of the Principal 
Investigator, pose an unacceptable risk to the patient in this study 
• 
Any psychological, familial, sociological, or geographical condition potentially 
hampering compliance with the study protocol requirements and/or follow-up 
procedures; those conditions should be discussed with the patient before trial entry 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label trial, for which the rationale is described in Section 3.3.4. 
Approximately 286 patients will be randomly assigned in a 1:1 allocation ratio to the two 
treatment arms via a block-stratified randomization procedure and over a planned 
recruitment period of 24 months. 
Randomization will guard against systematic selection bias and should ensure the 
comparability of treatment groups.  To assist balance in important prognostic factors, 
randomization will be stratified by ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and 
CNS metastases at baseline (yes vs. no). 
Central randomization and drug pack number allocations will be performed and 
managed by an IxRS.  Further details will be provided in an IxRS manual. 
The independent review of scans for the secondary endpoints of PFS and time to CNS 
progression on the basis of IRC will be performed in a blinded fashion. 
4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Alectinib 
Alectinib comes in a hard capsule dosage form containing the following active ingredient: 
[Chemical name] 9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-6,11-
dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride 
Each capsule contains 150 mg of alectinib (as free base) along with lactose 
monohydrate, carmellose calcium, hydroxypropyl cellulose, sodium lauryl sulfate (SLS), 
and magnesium stearate as excipients. 
Alectinib capsules should be stored in accordance with the storage instructions on the 
label. 
Alectinib capsules should be administered orally BID with food in the morning and 
evening. 


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The formulation contains SLS as an excipient.  This excipient is known to be potentially 
associated with GI adverse events such as nausea, vomiting, diarrhea, and abdominal 
pain. 
For further details, see the alectinib Investigator's Brochure. 
4.3.1.2 
Crizotinib 
Crizotinib comes in a hard capsule dosage form.  Each capsule contains 250 mg or 
200 mg crizotinib.  Crizotinib hard capsules should be stored in accordance with the 
storage instructions on the label.  Crizotinib capsules should be administered orally BID. 
For further details, see the local prescribing information for crizotinib (XALKORI® U.S. 
Package Insert). 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Alectinib 
Alectinib 600 mg (four 150-mg capsules) should be administered orally BID with food in 
the morning and evening. 
If a patient misses a dose, it can be taken within 6 hours of the scheduled time.  If the 
time is greater than 6 hours, or if the patient vomits the dose, the patient should wait until 
the next scheduled time and take the next scheduled dose.  Patients should not take 
two doses at the same time to make up for a missed dose. 
Guidelines for dosage modifications and treatment interruptions or discontinuation due to 
specified adverse events are provided in Section 5.1.3. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF. 
4.3.2.2 
Crizotinib 
Crizotinib at 250 mg (one 250-mg capsule) should be administered orally BID with or 
without food (in the morning and evening). 
If a dose is missed, then it should be taken as soon as the patient remembers unless it is 
less than 6 hours until the next dose, in which case the patient should not take the 
missed dose.  Patients should not take 2 doses at the same time to make up for a 
missed dose.  If vomiting occurs after taking a dose of crizotinib, the next dose should be 
taken as scheduled.  
If dose reduction is necessary, then the dose of crizotinib should be reduced to 200 mg 
taken BID.  If further dose reduction is necessary, then the dose should be modified to 


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250 mg taken once daily.  Guidelines for dosage modification and treatment interruption 
or discontinuation are provided in Section 5.1.4. 
Any overdose or incorrect administration of crizotinib should be noted on the crizotinib 
Administration eCRF.  Adverse events associated with an overdose or incorrect 
administration of crizotinib should be recorded on the Adverse Event eCRF. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(alectinib and crizotinib) will be provided by the Sponsor where required by local health 
authority regulations.  The study site will acknowledge receipt of IMPs and confirm the 
shipment condition and content.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Post-Trial Access to Alectinib 
The Sponsor will offer post-trial access to the study drug alectinib free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive study drug after the end of the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or would not 
otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for ALK-positive NSCLC 


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• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for ALK-positive NSCLC 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy 
Concomitant medication includes any medication (e.g., prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used 
by a patient from screening to the study completion/discontinuation visit.  All concomitant 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
All therapy and/or medication administered to manage adverse events should be 
recorded on the Adverse Event eCRF. 
The medications and/or treatments below are permitted: 
• 
Anticoagulants and antithrombotic agents (i.e., coumadin-derived anticoagulants, 
unfractionated heparin or low-molecular heparins, aspirin (≤ 325 mg/day), and 
clopidogrel) 
• 
Acetaminophen up to 2 g/day 
• 
Gastric pH elevating medications (such as proton pump inhibitors, H2 blockers, or 
antacids) 
• 
Local therapy (e.g., stereotactic radiotherapy or surgery) may be given to patients 
with isolated asymptomatic CNS progression (e.g., new CNS oligometastases). 
 
Caution should be exercised when the following are co-administered with alectinib: 
• 
For medications that are substrates of P-gp transporter or breast cancer resistance 
protein transporter, the investigator should use caution and monitoring when 
considering concomitant use of alectinib.  Alectinib has been shown to have 
potential for inhibition of these transporters.  Substrates with a narrow therapeutic 
index (e.g., methotrexate, digoxin) should be avoided.  If co-administration cannot 
be avoided, it is recommended that drug levels and/or signs for toxicity are carefully 
monitored (see Appendix 3). 
 
Caution should be exercised when the following are co-administered with crizotinib: 
• 
Crizotinib has been shown to be a moderate inhibitor of CYP3A.  Dose reduction 
may be needed for co-administered drugs that are predominantly metabolized by 


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CYP3A in patients receiving crizotinib.  Concurrent use of CYP3A substrates with 
narrow therapeutic indices should be avoided (see Appendix 3). 
• 
On the basis of an in vitro study, crizotinib is predicted to inhibit intestinal P-gp.  
Therefore, administration of crizotinib with medicinal products that are substrates of 
P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin) may increase their 
therapeutic effect and adverse reactions (see Appendix 3).  Close clinical 
surveillance is recommended when crizotinib is administered with these medicinal 
products. 
• 
Bradycardia has been reported during clinical studies; therefore, avoid using 
crizotinib in combination with other agents known to cause bradycardia 
(e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and 
digoxin) to the extent possible 
• 
In vitro studies in human hepatocytes indicated that crizotinib may induce 
pregnane X receptor and constitutive androstane receptor-regulated enzymes 
(e.g., CYP3A4, CYP2B6, CYP2C8, CYP2C9, UGT1A1).  However, there was no 
observed induction in vivo when crizotinib was coadministered with the CYP3A 
probe substrate midazolam.  Caution should be exercised in administering crizotinib 
in combination with medicinal products that are predominantly metabolized by these 
enzymes.  Of note, the effectiveness of concomitant administration of oral 
contraceptives may be altered. 
• 
In vitro studies indicated that crizotinib is an inhibitor of CYP2B6.  Therefore, 
crizotinib may have the potential to increase plasma concentrations of 
coadministered drugs that are metabolized by CYP2B6 (e.g., bupropion, efavirenz). 
 
4.4.2 
Prohibited Therapy 
Use of the following therapies (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) is prohibited during the study and for at 
least 14 days prior to initiation of study treatment (either alectinib or crizotinib), unless 
otherwise specified below.  Exceptions to restrictions of the concomitant therapies listed 
below (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) may be made if the rationale is discussed and documented 
between the investigator and the Sponsor’s Clinical Pharmacologist. 
• 
Potent inducers of CYP3A (e.g., rifampin, rifabutin, phenobarbital, phenytoin, 
carbamazepine, and St. John’s wort [Hypericum perforatum]) within 2 weeks or 
5 half-lives (whichever is longer) before the first dose of study drug treatment and 
while on treatment with study drugs (see Appendix 3). 
• 
Potent inhibitors of CYP3A (e.g., ketoconazole) within 2 weeks or 5 half-lives 
(whichever is longer) before the first dose of study drug treatment and while on 
treatment with study drug (see Appendix 3). 
• 
Any concomitant medications known to affect QT interval duration, including but not 
limited to the following drugs:  amiodarone, cisapride, clarithromycin, methadone, 
and quinidine, within 2 weeks before the first dose of study drug treatment for all 


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patients and while on treatment through the end of the study for crizotinib-treated 
patients only 
• 
Systemic immunosuppressive drugs, cytotoxic or chemotherapeutic agents 
(other than study drug treatment), ergot derivatives, probenecid, and bile 
acid-binding resins while on study treatment. 
• 
Systemic chemotherapy. 
• 
Radiotherapy/radionuclide therapy except for palliative radiotherapy to bone lesions 
or for pain control.  If palliative radiation is indicated for bone metastases, palliative 
radiation may start within 24 hours of the last dose of alectinib, unless, in the 
judgment of the investigator, patient safety will require a longer washout period prior 
to palliative therapy.  Dosing of alectinib may resume with the resolution of any 
radiation toxicity to ≤ Grade 1. 
• 
Additional investigational drug (except for during the follow-up period) 
 
The list of medications provided above is not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication 
as well as the Internet references provided below when determining whether a certain 
medication strongly inhibits or induces CYP3A.  In addition, the investigator should 
contact the Medical Monitor if questions arise regarding medications not listed above. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM292362.pdf 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx (for P450 drug interactions) 
 
4.4.3 
Prohibited Food 
Use of grapefruit or grapefruit juice should be avoided during the study and for at least 
14 days prior to the initiation of study treatment (either alectinib or crizotinib) because it 
is a potent CYP3A inhibitor and may increase plasma concentration of either alectinib or 
crizotinib. 
4.5 
STUDY ASSESSMENTS 
See Appendix 1 for the schedule of assessments performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 


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4.5.2 
Medical History and Demographic Data 
Medical history includes a record of clinically significant diseases, surgeries, cancer 
history (including prior cancer therapies and procedures), reproductive status, smoking 
history, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 28 days prior 
to the screening visit. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Corticosteroid Use for CNS Metastases 
For patients with CNS metastases requiring corticosteroid use, the corticosteroid intake 
should be captured at all tumor assessment visits and compared to the corticosteroid 
intake at the time of the last disease assessment.  The changes will be recorded as 
Increased, Unchanged, or Decreased.  Increases and decreases in corticosteroid intake 
should be clinically justified.  Increases in corticosteroid dose for reasons other than for 
CNS metastases control do not need to be taken into consideration when making this 
comparison. 
4.5.4 
Physical Examinations 
A complete physical examination at screening and baseline should include an evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, GI, genitourinary, and neurological systems as well as 
height and weight.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
Note:  for patients with known CNS metastases, a neurological examination must be 
performed at each tumor assessment visit and compared to the neurological 
examination performed at the time of the last disease assessment.  Definition of clear 
neurological worsening is difficult to describe because progression in the CNS can 
present in numerous ways.  Accordingly, evaluation of neurological function at each 
disease assessment will be based purely on the investigator’s assessment of the 
patient’s neurological state compared to the neurological function at the time of the last 
disease assessment.  Neurological status will be recorded as Improved, Stable, or 
Worsened. 
4.5.5 
Vital Signs 
Vital signs will include measurements of respiratory rate, oxygen saturation, pulse rate, 
and systolic and diastolic blood pressure while the patient is in a seated position, and 
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4.5.6 
ECOG Performance Status 
Performance Status (PS) will be measured using the ECOG PS Scale (see Appendix 5).  
It is recommended, where possible, that a patient’s PS be assessed by the same person 
throughout the study. 
4.5.7 
Tumor and Response Evaluations 
Disease burden must be documented at screening and re-assessed at each subsequent 
tumor evaluation.  Response will be assessed by the investigator on the basis of physical 
examinations.  Clinical lesions will be documented by color photography (with caliper 
measurement for measurable lesions), computed tomography (CT) scans, and other 
modalities (e.g., MRI, brain scans), using RECIST v1.1 (see Appendix 4).  For assessing 
response in patients with measurable disease, the preferred radiologic tumor response 
assessment is CT scan with intravenous contrast.  If intravenous contrast is 
contraindicated, a non-contrast-enhanced chest CT scan will be acceptable for chest 
lesions, and MRI can be used for non-chest lesions.  If contrast-enhanced MRI is 
contraindicated, then non-contrast-enhanced MRI will suffice.  Positron emission 
tomography (PET) scan, bone scan, and ultrasound cannot be used to measure lesion as 
per RECIST v1.1 (see Appendix 4).   
The same radiographic procedure used to define measurable disease sites at screening 
must be used throughout the study (e.g., the same contrast protocol for CT scans).  
Assessments should be performed by the same evaluator to ensure internal consistency 
across visits. 
CT/MRI scans of chest and abdomen, and MRI scans of the brain should be performed 
for all patients as described in Schedule of Assessments (see Appendix 1) at screening, 
then every 8 weeks subsequently until disease progression and during post-progression 
on treatment in case of isolated, asymptomatic CNS progression and at the 
post-treatment visit (4 weeks after permanent treatment discontinuation).  CT/MRI scans 
of the neck bone and pelvis should be included if clinically indicated.  At the investigator’s 
discretion, CT/MRI scans may be repeated at any time if PD is suspected. 
Note: Brain imaging should be performed using MRI with the following image acquisition 
requirements. 
• 
Minimum sequences required: 
Pre-contrast T1, T2/FLAIR 
Post-contrast T1, with two orthogonal planes (or a volume acquisition) 
recommended 
• 
Recommended slice thickness ≤ 5 mm with no gap 
 
Patients with known or suspected bone metastases should undergo radionuclide bone 
scan at screening.  Bone scan, PET scan, or plain films are not considered adequate 
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but can be used to confirm the presence or disappearance of bone lesions.  Lytic bone 
lesions or mixed lytic-blastic lesions, with identifiable soft tissue components that can be 
evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
measurable lesions of the soft tissue component and meet the definition of measurability 
and should be followed by cross-sectional imaging. 
4.5.8 
Laboratory, Biomarker, and Other Biological Sample 
4.5.8.1 
Laboratory Assessments 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Hematology (hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
absolute differential count [neutrophils, eosinophils, lymphocytes, monocytes, 
basophils, other cells]) 
• 
Coagulation (PT [or INR], and aPTT) 
• 
Serum chemistry (sodium, potassium, chloride, bicarbonate, fasting glucose, BUN 
or urea, creatinine [including calculated eGFR using the Modification of Diet in 
Renal Disease formula, see Appendix 7]; CPK; gamma-glutamyl transferase [GGT]; 
calcium; total and direct bilirubin; total protein; albumin; ALT; AST; alkaline 
phosphatase [ALP]; phosphorus; magnesium; thyroid-stimulating hormone; and total 
testosterone and free testosterone [either by direct measurement or by calculation 
using, albumin and SHBG], FSH, and LH [for male patients only]) 
• 
Urinalysis.  Urine samples will be collected according to the schedule of 
assessments (Appendix 1) (first morning urine sample for baseline and end of 
treatment visit, spot urine for rest of visits).  Urine protein will be measured by 
dipstick test. 
• 
Pregnancy test.  All women who are not postmenopausal (≥ 12 months of 
non-therapy-induced amenorrhea) or surgically sterile will have a serum pregnancy 
test at screening, within 3 days of dosing.  Urine pregnancy tests will be performed 
anytime during the course of the study, as per investigator’s discretion.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
 
4.5.8.2 
Pre-Treatment Tumor Samples (Mandatory) 
Mandatory pre-treatment tumor samples will be collected to centrally examine ALK 
status by Ventana IHC (eligibility criteria) and Vysis FISH.  Tumor blocks (formalin-fixed, 
preferred 10% neutral-buffered formalin) are the preferred source, but if blocks are not 
available, unstained slides (ten to fifteen 5-µm slides cut less than 3 months before 
screening) are also accepted.  Remaining tumor blocks will be returned to the sites; 
slides will not be returned. 
For fresh tumor biopsies (guided by ultrasound or CT scan), acceptable methods include 
core biopsies for lung and liver lesions and bronchoscopic biopsies for lung lesions.  The 
minimum size for the biopsy needle recommended is 20G. 


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Central ALK testing to determine or confirm patient ALK status will be performed at a 
Sponsor designated central laboratory.  After completion of ALK testing for enrollment 
with a pre-specified ALK test by Ventana IHC (Appendix 8), patient samples will also be 
centrally tested by FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott).  Additionally, 
other ALK assays may be used for testing patient samples to establish performance 
characteristics of these assays for diagnostic development.  Testing may be performed 
on all screened patients (screen- failed and enrolled).  These additional testing data will 
have no impact on eligibility, and testing will be performed only after eligibility is 
established for each patient.  In addition, local ALK test information, baseline 
demographic, and disease-related characteristic data for all screened patients may be 
collected in order to support potential registration of a companion diagnostic assay for 
alectinib. 
The tumor sample may also be tested for the presence of EGFR mutations, if requested 
by the investigator. 
Pre-treatment tumor samples may be used, after proper informed consent is obtained, 
for genomic sequencing. 
For sample handling procedures, storage conditions and shipment instructions, see the 
laboratory manual. 
4.5.8.3 
Pre- and Fresh Post-Treatment Tumor Biopsies (Optional) 
Pre-treatment tumor samples (preferably formalin-fixed blocks but if not available a 
minimum of 10-15 unstained 5 µm slides) for ALK testing is a mandatory requirement for 
this study.  Optional additional pre-treatment tumor samples and fresh post-treatment 
tumor biopsy at disease progression or permanent treatment discontinuation (at the last 
treatment or post-progression visit) may be collected, with proper informed consent.  
These samples will be used to help to understand molecular mechanisms of resistance 
to ALK inhibitors by genomic sequencing.  Remaining tumor blocks will be returned to 
the sites, slides will not be returned. 
The remaining mandatory (Section 4.5.8.2) and optional specimens (Section 4.5.8.3) will 
be destroyed within 5 years after the date of final closure of the clinical database.  Other 
residual tissue material (slides, extracts, etc.) will be destroyed within 5 years after the 
date of final closure of the clinical database. 
On the basis of continuous analysis of the data in this study and other studies, or on the 
basis of data from literature, collection of optional tumor biopsies with exploratory 
purposes may be stopped at any time if the data from the samples collected do not 
produce useful information. 


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4.5.8.4 
Blood and Plasma Samples 
Mandatory plasma samples will be obtained to determine: 
• 
Mutation status in ALK and other escape genes (e.g., EGFR, KRAS).  It will require 
20 mL of blood (2 tubes of 10 mL each) to be collected at baseline, at the 
Visit 3 (Week 16) treatment, and subsequently at every second treatment visit 
(every 16 weeks) (see Appendix 1 for detailed information) until disease progression, 
and during post-progression on treatment in case of isolated, asymptomatic CNS 
progression.  For sample handling procedures, storage conditions and shipment 
instructions, see the laboratory manual.  These samples will not be taken in 
countries where regulatory agency or Institutional Review Board (IRB) does not 
allow genetic testing. 
• 
ALK rearrangement in plasma.  This will require 20 mL of blood (2 tubes of 10 mL 
each) to be collected at baseline. 
 
Mandatory blood samples will be obtained to determine: 
• 
All patients who are randomized in alectinib arm will also participate in retrospective 
pharmacogenomic research to understand inter-individual variability of safety and 
pharmacokinetics of alectinib.  For this purpose, a 3-mL blood sample will be drawn 
at baseline (see Section 4.5.8.4.1). 
 
Optional blood samples will be collected to obtain: 
• 
Plasma.  Centrally ALK negative tested patients (by Ventana ALK IHC) who agree 
to donate 10 ml plasma will be assessed by plasma ALK assays (PCR and/or 
Sequencing) for the development of a plasma ALK diagnostic test 
• 
A source of healthy tissue for patients who agreed to participate in the optional 
genomic sequencing assessment.  For patients in the crizotinib arm, a 3-mL blood 
sample will be drawn at baseline.  For patients in the alectinib arm, a source of 
healthy tissue will be used as a portion of the sample for the pharmacogenomics 
research (see Section 4.5.8.4.1) 
• 
A portion of this blood sample will also be used as a source of healthy tissue for the 
patients on alectinib treatment who agree to participate in the optional genomic 
sequencing research. 
 
For biomarkers, a maximum of 43 mL of blood will be collected at baseline (20 mL of 
blood for plasma purification and determination of mutation status in ALK and other 
escape genes, 20 mL of blood for plasma purification and detection of ALK 
rearrangements, and 3 mL blood for pharmacogenomics research.  Twenty mL of blood 
(for plasma purification and determination of mutation status in ALK and other escape 
genes) will be collected at Visit 3 (Week 16) and subsequently at every second visit 
(every 16 weeks), and 20 mL will be collected at disease progression (CNS and/or 
systemic disease progression) for plasma purification, for determination of mutation 
status in ALK and other escape genes. 


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Details of sample handling procedures, sample storage, and shipment will be described 
in a separate laboratory manual. 
On the basis of continuous analysis of the data in this study and other studies, or on the 
basis of data from literature, collection of plasma with exploratory purposes may be 
stopped at any time if they are deemed not informative. 
4.5.8.4.1 
Samples for Pharmacogenomic Assessments 
One sample (approximately 3 mL of whole blood) will be collected from all patients on 
alectinib treatment.  Samples will be used for the evaluation of genetic polymorphisms of 
drug metabolic enzymes including but not limited to CYP2C9, CYP3A4/5, and UGT1A1, 
and transporters (e.g., organic anion transporter polypeptide 1B1) and for genetic 
variants that could contribute to potentially drug-related liver safety assessments 
(including but not limited to human leukocyte antigen, see Appendix 9 for more details). 
For sample handling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Only in circumstances where there is concern for collection of this 
genetic material for above evaluations can this assessment be considered not 
mandatory as part of study assessments in this study.  Results of any analyses from 
these samples will be reported outside the clinical study report. 
4.5.8.5 
Samples for Pharmacokinetic Assessments 
PK samples will be collected in all patients on alectinib treatment, as indicated in 
Appendix 1 and Appendix 2 for the analysis of alectinib and its major metabolite(s) 
(RO5468924, RO5507197, and/or others, if applicable and if appropriate, and if assays 
are available).  Residual samples following PK analysis may be used to evaluate 
profiling for alectinib metabolite(s). 
All trough/pre-dose PK samples should be collected within 2 hours BEFORE the 
morning doses of study medications.  
Serial/intensive samples will be collected in a subset of patients (10%–15% [at least 
approximately n = 20] of patients receiving alectinib) on Visit 0 (baseline, after the first 
dose) and Visit 1 (Week 4) at the timepoints specified in Appendix 2. 
Plasma concentrations for alectinib and its metabolite(s), if applicable, will be measured 
by specific and validated liquid chromatography tandem mass spectrometry methods. 
For each sample, approximately 2 mL of venous blood will be collected for alectinib PK 
analysis at the timepoints specified in the PK schedule in Appendix 1 and Appendix 2. 
Patients who permanently discontinue from study drugs will also discontinue from all PK 
assessments.  The procedures for the collection, handling, storage, and shipping of 
plasma samples for the PK analysis are specified in the Laboratory Manual.  


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These samples will be destroyed when the final Clinical Study Report is complete. 
On the basis of continuous analysis of the data in this study and other studies, any 
sample type collection may be stopped at any time if the data from the samples collected 
do not produce useful information or at the discretion of the Sponsor. 
4.5.9 
Electrocardiograms 
An ECG will be recorded at specified timepoints as outlined in the schedule of 
assessments (Appendix 1) at screening, Visit 0 (baseline), Visit 1 (Week 4), 
Visit 4 (Week 24), Visit 8 (Week 56), and at the last treatment visit and as clinically 
indicated throughout the study.  All ECG recordings must be performed using a standard 
high-quality, high-fidelity digital electrocardiograph machine equipped with 
computer-based interval measurements.  All ECGs are to be obtained prior to other 
procedures scheduled at that same time (e.g., vital sign measurements, blood draws, 
study drug administration) as well as prior to meals.  Circumstances that may induce 
changes in heart rate, including environmental distractions (e.g., television, radio, 
conversation), should be avoided during the pre-ECG resting period and during ECG 
recording. 
Patients must have been in a supine or semi-supine position for at least 5 minutes prior 
to the recording being taken.  The same recording position (supine or semi-supine) and 
the same equipment should be used for each patient throughout the study.  The ECG 
printout must be (1) reviewed by a medically qualified member of the study team at the 
site, (2) annotated to indicate any clinical finding, and (3) dated and signed by this 
person and filed in the patient notes.  ECG parameters will be entered on the ECG 
eCRF.  The following parameters should be captured on the eCRF: heart rate, RR, PQ, 
QRS and QT duration, and QT interval corrected using Fridericia’s formula (QTcF). In 
the event that the ECG machine does not directly provide results for RR and/or QTcF, 
these parameters can be derived using the formulae provided in Appendix 10. 
If any ECG abnormality is associated with an adverse event, it must be recorded and 
managed as described in Section 5.   
If considered appropriate by the Sponsor, ECGs may be analyzed retrospectively at a 
central laboratory.   
4.5.10 
Patient-Reported Outcomes 
PROs (EORTC QLQ-C30, QLQ-L13, and EQ-5D) will be collected to more fully 
characterize the clinical profile of alectinib.  The instruments will be translated as 
required in the local language.  To ensure instrument validity and that data standards 
meet health authority requirements, the PROs scheduled for administration during a 
clinic visit (EORTC QLQ-C30, QLQ-L13, and EQ-5D) should be completed prior to the 
performance of non-PRO assessments and the administration of study treatment. 


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Patients will use an ePRO device to capture PRO data and maintain a diary of daily drug 
intake (crizotinib arm) or drug intake with food (alectinib arm).  The ePRO device and 
instructions for completing the PRO questionnaires and diaries electronically will be 
provided by the investigator staff.  The data will be transmitted via pre-specified 
transmission method (e.g., web or wireless) automatically after entry to a centralized 
database at the ePRO vendor.  The data can be accessed by appropriate study 
personnel securely via the Internet. 
4.5.11 
Samples for Roche Clinical Repository 
4.5.11.1 
Overview of the Roche Clinical Repository 
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future. 
Specimens for the RCR will be collected from patients who give specific consent to 
participate in optional research.  RCR specimens will be used to achieve the following 
objectives: 
• 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.11.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's IRB or Ethics Committee (EC) and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval for RCR sampling, 
this section of the protocol (Section 4.5.11) will not be applicable at that site. 
4.5.11.3 
Sample Collection 
For RCR purposes, 10 mL of blood will be collected.  Any remaining tissue samples from 
study-related or non-study related procedures that are performed during the study may 
also be collected for RCR purposes.  For all samples, date of consent should be 
recorded on the associated RCR page of the eCRF.  For sampling procedures, storage 
conditions, and shipment instructions, see the laboratory manual. 


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RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below. 
4.5.11.4 
Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
4.5.11.5 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 


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objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether the patient has given consent to participate 
by completing the RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research. 
4.5.11.6 
Withdrawal from the Roche Clinical Repository 
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study BO28984 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study BO28984. 
4.5.11.7 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 


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• 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients who withdraw consent for treatment should continue to be 
followed for tumor assessments until progression and for OS, provided they have not 
withdrawn consent for the study.  However, patients will not be followed for any reason 
after consent for the study has been withdrawn.  Patients who withdraw from the study 
will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Pregnancy 
• 
Inability to tolerate study medication on the basis of the investigator judgment 
See guidelines for managing adverse events and for comprehensive guidance on study 
drug discontinuation in Section 5.1.3. 
Patients who discontinue study drug prematurely will be asked to return to the clinic for 
tumor assessments until progression as per study schedule (see Appendix 1). 
The primary reason for premature study drug discontinuation should be documented on 
the appropriate eCRF.  Patients who discontinue study drug prematurely will not be 
replaced. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 


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5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
5.1.1 
Adverse Events Collection 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events (SAEs) caused by a protocol-mandated intervention should be 
reported (e.g., SAEs related to invasive procedures such as biopsies).  After the first 
dose of study treatment and up to the 4-week follow-up after the last dose of study 
treatment, all adverse events (AEs) regardless of seriousness, causality assessment, or 
actions taken reported by the investigator or designated medically qualified study site 
personnel will be collected as described below.  At each visit, the investigator or 
designated medically qualified study personnel will ask the patient if any untoward 
medical event occurred since the last visit.  It is the investigator’s responsibility to record 
all AEs in the source patient’s medical records. 
All SAEs and non-SAEs will be reported on the standard AE/SAE eCRF. 
5.1.2 
Adverse Events Relating to ALK Inhibitors and/or the Tyrosine 
Kinase Inhibitor Class and Alectinib Data 
Events described in Section 5.1.2.1 through Section 5.1.2.10 will be closely monitored 
and represent selected AEs for this study. 
A more detailed safety profile of alectinib is provided in the alectinib Investigator's 
Brochure. 
5.1.2.1 
Interstitial Lung Disease 
TKIs, including ALK inhibitor crizotinib, have been associated with the occurrence of 
treatment-related ILD (including fatalities). 
See Section 5.1.3 for management and follow-up. 
5.1.2.2 
Hepatotoxicity 
Hepatobiliary findings were observed in both the rat and monkey 4- and 13-week toxicity 
studies with alectinib, and findings in the 13-week studies were similar to those of the 
4-week studies.  The findings were at or close to clinically relevant exposures.  
Hepatobiliary effects included increased hepatic ALP, direct bilirubin, GGT and liver 
weight, vacuolation/degeneration/necrosis of bile duct epithelium, inflammatory cell 
infiltration in Glisson’s sheath, enlargement/focal necrosis of hepatocytes, and 
enlargement of Kupffer cells. 
Abnormal hepatobiliary laboratory test values, such as increased ALT, AST, or bilirubin 
levels, have been observed after alectinib administration.  AST, ALT, and total bilirubin 
levels temporarily increased in the initial stages of treatment and then improved.  In 
patients with Grade 3−4 AST/ALT elevations, documented drug-induced liver injury by 
liver biopsy was reported with uncommon frequency in alectinib pivotal clinical trials.  


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Concurrent elevations in ALT or AST greater than or equal to three times the ULN and 
total bilirubin greater than or equal to two times the ULN, with normal alkaline 
phosphatase, occurred with uncommon frequency in patients treated in alectinib clinical 
trials. 
In patients treated with other tyrosine kinase ALK inhibitor drugs, abnormal liver function 
tests and drug-induced hepatotoxicity, including cases with fatal outcome, have been 
reported. 
See Section 5.1.3 for management and follow-up. 
5.1.2.3 
Anemia 
Hematologic findings were observed in both the rat and monkey 4- and 13-week toxicity 
studies with alectinib, and findings in the 13-week studies were similar to those of the 
4-week studies.  Findings were at or close to clinically relevant exposures.  Hematologic 
adverse effects such as anemia, thrombocytopenia, bleeding, and neutropenia have 
been observed with most TKIs, including ALK inhibitor crizotinib. 
Cases of anemia have been reported in patients treated with alectinib; the majority of the 
events were Grade 1 or 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.4 
Gastrointestinal Disorders 
In pivotal clinical trials, one case of GI perforation (0.4%) occurred and had a fatal 
outcome. In the post-market setting, cases of GI perforation were also reported with 
alectinib. 
GI disorders such as nausea, vomiting, constipation, and diarrhea have been reported 
with alectinib.  Similar GI disorders have been observed with other TKIs, including ALK 
inhibitor crizotinib. 
SLS (sodium lauryl sulfate, syn. sodium dodecyl sulfate) is a surfactant excipient in the 
clinical formulation at a concentration of 50% (w/w SLS to active pharmaceutical 
ingredient).  This excipient is a known GI irritant and may be associated with GI AEs 
including nausea, vomiting, diarrhea, and abdominal pain.  Of note, GI tract toxicity as 
the safety determinant of SLS is not because of systemic toxicity, but a consequence of 
local irritation to the GI tract.  In general, when mixed with diet, higher levels of SLS⎯a 
known GI tract mucosal irritant⎯are tolerated versus gavage administrations. 
See Section 5.1.3 for management and follow-up. 
5.1.2.5 
Skin Disorders 
Results of an in vitro phototoxicity study indicated that alectinib may have phototoxic 
potential. 


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Skin rash has been reported with majority of TKIs including those targeting the ALK 
receptor (Hartmann et al. 2009). 
Cases of skin rash and photosensitivity have been reported with alectinib and were 
generally Grade 1 or 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.6 
Vision Disorders 
In the rat quantitative whole body autoradiography study, tissue radioactivity 
disappeared over time, following a time course comparable to that of plasma 
radioactivity, except for melanin-containing tissues such as uveal tract of eyes, which 
had much higher and more sustained exposure in pigmented rats.  This is consistent 
with what is commonly observed for lipophilic basic drugs. 
Vision disorders, including diplopia, photopsia, blurred vision, visual impairment, and 
vitreous floaters, have been reported with several TKIs, including ALK inhibitors 
(crizotinib) (Shaw et al. 2013). 
Vision disorders, such as dry eye, blepharitis, conjunctivitis, blurred vision, and vision 
impaired, have been reported with alectinib and were generally Grades 1 and 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.7 
Edema 
Most TKIs, including ALK inhibitor crizotinib, have been associated with edema.  Events 
of edema have been reported with alectinib, mostly Grade 1 or 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.8 
Bradycardia 
In the monkey telemetry study, there were no effects on the ECG, any of the other 
cardiovascular parameters or body temperature at doses up to 15 mg/kg (mean 
maximum concentration [Cmax]: 279 ng/mL). 
In a preliminary non-Good Laboratory Practice telemetry study in conscious cynomolgus 
monkeys, a slight hypotensive effect (approximately 10 mmHg) was seen when alectinib 
was administered at 20 and 60 mg/kg orally with no effects on ECG or heart rate.  The 
hypotensive effect of alectinib observed in monkeys was considered to likely be caused 
by vasodilatation induced by L-type Ca2+ channel inhibition. 
Events of bradycardia have been reported with alectinib.  Preliminary heart rate data 
(based on ECG and pulse measurements) from the ongoing alectinib clinical trials show 
a decrease in heart rate during alectinib treatment, which is mainly asymptomatic.  In 
patients treated with other ALK inhibitors (crizotinib and ceritinib), bradycardia adverse 


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events, as well as decreases in heart rate based on ECG and pulse measurements, 
have also been reported (XALKORI® U.S. Package Insert; ZYKADIA® U.S. Package 
Insert).  
In case of bradycardia, concomitant medications must be evaluated to identify those that 
are known to cause bradycardia, as well as anti-hypertensive medications; and 
discontinuation or dose reduction of these concomitant medications must be considered. 
See Section 5.1.3 for management and follow-up. 
5.1.2.9 
Abnormal Renal Function 
In the 2-week non-human primate study at 60 mg/kg, an increase in creatinine was 
observed but no changes were observed in histopathology.  In all other non-human 
primate studies, no changes in creatinine were observed. 
Serum creatinine increases have been reported with alectinib treatment and were 
generally Grades 1 and 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.10 
Severe Myalgia and CPK Elevations 
Postmarketing experience with some TKIs includes reports of myopathy and 
rhabdomyolysis (Hohenegger 2012). 
Blood CPK increases, generally Grades 1 and 2, and muscular AEs have been reported 
with alectinib treatment.  Grade 3 myalgia and CPK elevations have been reported with 
alectinib treatment and were reversible upon dose reduction and interruption. 
See Section 5.1.3 for management and follow-up and Table 2 for guidelines for 
managing AEs. 


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5.1.3 
Management of Specific Adverse Events with Alectinib 
Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib 
Event 
Action to Be Taken 
Interstitial lung disease 
• 
Patients should be monitored for pulmonary symptoms 
indicative of pneumonitis.  
• 
Study drug should be permanently discontinued in patients 
diagnosed with interstitial lung disease. 
Hepatotoxicity 
 
Liver test laboratory abnormalities are to be reported as AEs only if 
fulfilling the criteria listed in Section 5.3.5.4 and Section 5.3.5.6. 
• 
If ALT or AST  > 3 × baseline, repeat testing of ALT, AST, ALP, 
and total bilirubin within 48–72 hours, with inquiry about 
symptoms.  If upon repeat testing the transaminases 
remain  > 3 × baseline, but are not  > 5 × baseline or not 
accompanied with bilirubin increases or do not match any other 
rule for permanent discontinuation, then monitoring can 
continue as per investigator judgment, and dose modification is 
not necessary. 
• 
At any time during the study treatment, if symptoms compatible 
with liver injury are observed, liver enzymes should be 
measured as soon as possible.  
• 
Study drug treatment has to be permanently discontinued if 
any of the following occurs: 
First observation of ALT or AST  > 8 × ULN 
ALT or AST > 5 × ULN for more than 2 weeks 
First observation of ALT or AST > 3 × ULN and total 
bilirubin > 2 × ULN  
First observation of ALT or AST > 3 × ULN and the 
appearance of jaundice or signs of hepatic dysfunction or 
other symptoms (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or 
eosinophilia [> 5%]). 
• 
Following study drug discontinuation, weekly monitoring of 
laboratory values should continue until the abnormal values 
have normalized to pre-treatment levels and/or an adequate 
explanation of the abnormal value is found. 
• 
Resumption of study drug is not allowed in patients 
discontinuing because of any of the above criteria. 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
Gastrointestinal 
perforation 
In patients at risk for GI perforation (e.g., concomitant use of 
medications with a risk of GI perforation, history of diverticulitis, 
or metastases to the GI tract), alectinib should be used with 
caution.  Patients should be informed of potential signs of GI
perforations and seek medical advice rapidly in case of occurrence. 
Study drug should be permanently discontinued in patients who 
develop GI perforation. 
Other gastrointestinal 
tract AEs (e.g., nausea, 
vomiting, diarrhea) 
The events are expected to be minimized by taking the study drug 
with meal.  In case GI events occur, appropriate measures should 
be taken in accordance with local clinical practice guidelines.  If GI 
toxicities are observed and not tolerable, treatment with study drug 
should be temporarily interrupted until recovery to Grade 1 or lower.
Skin disorder AEs 
(e.g., phototoxicity, rash) 
Patients should be advised to avoid prolonged sun exposure while 
taking alectinib and for at least 5 days after study drug 
discontinuation.  Patients should also be advised to use a 
broad-spectrum sun screen and lip balm of at least SPF 50 to help 
protect against potential sunburn 
Vision disorders 
Investigators should consider referring the patients for an 
ophthalmological evaluation according to local clinical practice 
guidelines, if vision disorders persist or worsen in severity, and to 
advise patients to exercise caution when driving or operating 
machinery due to the risk of developing a vision disorder. 
Edema 
Physical examinations will be performed routinely in clinical trials.  
In case edema events occur, appropriate measures should be taken 
in accordance with local clinical practice guidelines 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
Abnormal kidney function 
AEs 
Kidney function laboratory abnormalities are to be reported as AEs 
only if fulfilling the criteria listed in Section 5.3.5.4. 
• 
If, at any time during the study treatment, eGFR decreases 
by > 50% of the baseline visit value, the patient has to be 
carefully monitored.  All of the underlying factors that may have 
acutely impacted serum creatinine levels need to be evaluated 
and corrected (e.g., dehydration, recent exposure to contrast 
media, increased amount of cooked meat in diet, concomitant 
medications affecting renal function as appropriate, etc.). 
• 
Any eGFR decrease by > 50% of the baseline visit value 
requires repeat testing. 
If, at the repeat test, the eGFR decrease is still > 50% of 
the baseline visit value, the treatment with alectinib should 
be interrupted. 
• 
Alectinib treatment may be resumed with caution if the eGFR 
value has increased to approximately the baseline visit value. 
Severe myalgia and CPK 
elevations 
CPK laboratory abnormalities are to be reported as AEs only if 
fulfilling the criteria listed in Section 5.3.5.4. 
• 
Myopathy should be considered in any patient with diffuse 
myalgia, muscle tenderness or weakness, and/or marked 
elevations of CPK levels.  Patients should promptly report 
unexplained muscle pain, tenderness, or weakness, 
particularly if accompanied by malaise or fever.  CPK levels 
should be assessed in patients reporting these symptoms. 
• 
At the first occurrence of any of asymptomatic CPK values 
(> 10 × ULN, symptomatic CPK > 5 × ULN, or in the presence of 
severe muscular symptoms with CPK > ULN but  ≤ 5 × ULN) at 
any time during the study treatment, the patient requires 
monitoring of the CPK values until they are normalized to 
pre-treatment levels or a reasonable explanation for the CPK 
elevation and the symptoms is established. 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
Other AEs (including 
bradycardia, anemia, and 
CPK elevation) or 
laboratory abnormalities: 
• 
Grade 3 or 4: 
Temporarily interrupt alectinib for a maximum of 3 weeks. 
If improvement to Grade ≤ 1 or baseline does not occur 
within 3 weeks, permanently discontinue alectinib. 
First episode:  If improvement to Grade ≤ 1 or baseline 
within 21 days, decrease the current dose of alectinib by 
150 mg (1 capsule) BID (450 mg BID).  
Second episode:  If improvement to Grade ≤ 1 or baseline 
within 21 days, decrease the current dose of alectinib by 
another 150 mg (1 capsule) BID (300 mg BID). 
Third episode:  Permanently discontinue alectinib. 
• 
Grade 2 (except any symptoms and signs that can be 
corrected with supportive care): 
Temporarily interrupt alectinib and resume if recovering to 
Grade ≤ 1 or baseline if clinically indicated. 
First episode:  If improvement to Grade ≤ 1 or baseline 
within 10 days, continue same dose of alectinib.  If 
improvement occurs after 10 days, decrease the current 
dose of alectinib by 150 mg (1 capsule) BID when 
resuming treatment (450 mg BID). 
Second episode:  If improvement to Grade ≤ 1 or baseline 
within 10 days, decrease the current dose of alectinib by 
150 mg (1 capsule) BID (450 mg BID or 300 mg BID if 
after first episode dose was reduced to 450 mg BID).  If 
improvement occurs after 10 days, decrease the current 
dose of alectinib by 300 mg (2 capsules) when resuming 
treatment (300 mg BID or 150 mg BID if after first episode 
dose was reduced to 450 mg BID). 
Third episode:  Permanently discontinue alectinib. 
• 
Grade 1:  no action required 
ANC = absolute neutrophil count; eGFR = estimated glomerular filtration rate.  
Note:  Diarrhea, nausea, and vomiting should be handled with best supportive care first before 
considering dose modification.  Preexisting pleural effusion will not be considered as an adverse 
event. 
 
5.1.4 
Safety of Crizotinib and Management of Adverse Events  
Dosing interruption and/or dose reduction may be required on the basis of individual 
safety and tolerability.  If dose reduction is necessary, then the dose of crizotinib should 
be reduced to 200 mg taken BID.  If further dose reduction is necessary, then the dose 
should be modified to 250 mg taken once daily on the basis of individual safety and 
tolerability (XALKORI® U.S. Package Insert; Crizotinib SmPC).  Dose reduction 
guidelines for hematologic and non-hematologic toxicities are provided in Table 3 and 
Table 4. 


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Table 3 
Crizotinib Dose Modification⎯Hematologic Toxicities (Except 
Lymphopenia) 
CTCAEa Grade 
Crizotinib Dosing 
Grade 3 
Withhold until recovery to Grade ≤ 2, then resume at 
the same dose schedule 
Grade 4 
Withhold until recovery to Grade ≤ 2, then resume at 
200 mg twice dailyb 
a National Cancer Institute Common Terminology Criteria for Adverse Events 
b In case of second episode, dosing should be withheld until recovery to Grade ≤ 2, then dosing 
should be resumed at 250 mg once daily.  Crizotinib must be permanently discontinued in case 
of a third episode of Grade 4 hematologic toxicity. 
 


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Table 4 
Crizotinib Dose Modification⎯Non-Hematologic Toxicities 
Criteria 
Crizotinib Dosing 
ALT or AST elevation  > 5 × ULN with total 
bilirubin  ≤ 1.5 × ULN 
Withhold until recovery to baseline or 
≤ 3 × ULN, then resume at reduced dose.  
Crizotinib must be permanently discontinued in 
case of recurrence. 
ALT or AST elevation > 3 × ULN with 
concurrent total bilirubin elevation  > 1.5 × ULN 
(in the absence of cholestasis or hemolysis) 
Permanently discontinue 
Any grade drug-related ILD/pneumonitis 
Permanently discontinue 
QTc > 500 ms on at least 2 separate ECGs 
Withhold until recovery to baseline or < 481 ms, 
then resume at reduced dose.  Crizotinib must 
be permanently discontinued in case of 
recurrence (i.e., QTc > 500 ms on at least 
2 separate ECGs). 
QTc > 500 ms or ≥ 60 ms change from baseline 
with torsade de pointes or polymorphic 
ventricular tachycardia or signs/symptoms of 
serious arrhythmia 
Permanently discontinue 
Bradycardia (heart rate < 60 bpm, symptomatic, 
may be severe and medically significant, 
medical intervention indicated) 
Withhold until recovery to asymptomatic 
bradycardia or to a heart rate ≥ 60 bpm.  
Evaluate concomitant medications known to 
cause bradycardia, as well as anti-hypertensive 
medications.  If a contributing concomitant 
medication is identified and discontinued, or its 
dose is adjusted, resume crizotinib at previous 
dose upon recovery to asymptomatic 
bradycardia or to a heart rate ≥ 60 bpm. 
If no contributing concomitant medication is 
identified, or if contributing concomitant 
medication is identified but not discontinued or 
its dose was not modified, resume crizotinib at 
reduced dose upon recovery to asymptomatic 
bradycardia or to a heart rate of ≥ 60 bpm. 
Bradycardia (heart rate < 60 bpm, 
life-threatening consequences, urgent 
intervention indicated) 
Permanently discontinue if no contributing 
concomitant medication is identified. 
If contributing concomitant medication is 
identified and discontinued, or its dose is 
adjusted, resume at 250 mg once daily upon 
recovery to asymptomatic bradycardia or to a 
heart rate of ≥ 60 bpm, with frequent 
monitoring.  
Crizotinib must be permanently discontinued in 
case of recurrence. 
 
Gastrointestinal events were commonly reported with crizotinib in clinical trials.  Nausea, 
diarrhea, vomiting, and constipation were the most commonly reported gastrointestinal 


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events and were primarily Grade 1 in severity.  Supportive care for gastrointestinal 
events may include standard antiemetic and/or antidiarrheal or laxative medicinal 
products.  In clinical studies with crizotinib, events of gastrointestinal perforations were 
reported (XALKORI® U.S. Package Insert; Crizotinib SmPC). 
Blood counts and liver function tests including ALT, AST, and total bilirubin should be 
monitored as per local prescribing information for crizotinib. 
See local prescribing information for further crizotinib safety information. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
non-SAEs of special interest, performing protocol-specified safety laboratory 
assessments, measuring protocol-specified vital signs, and conducting other 
protocol-specified tests that are deemed critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical occurrence in a clinical investigation where a patient is administered a 
pharmaceutical product, regardless of causal attribution.  An AE can therefore be any of 
the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition). 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as 
biopsies) 
 


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5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
An SAE is any AE that meets any of the following criteria: 
• 
Is fatal (i.e., the AE actually causes or leads to death) 
• 
Is life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death) 
This does not include any AE that had it occurred in a more severe form or was 
allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an AE (e.g., rated as mild, moderate, or severe, or according to National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] criteria; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF. 
SAEs are required to be reported by the investigator to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2 for reporting 
instructions). 
5.2.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-SAEs of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2 for reporting instructions).  AEs of special interest for this study are the 
following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.6) 


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• 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs (see Section 5.2.1 for definition) 
are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Sections 5.4−5.6.  For each AE recorded 
on the Adverse Event eCRF, the investigator will make an assessment of seriousness 
(see Section 5.2.2 for seriousness criteria), severity (see Section 5.3.3), and causality 
(see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on AEs at each patient contact.  All AEs, whether 
reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
SAEs caused by a protocol-mandated intervention (e.g., invasive procedures such as 
biopsies, discontinuation of medications) should be reported (see Section 5.4.2 for 
instructions for reporting SAEs). 
After initiation of study drug, all AEs will be reported until 4 weeks after the last dose 
of study drug.  After this period, the investigator should report any SAEs that are 
believed to be related to study drug treatment (see Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient evaluation timepoints.  Examples of non-directive questions 
include the following: 
• 
"How have you felt since your last clinic visit?" 
• 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The AE severity grading scale for the NCI CTCAE (v4.0) will be used for assessing AE 
severity.  Table 5 will be used for assessing severity for AEs that are not specifically 
listed in the NCI CTCAE. 


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Table 5 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in the NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  On the basis of the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
AE is considered to be related to the study drug, indicating "yes" or "no" accordingly.  
The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 


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5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology and concepts when recording AEs 
on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 
5.3.5.1 
Diagnosis Versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported AEs based on 
signs and symptoms should be nullified and replaced by one AE report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events that are Secondary to Other Events 
In general, AEs that are secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events.  A medically significant secondary AE that is separated in 
time from the initiating event should be recorded as an independent event on the 
Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation timepoints.  Such events should only be recorded once on the Adverse Event 
eCRF.  The initial severity (intensity or grade) of the event will be recorded at the time 
the event is first reported.  If a persistent AE becomes more severe, the most extreme 
severity should also be recorded on the Adverse Event eCRF.  If the event becomes 


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serious, it should be reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 
to "serious," providing the date that the event became serious, and completing all data 
fields related to SAEs. 
A recurrent AE is one that resolves between patient evaluation timepoints and 
subsequently recurs.  Each recurrence of an AE should be recorded as a separate event 
on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE.  A laboratory test result must be 
reported as an AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
Note: For oncology trials, certain abnormal values may not qualify as AEs. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5 times the ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the AE.  For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent AEs).  


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5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported 
as an AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment 
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded one on the Adverse Event eCRF (see Section 5.3.5.3 for details 
on recording persistent adverse events). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an AE the occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as an SAE or a non-SAE of special interest (see Section 5.4.2). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified AE reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of NSCLC should be recorded only on the Study 
Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and 


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immediately reported to the Sponsor (see Section 5.4.2).  An independent monitoring 
committee will monitor the frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. 
During survival follow-up, deaths attributed to progression of NSCLC should be recorded 
only on the Survival eCRF. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such 
events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., "more 
frequent headaches"). 
5.3.5.9 
Lack of Efficacy or Worsening of Non-Small Cell Lung Cancer 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs.  These data will be captured as 
efficacy assessment data only.  In most cases, the expected pattern of progression will 
be based on RECIST criteria v1.1 (Appendix 4).  In rare cases, the determination of 
clinical progression will be based on symptomatic deterioration.  However, every effort 
should be made to document progression using objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an AE. 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization (i.e., in-patient admission to a hospital) or 
prolonged hospitalization should be documented and reported as an SAE (per the 
definition of SAE in Section 5.2.2), except as outlined below. 


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The following hospitalization scenarios are not considered to be AEs: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
The patient has not experienced an AE. 
• 
Hospitalization due solely to progression of the underlying cancer 
 
5.3.5.11 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an AE, but it may result in an AE.  All AEs associated with an overdose or incorrect 
administration of study drug should be recorded on the Adverse Event eCRF.  If the 
associated AE fulfills seriousness criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.3.5.12 
Patient-Reported Outcome Data 
AE reports will not be derived from PRO data by the Sponsor, and safety analyses will 
not be performed using PRO data.  However, if any PRO responses suggestive of a 
possible AE are identified during site review of the PRO data, the investigator will 
determine whether the criteria for an AE have been met and, if so, will report the event 
on the Adverse Event eCRF. 
5.3.5.13 
Adverse Events in Individuals Not Enrolled in the Study 
If an AE inadvertently occurs in an individual not enrolled in the study, the Adverse Event 
Form provided to investigators should be completed and submitted to Roche or its 
designee, either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
SAEs 


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• 
Non-SAEs of special interest 
• 
Pregnancies 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting SAEs to the local 
health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor (Roche Medical Responsible) Contact Information 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk as 
well as Medical Monitor contact information will be distributed to all investigators. 
This list can be generated using contact numbers found at the following link: 
http://gcpcenter.roche.com/synergy/portal/view/pdq-spi/gcpcenter/34-64711453. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
5.4.2.1 
Events That Occur Prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported.  The Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to Roche or its designee immediately (i.e., no more than 
24 hours after learning of the event), either by faxing or by scanning and emailing the 
form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur After Study Drug Initiation 
After initiation of study drug, SAEs and non-SAEs of special interest will be reported until 
4 weeks after the last dose of study drug.  Investigators should record all case details 
that can be gathered immediately (i.e., within 24 hours after learning of the event) on the 
Adverse Event eCRF and submit the report via the electronic data capture (EDC) system.  


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A report will be generated and sent to Roche Safety Risk Management by the EDC 
system. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to Roche or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system. 
Instructions for reporting post-study AEs are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 3 months after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Roche Safety Risk Management.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any SAEs associated 
with the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF. 
In the event that the EDC system is unavailable, the Clinical Trial Pregnancy Reporting 
Form provided to investigators should be completed and submitted to Roche or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Once the EDC system is available, all information will 
need to be entered and submitted via the EDC system. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
3 months after the last dose of study drug.  A Pregnancy Report eCRF should be 
completed by the investigator immediately (i.e., no more than 24 hours after learning of 
the pregnancy) and submitted via the EDC system.  Attempts should be made to collect 
and report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  The pregnant partner will need to sign an Authorization 
for Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy.  Once the authorization has been signed, the investigator will update the 


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Pregnancy Report eCRF with additional information on the course and outcome of the 
pregnancy.  An investigator who is contacted by the male patient or his pregnant partner 
may provide information on the risks of the pregnancy and the possible effects on the 
fetus, to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 
5.4.3.3 
Abortions 
Any abortion should be classified as an SAE (as the Sponsor considers abortions to be 
medically significant), recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2). 
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as an SAE, recorded on the Adverse Event eCRF, and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or 
the patient withdraws consent.  Every effort should be made to follow all SAEs considered 
to be related to study drug or trial-related procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.5.2 
Sponsor Follow-Up 
For SAEs, non-SAEs of special interest, and pregnancies, the Sponsor or a designee 
may follow up by telephone, fax, electronic mail, and/or a monitoring visit to obtain 
additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 


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5.6 
POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the investigator becomes aware of any SAE that 
occurs after the end of the AE reporting period (defined as 4 weeks after the last dose of 
study drug), if the event is believed to be related to study drug treatment.  
The investigator should report these events directly to Roche or its designee, either by 
faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all SAEs and non-SAEs of special interest against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators, IRBs, ECs, and applicable health authorities based on 
applicable legislation. 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference documents: 
• 
Alectinib Investigator's Brochure 
• 
Local prescribing information for crizotinib 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The primary analysis population for efficacy is the intent-to-treat (ITT) population defined 
as all randomized patients.  Patients will be assigned to the treatment group to which 
they were randomized. 
The primary analysis population for safety is the Safety Analysis Population (SAP) 
defined as all patients who received at least one dose of study medication.  Patients will 
be assigned to treatment groups as treated, and all patients who received any dose of 
alectinib will be included in the alectinib treatment arm. 
A secondary analysis population for efficacy is the FISH Positive Population (FPP).  This 
is defined as all patients in the ITT population who were ALK-positive using the Vysis 
FISH assay.  Patients will be assigned to the treatment group to which they were 


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randomized.  This analysis population will be used to perform a supportive analysis of 
the study data based on the Vysis FISH assay. 
An analysis of the primary endpoint of investigator-assessed PFS based on the FPP will 
be performed at the time of the primary analysis.  A major discrepancy between the 
Ventana IHC assay and the Vysis FISH assay may necessitate a follow-up analysis of 
the primary endpoint based on 170 PFS events observed in the FPP to ensure 80% 
power of the log-rank test under the assumption of a hazard ratio of 0.65 in this 
secondary population. 
The final analysis of the primary endpoint of PFS will occur when 170 PFS events have 
occurred, on the basis of the investigators’ assessments.  On the basis of the 
assumptions outlined in Section 6.1, this is estimated to occur approximately 33 months 
after the first patient has been enrolled.  A survival follow-up analysis will be performed 
once approximately 50% of patients (i.e., 143 patients) have died, which is estimated to 
occur approximately 42 months after the first patient has been enrolled. 
Hypothesis tests will be two-sided with a significance level of 5% unless otherwise 
indicated. 
The baseline value of any variable will be defined as the last available value recorded 
prior to the first administration of alectinib or crizotinib. 
Further details of all analyses will be provided in the Statistical Analysis Plan. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The focus of this clinical trial is hypothesis testing (Section 6.4.1), and the primary 
endpoint of PFS was used to determine the sample size of the study. 
At the time of initially writing the protocol, there were no Phase III data available on 
crizotinib in the first-line setting in ALK-positive patients.  The median PFS for crizotinib 
administered as second-line therapy from the global randomized Phase III PROFILE 
1007 study was 7.7 months (95% CI: 6.0%, 8.8%).  From the Phase II single arm study 
of patients who had received ≥ 1 line of chemotherapy (with 85% patients having 
received ≥ 2 prior chemotherapy regimens), the median PFS was 8.5 months 
(95% CI: 6.2%, 9.9%).  The Phase III PROFILE 1014 study of crizotinib versus standard 
pemetrexed-platinum-based chemotherapy in previously untreated patients with 
ALK-positive non-squamous NSCLC reported a median PFS of 10.9 months for 
crizotinib (Mok et al. 2014). 
Thus, an initial assumption of median PFS of 9.8 months for the crizotinib arm has been 
reassessed based on data from the Phase III study PROFILE 1014 to 10.9 months.  An 
HR of 0.65 for alectinib versus crizotinib (i.e., an increase from 10.9 months median PFS 
to 16.8 months) will be targeted. 


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In this study, 286 patients will be enrolled in a 1:1 randomization allocation.  Enrollment 
will take approximately 24 months on the basis of an assumption of non-linear 
recruitment as follows: 
• 
Month 1:  1 patient per month 
• 
Month 2:  2 patients per month 
• 
Month 3:  4 patients per month 
• 
Month 4:  6 patients per month 
• 
Month 5:  8 patients per month 
• 
Month 6:  10 patients per month 
• 
Month 7:  12 patients per month 
• 
Months 8−12:  13 patients per month 
• 
Months 13−14:  14 patients per month 
• 
Month 15 onwards:  15 patients per month 
 
A total of 170 PFS events are required to achieve 80% power at a two-sided alpha level 
of 5%.  This number of PFS events is estimated to occur approximately 33 months after 
the first patient has been enrolled. 
No interim analysis for efficacy or futility is planned. 
A survival follow-up analysis will be performed once approximately 50% of patients 
(i.e., 143 patients) have died.  The median OS in the crizotinib arm is assumed to be 
24 months, and the expected median OS in the alectinib treatment arm is 30 months, 
equating to an HR of 0.83.  On the basis of the sample size (N = 286), the trial will not be 
powered to demonstrate any statistically significant difference in OS of this magnitude.  
At the time of the final analysis of the primary endpoint of PFS, on the basis of the above 
assumptions, 106 OS events are expected to have occurred.  The survival follow-up 
analysis is expected to occur approximately 42 months after the first patient has been 
enrolled. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Study enrollment, study treatment administration, reasons for discontinuation from study 
treatment, and reasons for study termination will be summarized by treatment arm for all 
randomized patients.  Violations of inclusion and exclusion criteria, on the basis of 
information captured on the eCRF, will be reported and summarized by treatment arm. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Summaries of treatment group comparability will be based on the ITT population. 
Demographic, baseline disease characteristics and lung cancer history will be 
summarized by treatment arm for all randomized patients, including the randomization 


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stratification factors.  Descriptive baseline summaries of continuous data will present the 
group mean, standard deviation, median, minimum, and maximum.  Descriptive 
summaries of discrete data will present the category counts as frequency and 
percentages. 
Previous and concomitant cancer therapy will also be summarized, as well as 
anti-cancer subsequent therapy.  Previous and concurrent diseases and medications will 
also be summarized. 
6.4 
EFFICACY ANALYSES 
The primary population for all primary and secondary efficacy analyses will be the ITT 
population. 
6.4.1 
Primary Efficacy Endpoint 
PFS is defined as the time from date of randomization to the date of first documented 
disease progression or death, whichever occurs first.  The primary endpoint of PFS will 
be determined on the basis of investigator assessment of progression using 
RECIST v1.1.  Patients who have not experienced disease progression or death at the 
time of analysis will be censored at the last tumor assessment date either during study 
treatment or during follow-up.  Patients with no post-baseline tumor assessment will be 
censored at the date of randomization. 
Patients who discontinue treatment prior to disease progression (e.g., due to toxicity) will 
continue on study and will be followed until disease progression and for OS regardless 
of whether they subsequently receive anti-cancer therapy. 
The treatment comparison of PFS will be based on a stratified log-rank test at the 5% 
level of significance (two-sided).  The stratification factors are the randomization 
stratification factors:  ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS 
metastases at baseline (yes vs. no), as recorded on the eCRF.  Results from an 
unstratified log-rank test will also be presented. 
The Kaplan-Meier method will be used to estimate the median PFS for each treatment 
arm with 95% confidence limits, and a Kaplan-Meier curve will be constructed to provide 
a visual description of the difference between the treatment arms.  A stratified Cox 
proportional regression model will be used including treatment in order to provide an 
estimate of the treatment effect expressed as an HR (alectinib vs. crizotinib), as well as 
a 95% CI. 


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The difference between the two treatment groups will be assessed and tested for the 
following hypothesis:  the survival distribution function (SDF) of the alectinib treatment 
group is the same as for the crizotinib treatment group versus the alternative that the two 
distributions are different:  
H0:  SDF (alectinib) = SDF (crizotinib) 
versus 
H1:  SDF (alectinib) ≠ SDF (crizotinib) 
where SDF denotes the survival distribution function of the parameter PFS. 
6.4.2 
Secondary Efficacy Endpoints 
If the primary endpoint of PFS is statistically significant at a two-sided 5% significance 
level, the following secondary endpoints will be tested in the following sequential order, 
each at a two-sided 5% significance level: 
• 
PFS by IRC 
• 
Time to CNS progression 
• 
ORR 
• 
OS 
 
PFS by IRC 
An analysis of PFS on the basis of the IRC assessments will be performed using the 
same methodology as specified for PFS on the basis of investigator assessment. 
Time to CNS Progression 
Time to CNS progression is defined as the time from randomization until radiographic 
evidence of CNS progression.  An independent central radiological review will be 
performed for all patients, and the analysis of CNS progression or response will be on 
the basis of the data from the independent review.  All patients will be included in the 
analysis regardless of their baseline status of CNS metastases.  CNS progression is 
defined as progression due to newly developed CNS lesions and/or progression of 
preexisting baseline CNS lesions.  On the basis of RECIST v1.1, this is defined as a new 
post-baseline CNS/brain lesion(s) and/or an increase of ≥ 20% in the sum of longest 
diameters of the measurable baseline CNS lesions compared to nadir and/or 
unequivocal progression of non-measurable baseline CNS lesions. 
In order to account for the competing risks inherent in such an analysis, HRs, including 
statistical inference on the basis of a two-sided log-rank test, to compare the risk of CNS 
progression between the alectinib and crizotinib treatment groups, will be computed on 
the basis of cause-specific hazard functions. 
The probability of CNS progression, non-CNS progression, and death will each be 
estimated using cumulative incidence functions. 


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For descriptive purposes, estimates of the CNS progression rates over time with 
95% CIs on the basis of cumulative incidence functions will be presented.  A Gray’s test 
to compare the risk of CNS progression between alectinib and crizotinib will also be 
performed as a supportive analysis. 
An exploratory analysis of CNS Time to Progression on the basis of RANO criteria will 
also be performed on the basis of the IRC assessments. 
In the subgroup of patients with measurable CNS lesions at baseline, an exploratory 
analysis of C-ORR defined as the percentage of patients who achieve a best overall 
response of CR or PR (defined by RECIST v1.1 as a 30% decrease in the sum of 
longest diameters of measurable CNS lesions referencing baseline) will also be 
performed.  Duration of CNS response will be listed and may be analyzed if there are a 
sufficient number of CNS responses.  Similar analyses will be performed in the subgroup 
of patients with measurable and/or non-measurable CNS lesions at baseline.  An 
exploratory analysis of these endpoints will also be performed on the basis of RANO 
criteria assessed by the IRC. 
Objective Response Rate 
ORR, on the basis of investigator assessment, is defined as the percentage of patients 
who attain a CR or PR.  Per RECIST v1.1, confirmation of objective response is not 
required for this secondary endpoint.  Patients without a post-baseline tumor 
assessment will be considered non-responders, as will patients with a best overall 
response of stable disease (SD), PD, or NE (not evaluable). 
An estimate of ORR and its two-sided 95% CI will be calculated using the 
Clopper-Pearson method for each treatment arm.  Response rates in the treatment 
groups will be compared using a stratified Mantel-Haenszel test on the basis of the 
randomization stratification factors.  The difference in ORR between the two treatment 
arms will be presented together with a two-sided 95% CI on the basis of a normal 
approximation to the binomial distribution. 
DOR 
For patients who have experienced an objective response (CR or PR) during the study 
as assessed by the investigator, DOR is defined as the duration from the first tumor 
assessment that supports the patient’s objective response (CR or PR, whichever is first 
recorded) to first documented disease progression or death due to any causes, 
whichever occurred first.  Patients who have not progressed or died at the time of 
analysis will be censored at the last tumor assessment date.  Because the determination 
of DOR is based on a non-randomized subset of patients, formal hypothesis testing will 
not be performed.  DOR will be estimated using Kaplan-Meier methodology and an HR 
on the basis of a Cox proportional regression model will be calculated. 


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Overall Survival 
OS is defined as the time from the date of randomization to the date of death due to any 
cause.  Patients who are not reported as having died at the time of analysis will be 
censored at the date when they were last known to be alive.  Patients who do not have 
post-baseline information will be censored at the date of randomization.  OS will be 
analyzed using the same methodology as specified for the primary endpoint.  A survival 
follow-up will be performed based on more mature data. 
6.4.2.1 
Sensitivity Analyses 
The following sensitivity analyses will be performed on the primary endpoint of PFS: 
• 
The effect of non−protocol-specified anti-cancer therapy prior to progression will be 
assessed by censoring patients at the last adequate tumor assessment prior to the 
start of non−protocol-specified anti-cancer therapy. 
• 
The effect of missing tumor assessments will be assessed if the number of missing 
assessments in either arm is > 5%.  For patients with progression determined 
following one or more missing tumor assessments, the progression will be 
backdated to the first missing tumor assessment. 
• 
The effect of loss to follow-up will be assessed depending on the number of patients 
who are lost to follow-up.  If > 5% of patients are lost to follow-up for PFS in either 
treatment arm, a “worst-case” analysis will be performed in which patients who are 
lost to follow-up will be considered to have progressed at the last date they were 
known to be progression-free. 
 
6.4.2.2 
Subgroup Analyses 
Subgroup analyses of PFS will be performed for patients with baseline CNS metastases 
and for patients without baseline CNS metastases.  In addition, a subgroup analysis of 
Time to CNS Progression will be performed, excluding patients who had pre-treatment 
radiation therapy for CNS lesions. 
All other subgroup analyses will be specified in the SAP. 
6.5 
SAFETY ANALYSES 
The primary population for all safety analyses will be the SAP as defined in Section 6. 
All safety parameters will be summarized in tables to evaluate and compare the safety 
profile of patients treated with alectinib versus crizotinib in terms of: 
• 
Adverse events including adverse events leading to dose modifications or 
interruptions, study drug withdrawal, and death  
• 
Severe, serious, and selected adverse events 
• 
Deaths 
• 
Laboratory parameters and abnormalities 
• 
Vital signs 


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• 
ECGs 
• 
ECOG PS 
 
Adverse events will be coded using MedDRA and summarized by mapped term and 
appropriate thesaurus level.  All adverse events and routine laboratory parameters will 
be assessed according to the NCI CTCAE v4.0 grading system.  For adverse events, the 
most extreme severity will be used for reporting.  Adverse events will be described by 
individual listings and by body system, as well as by severity.  In tables showing the 
overall incidence of adverse events, patients who experienced the same event on more 
than one occasion are counted only once in the calculation of the event frequency. 
Laboratory values will be summarized by treatment arm including summary tables for the 
shifts in grades from baseline to the worst grade observed during treatment.  In order to 
evaluate and compare hypogonadism in the two treatment arms, testosterone levels in 
the blood will be summarized for males by treatment arm over time (for details, 
see Section 6.8). 
Descriptive summary tables of change from baseline over time will be provided for vital 
signs and descriptive statistics will be tabulated for ECOG PS.  ECG findings over time 
will be summarized. 
Study drug administration will be summarized by duration and cumulative dose.  In 
addition, treatment exposure will be summarized including the number of doses received, 
dose intensity, and the percentage of planned dose. 
Subgroup analyses will be performed to evaluate the safety profile within the subgroups 
of patients including by sex, age (< 65 vs. ≥ 65 years), and race (non-Asian vs. Asian). 
An iDMC will review the safety data collected during the conduct of the study.  Safety 
monitoring will be performed periodically.  Further details will be outlined in the iDMC 
Charter. 
6.6 
PHARMACOKINETIC ANALYSES 
Standard NCA may be conducted for PK data collected from patients participating in 
serial/intensive PK collections for relevant analytes, as data allow, as appropriate, and if 
needed.  PK parameters, including but not limited to AUC, Cmax, and time to maximum 
concentration (Tmax), will be calculated on the basis of the available data as appropriate 
and where data allow.  Additional PK parameters may be calculated as deemed 
appropriate. 
Individual and mean plasma concentrations at each sampling timepoint and/or PK 
parameters for alectinib and metabolite(s) will be listed, as appropriate. 


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Summary statistics (e.g., means, standard deviation, coefficient of variation %, 
geometric means, medians and ranges) for plasma concentrations and/or PK 
parameters for alectinib and metabolite(s) will be presented by treatment and nominal 
collection times (plasma concentrations only), as appropriate.  Additional plots or 
summary statistics may be constructed or calculated, as appropriate. 
Results of PK and/or any PK/pharmacodynamic analyses may be reported outside the 
clinical study report. 
Nonlinear mixed-effects modeling (with software NONMEM) (Beal et al. 1999) will be 
used to analyze the sparse and/or serial/intensive plasma concentration-time data for 
alectinib.  The PK data from this study may be pooled with data from other studies.  
Population and individual PK parameters will be estimated and the influence of various 
covariates (such as age, gender, and body weight) on these parameters will be 
investigated. 
Exploratory analyses will be conducted to investigate the relationship between alectinib 
PK exposure and efficacy/safety parameters. 
Details of the mixed-effects modeling and exploratory analyses will be reported in a 
document separate from the clinical study report. 
6.7 
PATIENT-REPORTED OUTCOME ANALYSES 
The following PRO endpoints will be analyzed and PRO data will be presented 
separately from adverse event data. 
6.7.1 
Time to Deterioration of Patient-Reported Lung Cancer 
Symptoms 
TTD from baseline will be assessed at every study visit (Week 4, Week 8, and then after 
every 4 weeks) until disease progression and during post-progression on treatment in 
case of isolated, asymptomatic CNS progression; at post-treatment Visit (4 weeks after 
permanent treatment discontinuation); and at subsequent 8-weekly survival follow-up 
visits for 6 months, for the following lung cancer symptoms: cough (Question 31 on the 
QLQ-LC13), dyspnea single item (Question 8 on the QLQ-C30), dyspnea multi-item 
subscale (Questions 33-35 on the QLQ-LC13), chest pain (Question 40 on the 
QLQ-LC13), arm/shoulder pain (Question 41 on the QLQ-LC13) and fatigue multi-item 
subscale (Questions 10, 12, and 18 on the QLQ-C30) for patients in each arm.  
Completion and compliance rates will be summarized at each timepoint by treatment 
arm with reasons for missing data.  TTD will be analyzed for the ITT population.  If a 
baseline or post-baseline PRO evaluation is not available, TTD will be censored at the 
date of randomization. If they have not deteriorated, patients will be censored at the last 
time when they completed an assessment for cough, dyspnea (single item), dyspnea 
(subscale items), chest pain, arm/shoulder pain, and fatigue. 


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6.7.2 
Additional Patient-Reported Outcomes 
PROs of HRQoL, lung cancer−related symptoms, and health status will be measured 
using the EORTC QLQ-C30 and EORTC QLQ-LC13. 
Summary statistics (mean, standard deviation, median, and range) of linear transformed 
scores will be reported for all the items and subscales of the EORTC 
QLQ-C30 questionnaire, and the QLQ-LC13 according to the EORTC scoring manual 
guidelines.  Completion and compliance rates will be summarized at each timepoint by 
treatment arm with reasons for missing data.  Only patients with a baseline assessment 
and at least one post-treatment assessment will be included in the analyses. 
6.8 
EXPLORATORY ANALYSES 
The EQ-5D-3L is a generic PRO instrument that is used for across diseases and 
indications cost-effectiveness analyses.  This instrument quantifies the QoL of various 
health outcomes and is applicable to a wide range of health states.  Analyses of this 
outcome will be exploratory and will generate utility scores for use in economic models 
for reimbursement purposes only.  The PRO will be administered every 4 weeks until 
disease progression and during post-progression on treatment in case of isolated, 
asymptomatic CNS progression; at the post-treatment visit (4 weeks after permanent 
treatment discontinuation); and every follow-up visit (every 8 weeks) after post-treatment 
visit for 6 months (see Appendix 1).  
It has been reported that crizotinib therapy triggers rapid suppression of testosterone 
levels in men causing rapid-onset hypogonadism.  It is unknown if reductions in 
testosterone reflect an effect of crizotinib on ALK or on some combination of the drug’s 
targets (i.e., c-MET) (Weickhardt et al. 2012; Weickhardt et al. 2013).  Total testosterone 
and free testosterone levels (either by direct measurement or by calculation using 
albumin and sex hormone-binding globulin [SHBG] calculator:  
http://www.issam.ch/freetesto.htm) and FSH and LH levels in blood will be measured 
(see Appendix 1) in male patients enrolled in the study for exploratory analysis of an 
onset of hypogonadism.  The recommended time of day to have a blood sample taken 
for this test is between 7 a.m. and 10 a.m. 
The Abbott Vysis FISH test will be used as an exploratory assay after patients have 
been enrolled in this study.  Results from these analyses will be used to quantify the 
degree of correlation between Vysis FISH and Ventana IHC for the detection of 
ALK-positive NSCLC. 
ALK plasma assays (PCR and/or sequencing) will be used as exploratory assays for 
ALK positive and consented ALK negative patients.  Results from these analyses will be 
used to quantify the degree of correlation between ALK plasma tests and Ventana IHC 
and Vysis FISH for the detection of ALK positive NSCLC.  The ALK plasma assay 
population may be used for exploratory efficacy and safety analysis.  This analysis 
population will be used to support diagnostic development.  Assays from this population 


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may be used for the registration of a plasma assay as a companion diagnostic. This 
analysis will be dependent on the successful technical development of a plasma ALK 
assay.  Results of analyses related to those alternative diagnostic tests and exploratory 
analyses on post-progression tumor samples to measure molecular mechanisms of 
resistance to ALK inhibitors and plasma samples to measure ALK rearrangements in 
circulating tumor cells will be communicated outside the main clinical study report. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC using eCRFs.  
Sites will be responsible for data entry into the EDC system.  In the event of discrepant 
data, the Sponsor will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data. Central laboratory data or other electronic 
data will be sent directly to the Sponsor, using the Sponsor’s standard procedures to 
handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
ePRO data will be collected through use of an electronic device provided by an ePRO 
vendor.  The device is designed for entry of data in a way that is attributable, secure, 
and accurate, in compliance with the FDA regulations for electronic records (21 CFR 
Part 11).  The ePRO device data are available for view access only via secure access to 
a web server.  Only identified and trained users may view the data, and their actions 
become part of the audit trail.  The Sponsor will have view access only.  System 
backups for data stored by the Sponsor and records retention for the study data will be 
consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 


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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
Patients will use an ePRO device to capture PRO data.  The data will be transmitted via 
pre-specified transmission method (e.g., web or wireless) automatically after entry to a 
centralized database at the ePRO vendor.  The data can be reviewed by site staff via 
secure access to a web server. 
Once the study is complete, the ePRO data, audit trail, and trial and system 
documentation will be archived.  The investigator will receive patient data for the site in 
both human- and machine-readable formats on an archival-quality compact disc that 
must be kept with the study records as source data.  Acknowledgement of receipt of the 
compact disc is required. In addition, the Sponsor will receive all patient data in a 
machine-readable format on a compact disc. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 


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7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a United States 
IND application will comply with FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the European Union or European Economic Area will comply 
with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 


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submission.  The final IRB/EC−approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient before his or her 
participation in the study.  The case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC−approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 


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8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  In 
addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 


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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, which includes an audit trail containing a complete record of all changes 
to data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
Steering Committee is established to provide the study Sponsor with recommendations 
related to any aspect of the trial, specifically study design, data interpretation, 
exploratory analyses, or alternate changes to the trial that may assist in patient accrual, 
data collection, analysis, and interpretation of the study results.  The Sponsor is 
ultimately responsible for all decisions regarding the study. 
The test for the study inclusion criteria of ALK-positive NSCLC will be performed at 
Sponsor’s designated central laboratories and assessed by Ventana IHC test. 
An iDMC will be established to monitor the progress of the study and ensure that the 
safety of patients enrolled in the study is not compromised.  Details of the composition, 
roles, and responsibilities, and processes of the iDMC are documented in a separate 
iDMC charter.  The iDMC will review safety data and can make recommendations to the 
Sponsor to stop or amend the study on the basis of safety findings.  The frequency of 
these reviews as well as the data to be reviewed will be agreed with the iDMC and 
outlined in the separate iDMC charter.  No stopping for early proof of efficacy will result 
from any of these regular safety reviews.  iDMC review meetings will be held in a blinded 
manner to the Sponsor. 


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An IRC will review the tumor assessments to determine the secondary endpoints of the 
overall disease PFS and time to CNS progression, both on the basis of RECIST v1.1.  In 
addition to the secondary endpoint of time to CNS progression together with C-ORR, 
C-DOR, and CNS progression rate at 6, 12, 18, and 24 months, an IRC will review the 
tumor assessments on the basis of RANO criteria. 
The independent review of MRI and CT scans will NOT determine either eligibility OR 
patient treatment.  All treatment decisions will be made by the investigator using local 
assessments. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 


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Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


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Appendix 1  
Schedule of Assessments 
Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) 
Until PD, 
Death, or 
Withdrawal 
from Study 
prior to PD a 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
 
 
 
 
 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation)a 
 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D) a 
Informed consent 
x 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
Pregnancy test b 
 
x 
To be repeated as necessary 
 
 
 
Physical 
examination c 
x 
 
x 
x 
x 
x 
x 
 
 
Vital signs 
x 
 
x 
x 
x 
x 
x 
 
 
ECOG PS 
x 
 
x 
x 
x 
x 
x 
 
 
ECG d 
x 
 
x e 
x 
 
x 
 
 
 
Hematology, 
Coagulation 
x 
 
x e 
x 
x 
x 
x 
 
 
Biochemistry 
x 
 
x e 
x 
x 
x 
x 
 
 
Urinalysis 
x 
 
x e 
x 
x 
x 
x 
 
 


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Appendix 1  
Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
112/Protocol BO28984, Version 5 (Canada) 
Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) 
Until PD, 
Death, or 
Withdrawal 
from Study 
prior to PD a 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
 
 
 
 
 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation)a 
 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D) a 
Concomitant 
medications 
x 
 
x 
x 
x 
x 
x 
 
 
Mandatory tumor 
sample for ALK 
testing f 
x 
 
 
 
 
 
 
 
 
Optional plasma 
sample from 
centrally confirmed 
ALK negative 
patients 
(20 ml of blood) 
x 
 
 
 
 
 
 
 
 
Optional tumor 
sample 
 
 
x g 
 
 
x h 
x h 
 
 


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Appendix 1  
Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
113/Protocol BO28984, Version 5 (Canada) 
Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) 
Until PD, 
Death, or 
Withdrawal 
from Study 
prior to PD a 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
 
 
 
 
 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation)a 
 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D) a 
Plasma sample for 
ALK fusion 
detection in nucleic 
acids (20 mL of 
blood) 
 
 
x i 
 
 
 
 
 
 
Plasma for 
detection of ALK 
mutation status 
(20 mL of blood) 
 
 
x 
 
 
x j 
x j 
 
 
Blood sample for 
pharmacogenomics 
research at 
pre-dose (3 mL of 
blood) k 
 
 
x 
 
 
 
 
 
 


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Appendix 1  
Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
114/Protocol BO28984, Version 5 (Canada) 
Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) 
Until PD, 
Death, or 
Withdrawal 
from Study 
prior to PD a 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
 
 
 
 
 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation)a 
 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D) a 
Tumor assessmentl 
x m 
 
x m 
 
x 
x n 
x 
x o 
 
MRI scan of the 
brain 
x m 
 
x m 
 
x 
x n 
x 
x o 
 
PK samples (2 mL 
blood) p 
 
 
x 
x 
x 
x 
 
 
 
PRO (EORTC 
QLQ-C30/LC13); 
EQ-5D q 
 
 
x 
x 
x 
x 
x 
x 
x r 
Total testosterone, 
(either by direct 
measurement or by 
calculation using 
albumin and 
SHBG), FSH, and 
LH s 
 
 
x 
x 
x 
x 
 
 
 
Adverse events t 
x 
x 
x 
x 
x 
x 
x 
x 
 


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Appendix 1  
Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
115/Protocol BO28984, Version 5 (Canada) 
Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) 
Until PD, 
Death, or 
Withdrawal 
from Study 
prior to PD a 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
 
 
 
 
 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation)a 
 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D) a 
Subsequent 
therapy for NSCLC 
 
 
 
 
 
 
x 
x 
xr 
Drug dispensing 
and accountability u 
 
 
x 
x 
x 
x 
x 
x (accountability 
only) 
 
Blood Sample for 
Roche Clinical 
Repository (10 mL) 
 
 
x 
 
 
 
 
 
 
ALK = anaplastic lymphoma kinase; ALP = alkaline phosphatase;  CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse 
Events; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30 = European Organization for the Research and 
Treatment of Cancer Quality of Life Questionnaire−Core; EQ-5D = EuroQoL 5 Dimension; FSH = follicle-stimulating hormone; LH = luteinizing 
hormone; MRI = magnetic resonance imaging; NCI = National Cancer Institute; NSCLC = non−small cell lung cancer; PD = progressive disease; 
PK = pharmacokinetic; PRO = patient-reported outcome; ULN = upper limit of normal. 
Notes: First dose of study drug to be taken as soon as patient has been randomized and appropriate drug has been provided–within ≤ 24 hours.  
Post-baseline assessments are to be performed within ± 1 week for the first two 4 weekly and subsequent 8 weekly assessments. 
a  For details on assessments when patient permanently discontinues from study treatment, see flowchart in Figure 1. 
b Urine or serum, to be repeated as necessary. 
c Including an ophthalmologic examination if clinically indicated. 


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Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
116/Protocol BO28984, Version 5 (Canada) 
d At screening, Visit 0 (baseline), Visit 1 (Week 4), Visit 4 (Week 24), Visit 8 (Week 56), last treatment visit, and as clinically indicated throughout 
the study. 
e Screening laboratory assessment done within 3 days can be counted as the baseline assessment. 
f Preferably blocks fixed in neutral buffered formalin; if blocks are not available, a minimum of 10 to 15 unstained 5-µm slides are required.  Tumor 
ALK status will be assessed by central laboratory before randomization. 
g Optional tumor sample could be taken from the tumor block obtained at screening. 
h At the time of disease progression from progressive lesions. 
i Mandatory blood sample (20 mL) for detection of ALK rearrangements in nucleic acids in plasma collected at baseline only. 
j Blood sample (20 mL) to obtain plasma for exploratory biomarkers will be collected at Visit 0 (baseline), during the study every second visit (i.e., 
every 16 weeks) until disease progression and during post-progression on treatment in case of isolated, asymptomatic CNS progression. 
k This sample is required in all patients in alectinib arm, and in those patients in the crizotinib arm who wish to participate in optional genomics 
sequencing. 
l Tumor assessment consists at minimum of a CT/MRI scan of chest and abdomen (for imaging of liver and adrenal glands).  Patients who are 
known to have bone metastasis or who display clinical or laboratory signs (e.g., serum ALP >1.5 × ULN) of bone metastasis should undergo 
radionuclide bone scan.  Clinical lesions should be assessed with caliper measurement and documented by color photography, including a ruler 
to estimate the size of the lesion. Post-baseline assessments are to be performed within ±1 week for the 8 weekly assessments.  If there is 
suspicion of disease progression on the basis of clinical or laboratory findings, a tumor assessment should be performed as soon as possible 
before the next scheduled evaluation. 
m Screening tumor assessment done within 14 days will be counted as the baseline assessment. 
n Tumor assessment can be performed whenever clinically indicated.  Brain assessment scans should be performed at every systemic imaging 
tumor assessment.  Tumor assessment should continue until disease progression if a patient discontinues treatment prior to PD, regardless of 
whether they subsequently receive non-study, anti-cancer therapy.  
o If treatment was permanently discontinued due to disease progression. 
p Pre-dose PK (2 mL) sampling for all patients on alectinib treatment will be performed at each visit during the treatment period and at the final 
study visit.  The pre-dose PK samples should be taken immediately before (within 2 hours) intake of study medication at all study visits. Remind 
the patient not to take a daily dose at home on the day of scheduled study visit.  For a subset of patients on alectinib treatment (10%−15%, or at 
least approximately n = 20) participating in serial/intensive PK sample collection, additional PK will be collected on Visits 0 (baseline) and 1 
(Week 4) at pre-dose (within 2 hours before intake of study medication), 1, 2, 4, 6, and 8 hours post-dose. 


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Appendix 1  
Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
117/Protocol BO28984, Version 5 (Canada) 
q PRO questionnaires are to be completed every 4 weeks until disease progression and during post-progression on treatment in case of isolated, 
asymptomatic CNS progression; at the post-treatment visit (4 weeks after permanent treatment discontinuation); and every follow up visit (every 
8 weeks) after post-treatment visit for 6 months..  Further guidelines on PRO questionnaire administration will be provided in the study manual. 
r Performed every 8 weeks after post-treatment visit during the first 6 months and then every 12 weeks.  The PRO assessments should be 
performed during the first 6 months.  For patients who discontinue treatment for reasons other than disease progression and who progress within 
the first 6 months of survival follow-up, PRO measures will be administered every 4 weeks until disease progression and then decreased to 
every 8 weeks until 6 months post treatment. For patients who discontinue treatment for reasons other than disease progression and have not 
yet progressed at 6 months post treatment, PRO measures will be administered every 4 weeks until disease progression and will no longer be 
required thereafter.  
s Male patients only, using institutional standard assay. The recommended time of day to have a blood sample taken for this test is between 7 a.m. 
and 10 a.m.  Albumin and SHBG measurements are not required when a direct assessment of free testosterone is available.  If free testosterone 
level cannot be directly assessed, it will be calculated from albumin and SHBG using a free testosterone calculator: 
http://www.issam.ch/freetesto.htm. 
t Graded according to NCI CTCAE (version 4.0).  Serious adverse events collection must start from first study-specific procedure. 
u For details on drug dispensing and accountability, see Section 4.3.3. 




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Appendix 2  
Schedule of Alectinib Pharmacokinetic Assessments 
Visit 
Timepoint 
Visit 0 (baseline) 
Pre-dose (within 2 hours before intake of alectinib)
Visit 1 (Week 4) 
Pre-dose (within 2 hours before intake of alectinib)
Visit 2 (Week 8) 
Pre-dose (within 2 hours before intake of alectinib)
All subsequent visits (every 
8 weeks) until PD or 
death/withdrawal from study prior to 
PD 
Pre-dose (within 2 hours before intake of alectinib)
Visit 0 (baseline) and Visit 1 
(Week 4)a 
Pre-dose (within 2 hours before intake of 
alectinib), 1, 2, 4, 6, and 8 hours post-dose 
PD = progressive disease; PK = Pharmacokinetic. 
a For patients participating in the serial/intensive PK sample collection only. 


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Appendix 3  
List of Substrates, Inhibitors, and Inducers of Drug-Metabolizing 
Enzymes and Transporters 
This representative list is not intended to be an exhaustive list.  Each patient’s 
concomitant medications should be carefully considered by the investigator with regard 
to the risk-benefit for the particular patient and appropriate monitoring, including any 
concomitant medication, dose adjustment, or therapeutic alternatives, which should be 
determined by the investigator caring for the patient. 
CYP3A Potent Inducers 
CYP3A Potent Inhibitors 
avasimibe, barbiturates, carbamazepine, 
efavirenz, ethosuximide, garlic supplements, 
modafinil, nevirapine, oxcarbazepine, 
phenobarbital, phenytoin, pioglitazone, 
primidone, rifabutin, rifampin, rifapentine, St. 
John’s wort, troglitazone 
aprepitant, atazanavir, boceprevir, 
ciprofloxacin, clarithromycin, conivaptan, 
diltiazem, erythromycin, fluconazole, grapefruit 
juice, indinavir, itraconazole, ketoconazole, 
lopinavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, troleandomycin, verapamil, 
voriconazole 
 
P-gp 
Substrates 
 
Inducers 
aliskiren, ambrisentan, 
colchicine, dabigatran, 
digoxin, everolimus, 
fexofenadine, imatinib, 
lapatinib, maraviroc, nilotinib, 
posaconazole, pravastatin, 
ranolazine, saxagliptin, 
sirolimus, sitagliptin, talinolol, 
tolvaptan, topotecan 
 
avasimibe, carbmazepine, 
phenytoin, rifampin, St John’s 
wort, tipranavir 
Dual UGT1A1/CYP3A 
Substrates 
Inhibitors 
Inducers 
buprenorphine, raltegravir 
atazanavir 
rifampin 
 Levien TL, and Baker DE Cytochrome P450 Drug Interactions. Therapeutic Research Center 
Pharmacist’s Letter/Prescriber’s Letter [resource on the Internet]. 2003. Available from: 
www.pharmacistsletter.com and www.prescribersletter.com. 
 Zhang L. Transporter Mediated Drug-Drug Interactions. FDA. Clinical Pharmacology Advisory 
Committee Meeting Topic 4: Transporter-Mediated Drug-Drug Interactions Atlanta, GA, March 
17, 2010. 
 
This information in this appendix is adapted from Levien and Baker 20031, Zhang 20102, 
and FDA Guidance on Drug-Drug Interactions. 
                                            
 
 


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Appendix 3  
List of Substrates, Inhibitors, and Inducers of Drug-Metabolizing 
Enzymes and Transporters (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
121/Protocol BO28984, Version 5 (Canada) 
Also see: 
• 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dr
ugInteractionsLabeling/ucm080499.htm  
• 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
 
Potent inhibitors of CYP3A are those considered to be “strong CYP3A inhibitors” 
previously shown to result in a ≥ 5-fold increase in the AUC of a concomitantly 
administered CYP3A substrate.  These are based on the available published literature 
and, thus, are not considered exhaustive or inclusive.  See FDA Guidance on Drug-Drug 
Interactions for further detail. 


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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1: Excerpt from Original Publication 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1,1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2 
MEASURABILITY OF TUMOR AT BASELINE 
DEFINITIONS 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below. 
Measurable tumor lesions 
Tumor lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 
• 
10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater than 
5 mm) 
• 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
• 
20 mm by chest X-ray 
Malignant lymph nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
≥ 15 mm in the short axis when assessed by CT scan (CT scan slice thickness is 
recommended to be no greater than 5 mm).  At baseline and follow-up, only the short 
axis will be measured and followed.  See also notes below on “Baseline Documentation 
of Target and Non-Target Lesions” for information on lymph node measurement. 
Non-Measurable tumor lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 
                                            
1  Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors:  revised 
RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47. 
2  For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made. 


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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
123/Protocol BO28984, Version 5 (Canada) 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone lesions 
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions.  However, these techniques 
can be used to confirm the presence or disappearance of bone lesions. 
Lytic bone lesions or mixed lytic−blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques, such as CT or MRI, can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
Blastic bone lesions are non-measurable. 
Cystic lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
TARGET LESIONS: SPECIFICATIONS BY METHODS OF MEASUREMENTS  
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 


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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
124/Protocol BO28984, Version 5 (Canada) 
Method of assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 
Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
clinical lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is required. 
Chest X-Ray 
Chest CT is preferred over chest X-Ray, particularly when progression is an important 
endpoint, because CT is more sensitive than X-Ray, particularly in identifying new 
lesions.  However, lesions on chest X-Ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 
CT, MRI 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  This guideline has defined measurability of lesions on CT 
scan on the basis of the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable.  
If, prior to enrollment, it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease and should be 
optimized to allow for comparison with the prior studies if possible.  Each case should be 
discussed with the radiologist to determine if the substitution of these other approaches 
is possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of non-target disease or new lesions because the same lesion may 
appear to have a different size using a new modality. 


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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
125/Protocol BO28984, Version 5 (Canada) 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. 
Endoscopy, laparoscopy, tumor markers, cytology, histology 
The utilization of these techniques for objective tumor evaluation cannot generally be 
advised. 
TUMOR RESPONSE EVALUATION 
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least one 
measurable lesion, as detailed above. 
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions, up to a 
maximum of five lesions total and a maximum of two lesions per organ, representative of 
all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be recorded as non-measurable lesions (even if the size is > 10 mm by CT scan).   
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but, in addition, the lesions 
should lend themselves to reproducible repeated measurements.  It may be the case 
that, on occasion, the largest lesion does not lend itself to reproducible measurement, in 
which circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT this is 


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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
126/Protocol BO28984, Version 5 (Canada) 
almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or 
coronal).  The smaller of these measures is the short axis.  For example, an abdominal 
node that is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node.  In this example, 20 mm should be recorded as the 
node measurement.  All other pathological nodes (those with short axis ≥ 10 mm but 
< 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
< 10 mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
All other lesions or sites of disease, including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression”. 
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). 
RESPONSE CRITERIA 
Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
• 
CR:  Disappearance of all target lesions 
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm. 
• 
PR:  At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum of diameters. 
• 
PD:  At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (nadir), including baseline. 
In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered progression. 


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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
127/Protocol BO28984, Version 5 (Canada) 
• 
SD:  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum on study. 
 
Special notes on the assessment of target lesions 
Lymph nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to < 10 mm on study.  This means that when 
lymph nodes are included as target lesions, the sum of lesions may not be zero even if 
CR criteria are met, since a normal lymph node is defined as having a short axis of 
< 10 mm. 
Target lesions that become too small to measure 
During the study, all lesions (nodal and non-nodal) recorded at baseline should have 
their actual measurements recorded at each subsequent evaluation, even when very 
small (e.g., 2 mm).  However, sometimes lesions or lymph nodes that are recorded as 
target lesions at baseline become so faint on the CT scan that the radiologist may not 
feel comfortable assigning an exact measure and may report them as being too small to 
measure.  When this occurs, it is important that a value be recorded on the CRF, as 
follows:   
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
If the lesion is believed to be present and is faintly seen but is too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should be 
ticked.  (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such as 
in the retroperitoneum; however, if a lymph node is believed to be present and is faintly 
seen but is too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well and BML should also be ticked). 
To reiterate:  If the radiologist is able to provide an actual measure, this 
measurement should be recorded, even if it is below 5 mm, and, in that case, BML 
should not be ticked. 
Lesions that split or coalesce on treatment 
When non-nodal lesions fragment, the longest diameters of the fragmented portions 
should be added together to calculate the target lesion sum.  Similarly, as lesions 
coalesce, a plane between them may be maintained that would aid in obtaining maximal 


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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
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diameter measurements of each individual lesion.  If the lesions have truly coalesced 
such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximum longest diameter for the coalesced lesion. 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  Whereas some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the protocol. 
• 
CR:  Disappearance of all non-target lesions 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• 
Non-CR/Non-PD:  Persistence of one or more non-target lesions 
• 
PD:  Unequivocal progression of existing non-target lesions 
The appearance of one or more new lesions is also considered progression. 
Special notes on assessment of progression of non-target disease 
When the patient also has measurable disease 
In this setting, to achieve unequivocal progression on the basis of the non-target 
disease, there must be an overall level of substantial worsening in non-target disease in 
a magnitude that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy.  A modest increase 
in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or PR of target disease will 
therefore be extremely rare. 
When the patient has only non-measurable disease 
This circumstance arises in some Phase III trials when it is not a criterion of study entry 
to have measurable disease.  The same general concepts apply here as noted above; 
however, in this instance, there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden.  Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly 
non-measurable), a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden on the 
basis of the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease, that is, an 
increase in tumor burden representing an additional 73% increase in volume (which is 
equivalent to a 20% increase in diameter in a measurable lesion).  Examples include an 
increase in a pleural effusion from “trace” to “large” or an increase in lymphangitic 


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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
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disease from localized to widespread.  Examples may be described in protocols as 
“sufficient to require a change in therapy”.  If unequivocal progression is seen, the 
patient should be considered to have had overall PD at that point.  Though it would be 
ideal to have objective criteria to apply to non-measurable disease, the very nature of 
that disease makes it impossible to do so; therefore, the increase must be substantial. 
New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(e.g., some “new” bone lesions may be simply healing or flare of preexisting lesions).  
This is particularly important when the patient’s baseline lesions show PR or CR (e.g., 
necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, 
which it is not). 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal (e.g., because of its small size) continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan. 
EVALUATION OF RESPONSE 
Timepoint response (overall response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used. 


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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
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Table 1 
Timepoint Response: Patients with Target Lesions (with or 
without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
 
Table 2 
Timepoint Response: Patients with Non-Target Lesions Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised. 
 
Missing assessments and not-evaluable designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned timepoint response.  This would be most likely 


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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
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131/Protocol BO28984, Version 5 (Canada) 
to happen in the case of PD (e.g., if a patient had a baseline sum of 50 mm with three 
measured lesions and during the study only two lesions were assessed, but those gave 
a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution 
of the missing lesion).  
If one or more target lesions were not assessed either because the scan was not done 
or because the scan could not be assessed due to poor image quality or obstructed 
view, the response for target lesions should be “unable to assess” since the patient is 
not evaluable.  Similarly, if one or more non-target lesions are not assessed, 
the response for non-target lesions should be “unable to assess”, except where there is 
clear progression.  Overall response would be “unable to assess” if either the target 
response or the non-target response is “unable to assess”, except where this is clear 
evidence of progression, as this equates with the case being not evaluable at that 
timepoint. 


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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
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Table 3 
Best Overall Response When Confirmation Is Required 
Overall Response at First 
Timepoint 
Overall Response at 
Subsequent Timepoint 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR a 
CR 
SD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
CR 
PD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
CR 
NE 
SD, provided minimum 
duration for SD was met; 
otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
PR 
NE 
SD, provided minimum 
duration for SD was met; 
otherwise, NE 
NE 
NE 
NE 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even 
disease meeting PR criteria relative to baseline, qualifies as PD at that point (since disease 
must have reappeared after CR).  Best response would depend on whether the minimum 
duration for SD was met.  However, sometimes CR may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR, at the 
first timepoint.  Under these circumstances, the original CR should be changed to PR and the 
best response is PR. 
 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (< 10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF. 


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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
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Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Table 1 to Table 3. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes, or necrosis in existing lesions), treatment may continue until the 
next scheduled assessment.  If at the next scheduled assessment, progression is 
confirmed, the date of progression should be the earlier date when progression was 
suspected. 
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or non-target lesion.


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Appendix 5  
Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework or 
office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about > 50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair > 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair 
5 
Dead 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires 
 
 
 
 
 
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 
 


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Appendix 7  
Modification of Diet in Renal Disease (MDRD) Formula 
The estimating glomerular filtration rate (eGFR) will be calculated on the basis of the 
following formula: 
eGFR [mL/min/1.73 m2] = 175 × SCRT -1.154 × AGE -0.203 [× 0.742 if 
female] [× 1.212 if African American] (conventional units) 
 
where SCRT =  serum creatinine in conventional units, i.e. mg/dL. The following 
conversion factor should be used in case the serum creatinine value is provided by the 
lab in μmol/L units:  
Serum creatinine [mg/dL] = Serum creatinine [μmol/L] × 0.0113 
 
 
References:  
Miller WG. Estimating glomerular filtration rate. Clin Chem Lab Med 2009;47(9):1017−9. 
Heil W., Koberstein R, Zawta B. Reference Ranges for Adults and Children−Pre-
Analytical Considerations. Roche Diagnostics GmbH 2014, 8th edition, p.159.  


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Appendix 8  
Anaplastic Lymphoma Kinase (ALK) Immunohistochemistry 
Overview 
The VENTANA anti-ALK (D5F3) Rabbit Monoclonal Primary Antibody (VENTANA 
anti-ALK [D5F3]) IHC assay will be used to determine anaplastic lymphoma kinase (ALK) 
IHC status and to select patients with positive ALK for enrollment in Study BO28984.  
The anti-ALK (D5F3) rabbit monoclonal antibody IHC assay is currently being developed 
by Ventana Medical Systems as a companion diagnostic to Roche’s ALK inhibitor, 
alectinib.  For Study BO28984, the VENTANA anti-ALK (D5F3) assay will be used for 
investigational purposes only. 
VENTANA anti-ALK (D5F3) is intended for laboratory use in the detection of the ALK 
protein in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) 
tissue stained with using a VENTANA automated slide stainer.  It is indicated as an aid 
in identifying patients eligible for treatment with alectinib. 
Device Description 
The VENTANA anti-ALK (D5F3) IHC assay is an automated IHC staining assay system 
comprising a pre-diluted, ready to-use anti-ALK (D5F3) rabbit monoclonal primary 
antibody, the BenchMark® automated slide staining platform, OptiView DAB detection kit, 
OptiView Amplification kit, Rabbit Monoclonal Negative Control Ig, and VENTANA 
anti-ALK 2-in-1 cell line control slides or other appropriate system run control. 
Scoring System 
The IHC scoring system evaluates specific VENTANA anti-ALK (D5F3) staining in 
NSCLC tumor cells by the presence of a strong, granular, cytoplasmic staining pattern.  
Pathologists must rely on the Negative Reagent Control (NRC) slides to distinguish 
non-specific staining from specific ALK positivity.  Samples must be assessed for 
morphological damage and the presence of viable tumor versus necrosis.  Light, 
granular, cytoplasmic stippling in alveolar macrophages can occur on anti-ALK (D5F3) 
and/or NRC slides as an artifact of the detection system.  This staining artifact should be 
noted on the Slide Evaluation Form comment field but should NOT be interpreted as 
ALK-positive staining.  Some background staining has also been observed on normal 
mucosa in NSCLC specimens, as well as in necrotic tumor areas; this staining also 
should not be interpreted as ALK-positive staining.  Case slide sets failing to show 
specific staining of the case tissue with VENTANA anti-ALK (D5F3) cannot be 
considered ALK-positive.  Refer to VENTANA ALK Scoring Interpretation Guide for 
non-small cell lung carcinoma (NSCLC) for additional information. 
 


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Appendix 9  
Drug Metabolism Enzymes, Transporters (DMET), and Liver Injury Polymorphisms 
ABCB1 
CHST13 
CYP3A5 
HNMT 
SLC22A3 
UGT1A4 
ADRB3 
HSP90AA1 
STAT6 
ABCB11 
CHST2 
CYP3A7 
MAOA 
SLC22A4 
UGT1A5 
ALG10B 
IGF1 
TNF 
ABCB4 
CHST3 
CYP46A1 
MAOB 
SLC22A5 
UGT1A6 
APOA1 
IGF2 
TNFRSF1B 
ABCB7 
CHST4 
CYP4A11 
MAT1A 
SLC22A6 
UGT1A7 
APOC3 
IL10 
TXNIP 
ABCC1 
CHST5 
CYP4B1 
METTL1 
SLC22A7 
UGT1A8 
ARHGAP24 
IL22 
UBC 
ABCC2 
CHST6 
CYP4F11 
NAT1 
SLC22A8 
UGT1A9 
ATF3 
IL4 
UCP1 
ABCC3 
CHST7 
CYP4F12 
NAT2 
SLC25A27 
UGT2A1 
ATIC 
IL4R 
VDR 
ABCC4 
CHST8 
CYP4F2 
NNMT 
SLC28A1 
UGT2B11 
BIRC2 
IL6 
 
ABCC5 
CHST9 
CYP4F3 
NQO1 
SLC28A2 
UGT2B15 
BIRC3 
IL8 
 
ABCC6 
COMT 
CYP4F8 
NR1I2 
SLC28A3 
UGT2B17 
C3orf38 
INSR 
 
ABCC8 
CROT 
CYP4Z1 
NR1I3 
SLC29A1 
UGT2B28 
CALCA 
IRS1 
 
ABCC9 
CYP11A1 
CYP51A1 
NR3C1 
SLC29A2 
UGT2B4 
CASP9 
IRS2 
 
ABCG1 
CYP11B1 
CYP7A1 
ORM1 
SLC5A6 
UGT2B7 
CD33 
IRS4 
 
ABCG2 
CYP11B2 
CYP7B1 
ORM2 
SLC6A6 
UGT8 
CD36 
ITPA 
 
ABP1 
CYP17A1 
CYP8B1 
PGAP3 
SLC7A5 
VKORC1 
CD44 
JAK1 
 
ADH1A 
CYP19A1 
DCK 
PNMT 
SLC7A7 
XDH 
CDK4 
JUN 
 
ADH1B 
CYP1A1 
DPYD 
PON1 
SLC7A8 
 
CDK6 
KCNIP4 
 
ADH1C 
CYP1A2 
EPHX1 
PON2 
SLCO1A2 
 
CEBPB 
KRT18 
 
ADH4 
CYP1B1 
EPHX2 
PON3 
SLCO1B1 
 
CEP44 
KRT8 
 
ADH5 
CYP20A1 
FAAH 
POR 
SLCO1B3 
 
CES1 
LEP 
 
ADH6 
CYP21A2 
FMO1 
PPARD 
SLCO2B1 
 
CTLA4 
LEPR 
 
ADH7 
CYP24A1 
FMO2 
PPARG 
SLCO3A1 
 
CYP3A 
LMX1A 
 
AHR 
CYP26A1 
FMO3 
PPP1R9A 
SLCO4A1 
 
EGFR 
LPL 
 


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Appendix 9  
Drug Metabolism Enzymes, Transporters (DMET), and Liver Injury Polymorphisms (cont.) 
 
AKAP9 
CYP26C1 
FMO4 
PRSS53 
SLCO5A1 
 
ETNK2 
MCTP2 
 
ALB 
CYP27A1 
FMO5 
PTGIS 
SPG7 
 
FASLG 
MT-CO2 
 
ALDH1A1 
CYP27B1 
FMO6 
QPRT 
SPN 
 
FMOD 
MTHFR 
 
ALDH2 
CYP2A13 
G6PD 
RALBP1 
SULT1A1 
 
FOS 
NFE2L2 
 
ALDH3A1 
CYP2A6 
GSTA1 
RPL13 
SULT1A2 
 
FPGS 
NOS2 
 
ALDH3A2 
CYP2A7 
GSTA2 
RXRA 
SULT1A3 
 
GGH 
NOS3 
 
AOX1 
CYP2B6 
GSTA3 
SERPINA7 
SULT1B1 
 
GPNMB 
OR5H2 
 
APOA2 
CYP2B7P1 
GSTA4 
SLC10A1 
SULT1C2 
 
GPT 
PARD3B 
 
ARNT 
CYP2C18 
GSTA5 
SLC10A2 
SULT1C4 
 
GPX1 
PRKCZ 
 
ARSA 
CYP2C19 
GSTM1 
SLC13A1 
SULT1E1 
 
GPX3 
RASGRP1 
 
ATP7A 
CYP2C8 
GSTM2 
SLC15A1 
SULT2A1 
 
GPX4 
RB1 
 
ATP7B 
CYP2C9 
GSTM3 
SLC15A2 
SULT2B1 
 
GYS1 
RDH5 
 
CA5P 
CYP2D6 
GSTM4 
SLC16A1 
SULT4A1 
 
GYS2 
RIPK1 
 
CBR1 
CYP2E1 
GSTM5 
SLC19A1 
TBXAS1 
 
HCP5 
SOCS3 
 
CBR3 
CYP2F1 
GSTO1 
SLC22A1 
TPMT 
 
HGF 
SOD1 
 
CDA 
CYP2J2 
GSTP1 
SLC22A11 
TPSG1 
 
HLA-A 
SOD2 
 
CES2 
CYP2S1 
GSTT1 
SLC22A12 
TYMS 
 
HLA-B 
SPP1 
 
CHST1 
CYP39A1 
GSTT2 
SLC22A13 
UGT1A1 
 
HLA-DQA1 
SQSTM1 
 
CHST10 
CYP3A4 
GSTZ1 
SLC22A14 
UGT1A10 
 
HLA-DQB1 
ST6GAL1 
 
CHST11 
CYP3A43 
HMGCR 
SLC22A2 
UGT1A3 
 
HLA-DRB1 
STAT1 
 
 


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Appendix 10  Formulae for the Calculation of QTcF and RR  
 
QtcF  − Fridericia’s correction for QTc measurement (if not provided directly by the ECG machine): 
 
 
 
RR Interval Formula (if not provided directly by the ECG machine): 
RR (ms) = 60000/heart rate (bpm) 
 
 
 
 
 
 
 
 
 
 


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Title
15-Apr-2016 00:17:48
Date and Time (UTC)
Company Signatory
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 4 
PROTOCOL 
TITLE: 
RANDOMIZED, MULTICENTER, PHASE III, 
OPEN-LABEL STUDY OF ALECTINIB VERSUS 
CRIZOTINIB IN TREATMENT-NAIVE ANAPLASTIC 
LYMPHOMA KINASE-POSITIVE ADVANCED 
NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: BO28984 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2013-004133-33 
IND NUMBER: 
111723 
UTN NUMBER: 
 
TEST PRODUCT: 
Alectinib (RO5424802) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  10 February 2014 
DATE AMENDED: 
Version 2:  08 October 2014 
Version 3:  14 May 2015 
Version 4:  See electronic date stamp below. 


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PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE 
Protocol BO28984 has been amended to incorporate the latest safety and drug 
administration information.  Changes include those to adverse events (AEs) relating to 
alectinib data and management of alectinib AEs guidelines, restrictions related to 
QT-prolonging concomitant medications for alectinib, and guideline for the management 
of missing doses of alectinib. 
The major changes to the protocol are as follows: 
Change of the risk of hepatobiliary laboratory tests elevations to hepatotoxicity for 
alectinib, on the basis of the following information:  two patients with Grade 3-4 AST/ALT 
elevations had documented drug-induced liver injury by liver biopsy in alectinib pivotal 
Phase II clinical trials.  Concurrent elevations in ALT or AST greater than or equal to 
three times the upper limit of normal (ULN) and total bilirubin greater than or equal to two 
times the ULN, with normal alkaline phosphatase, occurred in 1 patient treated in 
alectinib clinical trials (0.2%) (Section 5.1.2.2 and Section 5.1.3). 
Change of the risk of muscular adverse events and CPK elevations to severe myalgia 
and CPK elevations for alectinib, on the basis of the following information:  Grade 3 
myalgia and CPK elevations have been reported with alectinib treatment and were 
reversible upon dose reduction and interruption (Section 5.1.2.10 and Section 5.1.3). 
The list of adverse events relating to ALK inhibitors and/or tyrosine kinase inhibitor class 
and alectinib data has been updated accordingly.  The list was updated to replace the 
“hematologic abnormalities” events with the “anemia” events.  This is in line with the 
alectinib Investigator’s Brochure (IB) version 6.  The guideline for management of 
specific adverse events related to hematological abnormalities in alectinib-treated 
patients has been removed accordingly.  In case of the occurrence of events falling in 
the category of hematological abnormalities, appropriate management of the adverse 
events is already covered by the guideline “Other AEs or laboratory abnormalities”, also 
included in Table 2 (Section 5.1.2.3). 
Restrictions related to concomitant medications known to prolong the QT interval have 
been modified.  The restriction is no longer required for alectinib-treated patients on the 
basis of the detailed evaluation of the pooled ECG data from the two pivotal 
Studies NP28761 and NP28673 and ECG data from the supportive Study AF-001JP, 
which showed no evidence that alectinib caused any clinically relevant QTcF 
prolongation.  Furthermore, there was no apparent correlation between the change in 
QTcF and alectinib plasma concentration.  For crizotinib-treated patients, this restriction 
still applies.  For the same reason, the guideline for management of specific adverse 
events related to QT prolongation in alectinib-treated patients has been removed from 
Table 2 (Section 4.1.2 and Section 4.4.2).   


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The guideline for management of specific adverse events related to skin disorder 
adverse events in alectinib-treated patients has been updated to advise patients to use a 
broad-spectrum sunscreen and lip balm of at least sun protection factor SPF 50 to help 
protect against potential photosensitivity (Section 5.1.3).  
Guidelines for the management of missing doses of alectinib have been updated.  
Following oral administration of 600 mg twice daily (BID) under fed conditions in patients 
with ALK-positive non−small cell lung cancer (NSCLC), alectinib was rapidly absorbed 
reaching Tmax after approximately 4 to 6 hours (Studies NP28761 and NP28673).  On the 
basis of the known Tmax, if a dose of alectinib is missed, the dose should be made up 
unless the next dose is due within 6 hours.  This is to ensure any missed dose is taken 
during the expected elimination phase (post-Tmax) of the alectinib dosing interval.  This 
approach is consistent with other molecules with similar PK characteristics (Tmax of 4 to 
6 hours and an apparent T1/2 of greater than 30 hours) and BID dosing interval 
(XALKORI® U.S. Package Insert, ZELBORAF® U.S.Package Insert) (Section 4.3.2.1). 
The FISH Positive Population (FPP) was intended to be used for possible registration 
purposes in the event that the Ventana IHC companion diagnostic for Alectinib would not 
be registered.  All analyses would, in that event, have been based on the 
FPP-population and the same pre-specified testing strategy of secondary endpoints 
would have been applied for the FPP.  Following the FDA approval in June 2015 of the 
Ventana ALK IHC assay as companion diagnostic for crizotinib the fully powered 
analyses of the FPP have become redundant and are removed from the BO28984 study 
protocol.  The ALK FISH positive secondary population will be used to perform a 
supportive analysis of the study data based on the Vysis FISH assay (Section 6 and 
Section 6.8). 
Appendix 3, List of Substrates, Inhibitors, and Inducers of Drug-Metabolizing Enzymes 
and Transporters, has been updated to include only potent CYP3A4 Inducers. 
Additional minor changes have been made to improve clarity and consistency.  This 
amendment represents cumulative changes to the original protocol. 


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PROTOCOL AMENDMENT, VERSION 4: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.3:  STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
On the basis of available preliminary data, the estimated benefits of alectinib treatment 
outweigh the risks.  Specifically: 
• 
Clinical safety data in humans up to 900 mg BID demonstrate that its safety profile 
is consistent to the one known to be associated with TKIs ALK inhibitors. 
 
SECTION 2.5:  EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are: 
• 
To evaluate and compare efficacy and safety in patients with treatment-naive 
ALK-positive NSCLC as assessed by the FISH Vysis® ALK Break Apart FISH Probe 
Kit (Abbott) 
 
SECTION 3.4.5:  Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Results from the FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) to evaluate 
and compare efficacy and safety in patients with treatment-naive NSCLC that is 
ALK-positive by FISH test  
 
SECTION 4.1.1:  Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus), agreement to 
remain abstinent or use single or combined contraceptive methods that result in a 
failure rate of < 1% per year during the treatment period and for at least 3 months 
after the last dose of study drug.  Abstinence is only acceptable if it is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.  Examples of non hormonal contraceptive 
methods with a failure rate of < 1% per year include tubal ligation, male sterilization, 
hormonal implants, established and proper use of combined oral or injected 
hormonal contraceptives, and certain intrauterine devices.  Alternatively, two 
methods (e.g., two barrier methods such as condom and cervical cap use) may be 
combined to achieve a failure rate of < 1% per year.  Barrier methods must always 
be supplemented with the use of a spermicide.  
 
SECTION 4.1.2:  Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients with baseline QTc > 470 ms or symptomatic bradycardia 


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• 
Administration of agents with potential QT interval prolonging effects within 14 days 
prior to the first administration of study drug for all patients and while on treatment 
through the end of the study for crizotinib-treated patients only (see Section 4.4.2 
for further details) 
• 
Pregnant or lactating women 
 
SECTION 4.3.2.1:  Alectinib 
If a patient misses a dose, it can be taken within 46 hours of the scheduled time.  If the 
time is greater than 46 hours, or if the patient vomits the dose, the patient should wait 
until the next scheduled time and take the next scheduled dose.  Patients should not 
take two doses at the same time to make up for a missed dose. 
SECTION 4.4.2:  Prohibited Therapy 
Use of the following therapies (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) is prohibited during the study and for at 
least 14 days prior to initiation of study treatment (either alectinib or crizotinib), unless 
otherwise specified below.  Exceptions to restrictions of the concomitant therapies listed 
below (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) may be made if the rationale is discussed and documented 
between the investigator and the Sponsor’s Clinical Pharmacologist. 
• 
Any concomitant medications known to affect QT interval duration, including but not 
limited to the following drugs:  amiodarone, cisapride, clarithromycin, methadone, 
and quinidine, within 2 weeks before the first dose of study drug treatment for all 
patients and while on treatment with study drugs and through the end of the study 
for crizotinib-treated patients only 
 
SECTION 4.5.8.1:  Laboratory Assessments 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis of the following: 
 
SECTION 4.5.8.2:  Pre-Treatment Tumor Samples (Mandatory) 
Central ALK testing to determine or confirm patient ALK status will be performed at a 
Sponsor designated central laboratory.  After completion of ALK testing for enrollment 
with a pre-specified ALK test by Ventana IHC (Appendix 8), patient samples will also be 
centrally tested by FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) for possible 
companion diagnostic development.…   
SECTION 4.5.9:  Electrocardiograms 
If any ECG abnormality is associated with an adverse event, it must be recorded and 
managed as described in Section 5.  Management of QT interval prolongation should be 
done according to guidance provided in Section 5.1.3.  
If considered appropriate by the Sponsor, ECGs may be analyzed retrospectively at a 
central laboratory.  Guidance for abnormal ECG results (QT prolongation) is provided in 
Table 2. 


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SECTION 5.1.2.2:  Hepatobiliary Laboratory Test ElevationsHepatotoxicity 
Abnormal hepatobiliary laboratory test values, such as increased ALT, AST, or bilirubin 
levels, have been observed after alectinib administration.  AST, ALT, and total bilirubin 
levels temporarily increased in the initial stages of treatment and then improved.  In 
patients with Grade 3−4 AST/ALT elevations, documented drug-induced liver injury 
by liver biopsy was reported with uncommon frequency in alectinib pivotal clinical 
trials.  Concurrent elevations in ALT or AST greater than or equal to three times the 
ULN and total bilirubin greater than or equal to two times the ULN, with normal 
alkaline phosphatase, occurred with uncommon frequency in patients treated in 
alectinib clinical trials. 
In patients treated with other tyrosine kinase ALK inhibitor drugs, abnormal liver function 
tests and fatal cases of hepatic failuredrug-induced hepatotoxicity, including cases with 
fatal outcome, have been reported. 
SECTION 5.1.2.3:  Hematologic AbnormalitiesAnemia 
Hematologic abnormalities of neutropenia, leukopenia, thrombocytopenia, and anemia 
have been reported with alectinib administration.  Neutrophil counts generally decreased 
early and remained stable thereafter. 
Cases of anemia have been reported in patients treated with alectinib; the majority of 
the events were Grade 1 or 2. 
SECTION 5.1.2.8:  Cardiovascular EffectsBradycardia 
QT interval prolongation appears to be an off target class effect of some TKIs, including 
ALK inhibitor crizotinib (Shah et al. 2013; XALKORI® U.S. Package Insert).  Many TKIs 
have been associated with bradycardia and hypertension. 
In the in vitro study of the cardiovascular system, alectinib inhibited the hERG current 
(IC20: 58 ng/mL; IC50: 217 ng/mL).  Because plasma protein binding by alectinib is ≥ 99%, 
the plasma concentration of alectinib required to induce the same inhibition in vivo would 
be 100 or more times greater than the concentration required in vitro.  In the monkey 
telemetry study, there were no effects on the ECG, any of the other cardiovascular 
parameters or body temperature at doses up to 15 mg/kg (mean maximum 
concentration [Cmax]: 279 ng/mL). 
Events of bradycardia have been reported with alectinib.  Preliminary heart rate data 
(based on ECG and pulse measurements) from the ongoing alectinib clinical trials show 
a decrease in heart rate during alectinib treatment, which is mainly asymptomatic.  In 
patients treated with other ALK inhibitors (crizotinib and ceritinib), bradycardia adverse 
events, as well as decreases in heart rate based on ECG and pulse measurements, 
have also been reported (XALKORI® U.S. Package Insert; ZYKADIA™ U.S. Package 
Insert).  


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SECTION 5.1.2.10:  Muscular Adverse EventsSevere Myalgia and CPK 
Elevations 
Blood CPK increases, generally Grades 1 and 2, and muscular AEs have been reported 
with alectinib treatment.  Grade 3 myalgia and CPK elevations have been reported with 
alectinib treatment and were reversible upon dose reduction and interruption. 
SECTION 6:  STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
A secondary analysis population for efficacy and safety is the FISH Positive Population 
(FPP).  For efficacy, tThis is defined as all patients in the ITT population who were 
ALK-positive using the Vysis FISH assay.  Patients will be assigned to the treatment 
group to which they were randomized.  For safety, this is defined as all patients in the 
SAP who were ALK positive using the Vysis FISH assay.  Patients will be assigned to 
treatment groups as treated.  This analysis population will be used to perform a 
supportive analysis of the study data based on the Vysis FISH assay rather than the 
Ventana IHC.  This population may be used for registration purposes in the unlikely 
event of registrational failure of the Ventana IHC companion diagnostic, in which case all 
analyses will be based on this population and the same prespecified testing strategy of 
secondary endpoints defined in Section 6.4.2 will be applied. 
An analysis of the primary endpoint of investigator-assessed PFS based on the FPP will 
be performed at the time of the primary analysis.  A major discrepancy between the 
Ventana IHC assay and the Vysis FISH assay may necessitate a follow-up analysis of 
the primary endpoint based on 170 PFS events observed in the FPP to ensure 80% 
power of the log-rank test under the assumption of a hazard ratio of 0.65 in this 
secondary population. 
SECTION 6.1:  DETERMINATION OF SAMPLE SIZE 
A follow up analysis will be performed based on the FPP.  This will occur once 170 PFS 
events have occurred in the FPP to ensure 80% power of the log rank test assuming a 
hazard ratio of 0.65 in this sub population.  Based on a potential discrepancy/technical 
failure rate of 10% between the Ventana IHC assay and the Vysis FISH assay, 
257 patients would be eligible for the FPP analysis, which is estimated to occur 
approximately 35 months after the first patient has been enrolled (i.e., 2 months after the 
primary IHC analysis) based on the above assumptions. 
SECTION 6.4.2:  Secondary Efficacy Endpoints 
Time to CNS Progression 
In the subgroup of patients with measurable CNS lesions at baseline, an exploratory 
analysis of C-ORR defined as the percentage of patients who achieve a best overall 
response of CR or PR (defined by RECIST v1.1 as a 30% decrease in the sum of 
longest diameters of measurable CNS lesions referencing baseline) will also be 
performed.  Duration of CNS response will be listed and may be analyzed if there are a 
sufficient number of CNS responses.  Similar analyses will be performed in the 
subgroup of patients with measurable and/or non-measurable CNS lesions at baseline.  


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An exploratory analysis of these endpoints will also be performed on the basis of RANO 
criteria assessed by the IRC. 
SECTION 6.8:  EXPLORATORY ANALYSES 
The Abbott Vysis FISH test will be used as an exploratory assay after patients have 
been enrolled in this study.  Results from these analyses will be used to quantify the 
degree of correlation between Vysis FISH and Ventana IHC for the detection of 
ALK-positive NSCLC.  The FPP will be a secondary analysis population for efficacy and 
safety.  This analysis population will be used to perform a supportive analysis of the 
study data based on the Vysis FISH assay rather than the Ventana IHC.  This population 
may be used for registration purposes in the unlikely event of registrational failure of the 
Ventana IHC companion diagnostic, in which case all analyses will be based on this 
population. 
…Results of analyses related to those alternative diagnostic tests and exploratory 
analyses on post-progression tumor samples to measure molecular mechanisms of 
resistance to ALK inhibitors and plasma samples to measure ALK rearrangements in 
circulating tumor cells will be communicated outside the main clinical study report. 
TABLE 2:  Guidelines for Management of Specific Adverse Events with 
Alectinib 
Table 2, Guidelines for Management of Specific Adverse Events with Alectinib, has been 
revised to reflect changes in the protocol. 
TABLE 4:  Crizotinib Dose Modification⎯Non-Hematologic Toxicities 
Table 4, Crizotinib Dose Modification⎯Non-Hematologic Toxicities, has been modified 
to remove some typographical errors around the QTc interval, thus clarifying that the 
QTc interval should be >500 ms. 
APPENDIX 1:  Schedule of Assessments 
Appendix 1, Schedule of Assessments, has been revised to add a flowchart detailing 
assessments needed when a patient permanently discontinues from study treatment. 
APPENDIX 3:  List of Substrates, Inhibitors, and Inducers of 
Drug-Metabolizing Enzymes and Transporters 
Appendix 3, List of Substrates, Inhibitors, and Inducers of Drug-Metabolizing Enzymes 
and Transporters, has been updated to include only potent CYP3A4 Inducers. 
APPENDIX 10:  Formulae for the Calculation of QTcF and RR 
Appendix 10, Formulae for the Calculation of QTcF and RR, has been corrected. 
SAMPLE INFORMED CONSENT FORM 
The sample Informed Consent Form has been revised to reflect the changes to the 
protocol. 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 16 
PROTOCOL SYNOPSIS .................................................................................... 17 
1. 
BACKGROUND .......................................................................................... 28 
1.1 
Background on Anaplastic Lymphoma Kinase-
Positive Non-Small Cell Lung Cancer.................................... 28 
1.2 
Background on Alectinib........................................................ 30 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 35 
2. 
OBJECTIVES.............................................................................................. 37 
2.1 
Efficacy Objectives ................................................................ 37 
2.2 
Safety Objectives................................................................... 38 
2.3 
Pharmacokinetic Objectives .................................................. 38 
2.4 
Patient-Reported Outcome Objectives .................................. 38 
2.5 
Exploratory Objectives........................................................... 38 
3. 
STUDY DESIGN ......................................................................................... 39 
3.1 
Description of Study .............................................................. 39 
3.2 
End of Study.......................................................................... 41 
3.3 
Rationale for Study Design.................................................... 42 
3.3.1 
Rationale for Alectinib Dosage .............................................. 42 
3.3.2 
Rationale for Patient Population ............................................ 43 
3.3.3 
Rationale for Control Group................................................... 43 
3.3.4 
Rationale for Open-Label Design .......................................... 44 
3.3.5 
Rationale for Primary Endpoint Selection .............................. 45 
3.3.6 
Rationale for Secondary Endpoint of Time to 
CNS Progression................................................................... 46 
3.3.7 
Rationale for PK Sample Collection Schedule....................... 47 
3.3.8 
Rationale for Biomarker Assessments................................... 47 
3.3.9 
Rationale for PRO Assessments ........................................... 48 
3.4 
Outcome Measures ............................................................... 49 
3.4.1 
Efficacy Outcome Measures.................................................. 49 
3.4.2 
Safety Outcome Measures .................................................... 49 
3.4.3 
Pharmacokinetic Outcome Measures.................................... 50 


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3.4.4 
Patient-Reported Outcome Measures ................................... 50 
3.4.5 
Exploratory Outcome Measures ............................................ 51 
4. 
MATERIALS AND METHODS .................................................................... 51 
4.1 
Patients.................................................................................. 51 
4.1.1 
Inclusion Criteria.................................................................... 51 
4.1.2 
Exclusion Criteria................................................................... 53 
4.2 
Method of Treatment Assignment and Blinding..................... 54 
4.3 
Study Treatment.................................................................... 54 
4.3.1 
Formulation, Packaging, and Handling.................................. 54 
4.3.1.1 
Alectinib................................................................................. 54 
4.3.1.2 
Crizotinib................................................................................ 55 
4.3.2 
Dosage, Administration, and Compliance.............................. 55 
4.3.2.1 
Alectinib................................................................................. 55 
4.3.2.2 
Crizotinib................................................................................ 55 
4.3.3 
Investigational Medicinal Product Accountability ................... 56 
4.3.4 
Post-Trial Access to Alectinib ................................................ 56 
4.4 
Concomitant Therapy ............................................................ 57 
4.4.1 
Permitted Therapy ................................................................. 57 
4.4.2 
Prohibited Therapy ................................................................ 58 
4.4.3 
Prohibited Food ..................................................................... 59 
4.5 
Study Assessments ............................................................... 59 
4.5.1 
Informed Consent Forms and Screening Log........................ 59 
4.5.2 
Medical History and Demographic Data ................................ 60 
4.5.3 
Corticosteroid Use for CNS Metastases ................................ 60 
4.5.4 
Physical Examinations........................................................... 60 
4.5.5 
Vital Signs.............................................................................. 60 
4.5.6 
ECOG Performance Status ................................................... 61 
4.5.7 
Tumor and Response Evaluations......................................... 61 
4.5.8 
Laboratory, Biomarker, and Other Biological 
Sample .................................................................................. 62 
4.5.8.1 
Laboratory Assessments ....................................................... 62 
4.5.8.2 
Pre-Treatment Tumor Samples (Mandatory)......................... 62 


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4.5.8.3 
Pre- and Fresh Post-Treatment Tumor Biopsies 
(Optional)............................................................................... 63 
4.5.8.4 
Blood and Plasma Samples................................................... 64 
4.5.8.5 
Samples for Pharmacokinetic Assessments.......................... 65 
4.5.9 
Electrocardiograms................................................................ 66 
4.5.10 
Patient-Reported Outcomes .................................................. 66 
4.5.11 
Samples for Roche Clinical Repository.................................. 67 
4.5.11.1 
Overview of the Roche Clinical Repository............................ 67 
4.5.11.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 67 
4.5.11.3 
Sample Collection.................................................................. 67 
4.5.11.4 
Confidentiality........................................................................ 68 
4.5.11.5 
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 68 
4.5.11.6 
Withdrawal from the Roche Clinical Repository..................... 69 
4.5.11.7 
Monitoring and Oversight....................................................... 69 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 69 
4.6.1 
Patient Discontinuation.......................................................... 69 
4.6.2 
Study Treatment Discontinuation........................................... 70 
4.6.3 
Study and Site Discontinuation.............................................. 70 
5. 
ASSESSMENT OF SAFETY....................................................................... 71 
5.1 
Safety Plan ............................................................................ 71 
5.1.1 
Adverse Events Collection..................................................... 71 
5.1.2 
Adverse Events Relating to ALK Inhibitors and/or 
the Tyrosine Kinase Inhibitor Class and Alectinib 
Data....................................................................................... 71 
5.1.2.1 
Interstitial Lung Disease ........................................................ 71 
5.1.2.2 
Hepatotoxicity........................................................................ 71 
5.1.2.3 
Anemia .................................................................................. 72 
5.1.2.4 
Gastrointestinal Disorders ..................................................... 72 
5.1.2.5 
Skin Disorders ....................................................................... 72 
5.1.2.6 
Vision Disorders .................................................................... 73 
5.1.2.7 
Edema ................................................................................... 73 


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5.1.2.8 
Bradycardia ........................................................................... 73 
5.1.2.9 
Abnormal Renal Function ...................................................... 74 
5.1.2.10 
Severe Myalgia and CPK Elevations ..................................... 74 
5.1.3 
Management of Specific Adverse Events with 
Alectinib................................................................................. 75 
5.1.4 
Safety of Crizotinib and Management of Adverse 
Events.................................................................................... 78 
5.2 
Safety Parameters and Definitions ........................................ 81 
5.2.1 
Adverse Events ..................................................................... 81 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 82 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 82 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 83 
5.3.1 
Adverse Event Reporting Period ........................................... 83 
5.3.2 
Eliciting Adverse Event Information ....................................... 83 
5.3.3 
Assessment of Severity of Adverse Events ........................... 83 
5.3.4 
Assessment of Causality of Adverse Events ......................... 84 
5.3.5 
Procedures for Recording Adverse Events............................ 85 
5.3.5.1 
Diagnosis Versus Signs and Symptoms................................ 85 
5.3.5.2 
Adverse Events that are Secondary to Other 
Events.................................................................................... 85 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 85 
5.3.5.4 
Abnormal Laboratory Values ................................................. 86 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 87 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 87 
5.3.5.7 
Deaths ................................................................................... 87 
5.3.5.8 
Preexisting Medical Conditions.............................................. 88 
5.3.5.9 
Lack of Efficacy or Worsening of Non-Small Cell 
Lung Cancer.......................................................................... 88 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 88 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 89 
5.3.5.12 
Patient-Reported Outcome Data ........................................... 89 


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5.3.5.13 
Adverse Events in Individuals Not Enrolled in the 
Study ..................................................................................... 89 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 89 
5.4.1 
Emergency Medical Contacts................................................ 90 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 90 
5.4.2.1 
Events That Occur Prior to Study Drug Initiation ................... 90 
5.4.2.2 
Events That Occur After Study Drug Initiation ....................... 90 
5.4.3 
Reporting Requirements for Pregnancies.............................. 91 
5.4.3.1 
Pregnancies in Female Patients............................................ 91 
5.4.3.2 
Pregnancies in Female Partners of Male Patients................. 91 
5.4.3.3 
Abortions ............................................................................... 92 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 92 
5.5 
Follow-Up of Patients after Adverse Events .......................... 92 
5.5.1 
Investigator Follow-Up........................................................... 92 
5.5.2 
Sponsor Follow-Up ................................................................ 92 
5.6 
Post-Study Adverse Events .................................................. 93 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 93 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 93 
6.1 
Determination of Sample Size ............................................... 94 
6.2 
Summaries of Conduct of Study............................................ 95 
6.3 
Summaries of Treatment Group Comparability ..................... 95 
6.4 
Efficacy Analyses .................................................................. 96 
6.4.1 
Primary Efficacy Endpoint...................................................... 96 
6.4.2 
Secondary Efficacy Endpoints............................................... 97 
6.4.2.1 
Sensitivity Analyses............................................................... 99 
6.4.2.2 
Subgroup Analyses ............................................................... 99 
6.5 
Safety Analyses..................................................................... 99 
6.6 
Pharmacokinetic Analyses................................................... 100 
6.7 
Patient-Reported Outcome Analyses .................................. 101 


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6.7.1 
Time to Deterioration of Patient-Reported Lung 
Cancer Symptoms............................................................... 101 
6.7.2 
Additional Patient-Reported Outcomes ............................... 102 
6.8 
Exploratory Analyses........................................................... 102 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 103 
7.1 
Data Quality Assurance....................................................... 103 
7.2 
Electronic Case Report Forms............................................. 103 
7.3 
Electronic Patient-Reported Outcome Data......................... 104 
7.4 
Source Data Documentation................................................ 104 
7.5 
Use of Computerized Systems ............................................ 105 
7.6 
Retention of Records........................................................... 105 
8. 
ETHICAL CONSIDERATIONS.................................................................. 105 
8.1 
Compliance with Laws and Regulations .............................. 105 
8.2 
Informed Consent ................................................................ 105 
8.3 
Institutional Review Board or Ethics Committee.................. 107 
8.4 
Confidentiality...................................................................... 107 
8.5 
Financial Disclosure ............................................................ 107 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 108 
9.1 
Study Documentation .......................................................... 108 
9.2 
Protocol Deviations ............................................................. 108 
9.3 
Site Inspections ................................................................... 108 
9.4 
Administrative Structure....................................................... 108 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 109 
9.6 
Protocol Amendments ......................................................... 110 
10. REFERENCES ......................................................................................... 111 


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LIST OF TABLES 
Table 1 
Overall Response Rates and Time to Response in Patients 
in Part 2 of Study AF-001JP........................................................ 32 
Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib ...................................................................................... 75 
Table 3 
Crizotinib Dose Modification-Hematologic Toxicities (Except 
Lymphopenia) ............................................................................. 79 
Table 4 
Crizotinib Dose Modification-Non-Hematologic Toxicities........... 80 
Table 5 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in the NCI CTCAE ......................................... 84 
 
 
LIST OF FIGURES 
Figure 1 
Change in Size of Target Lesions as Assessed by the 
Independent Review Committee in Part 2 of Study AF-001JP 
Using RECIST v1.1 (Data Cutoff Date: 18 April 2013)................ 31 
Figure 2 
Duration of Dosing by Cohort in Patients in Part 1 of 
Study NP28761/AF-002JG (Data Cutoff Date: 
12 September 2013) ................................................................... 33 
Figure 3 
Best Percent Change in Size of Target Lesions from 
Baseline as Assessed by the Investigator in Patients in 
Part 1 of Study NP28761/AF-002JG (Data Cutoff Date: 
12 September 2013) ................................................................... 34 
Figure 4 
Summary of Study Design .......................................................... 41 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 116 
Appendix 2 
Schedule of Alectinib Pharmacokinetic Assessments............... 124 
Appendix 3 
List of Substrates, Inhibitors, and Inducers of Drug-
Metabolizing Enzymes and Transporters.................................. 125 
Appendix 4 
Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1: Excerpt from Original Publication.......................... 127 
Appendix 5 
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 138 
Appendix 6 
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires .......... 139 
Appendix 7 
Modification of Diet in Renal Disease (MDRD) Formula ........... 147 
Appendix 8 
Anaplastic Lymphoma Kinase (ALK) Immunohistochemistry.... 148 
Appendix 9 
Drug Metabolism Enzymes, Transporters (DMET), and Liver 
Injury Polymorphisms................................................................ 149 
Appendix 10 Formulae for the Calculation of QTcF and RR.......................... 151 


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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
RANDOMIZED, MULTICENTER, PHASE III, 
OPEN-LABEL STUDY OF ALECTINIB VERSUS 
CRIZOTINIB IN TREATMENT-NAIVE ANAPLASTIC 
LYMPHOMA KINASE-POSITIVE ADVANCED 
NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: BO28984 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2013-004133-33 
IND NUMBER: 
111723 
UTN NUMBER: 
 
TEST PRODUCT: 
Alectinib (RO5424802) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy to 
your local study monitor. 
 


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PROTOCOL SYNOPSIS 
TITLE: 
RANDOMIZED, MULTICENTER, PHASE III, OPEN-LABEL STUDY 
OF ALECTINIB VERSUS CRIZOTINIB IN TREATMENT-NAIVE 
ANAPLASTIC LYMPHOMA KINASE-POSITIVE ADVANCED 
NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: 
BO28984 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2013-004133-33 
IND NUMBER: 
111723 
UTN NUMBER: 
 
TEST PRODUCT: 
Alectinib (RO5424802) 
PHASE: 
Phase III 
INDICATION: 
Anaplastic lymphoma kinase−positive (ALK-positive) non−small cell 
lung cancer (NSCLC) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Efficacy Objectives 
The primary efficacy objective for this study is as follows: 
• 
To evaluate and compare the efficacy of alectinib compared to crizotinib in patients with 
treatment-naive anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung 
cancer (NSCLC), as measured by investigator-assessed progression-free survival (PFS) 
The secondary efficacy objectives for this study are as follows: 
• 
To evaluate and compare the Objective Response Rate (ORR) and Duration of Response 
(DOR) 
• 
To evaluate and compare the time to progression in the CNS on the basis of Independent 
Review Committee (IRC) review of radiographs by Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 and Revised Assessment in Neuro Oncology (RANO) criteria, as 
well as: 
To evaluate CNS objective response rate (C-ORR) in patients with CNS metastases 
who have measurable disease in the CNS at baseline  
To assess CNS duration of response (C-DOR) in patients who have a CNS Objective 
Response  
To assess CNS progression rates (C-PR) at 6, 12, 18, and 24 months on the basis of 
cumulative incidence  
• 
To evaluate and compare the PFS assessment by the IRC 
• 
To evaluate and compare the overall survival (OS) 
 
Safety Objective 
The safety objective for this study is as follows: 
• 
To evaluate the safety and tolerability of alectinib compared to crizotinib 
 


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Pharmacokinetic Objective 
The secondary pharmacokinetic (PK) objective for this study is as follows: 
• 
To characterize the pharmacokinetics of alectinib and metabolite(s) 
 
Patient-Reported Outcome Objectives 
The secondary patient-reported outcome (PRO) objectives for this study are as follows: 
• 
To evaluate and compare time to deterioration (TTD) in patient-reported lung cancer 
symptoms of cough, dyspnea (single item and multi-item subscales), chest pain, arm and 
shoulder pain, and fatigue as measured by the European Organization for the Research 
and Treatment of Cancer (EORTC) Quality of Life Questionnaire − Core (QLQ-C30) and the 
supplemental lung cancer module (QLQ-LC13) as well as a composite of three symptoms 
(cough, dyspnea, chest pain) 
• 
To evaluate and compare PROs of health-related quality of life (HRQoL), patient functioning, 
and side effects of treatment as measured by the EORTC QLQ-C30 and EORTC 
QLQ-LC13 
 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To evaluate and compare patient's health status as assessed by the EuroQoL 5 Dimension 
(EQ-5D-3L) questionnaire to generate utility scores for use in economic models for 
reimbursement 
• 
To evaluate and compare an onset of hypogonadism in adult men by measuring total 
testosterone and free testosterone (either by direct measurement or by calculation using 
albumin and sex hormone-binding globulin [SHBG]), follicle-stimulating hormone (FSH), and 
luteinizing hormone (LH) levels in blood 
• 
To evaluate and compare efficacy in patients with treatment-naive ALK-positive NSCLC as 
assessed by the FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott). 
• 
To evaluate and compare efficacy and safety in patients having treatment-naive ALK 
positive NSCLC as assessed by plasma ALK assays (polymerase chain reaction [PCR] 
and/or sequencing)  
• 
To determine the correlation between ALK status as assessed by plasma ALK PCR and/or 
plasma ALK sequencing tests, with ALK status obtained using the Ventana ALK IHC and 
FISH Vysis ALK Break Apart FISH Probe Kit (Abbott) 
• 
To investigate molecular mechanisms of resistance to ALK inhibitors 
• 
To investigate detection of ALK mutations/fusions in plasma  
 
Study Design 
Description of Study 
This is a randomized, active controlled, multicenter Phase III open-label study in patients with 
treatment-naive ALK-positive advanced NSCLC.  All patients are required to provide 
pretreatment tumor tissue to confirm the presence of ALK rearrangement (by Ventana 
immunohistochemistry [IHC] testing).  Patients will be randomized 1:1 into one of the two 
treatment arms to receive either alectinib or crizotinib. 
This study will comprise approximately 180 centers, in around 30 countries worldwide. 
The primary endpoint of the study is investigator-assessed PFS. 
Central randomization will be performed via an interactive voice or web-based response system 
(IxRS) using the following stratification factors:  Eastern Cooperative Oncology Group 
Performance Status (ECOG PS) (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at 
baseline (yes vs. no).  An IxRS manual containing relevant information will be provided to each 
study site. 
The experimental arm will receive alectinib at 600 mg orally twice daily (BID), taken with food.  
The control arm will receive crizotinib at 250 mg orally BID, taken with or without food.  The first 


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dose of the study drug should be administered as soon as possible after randomization, 
preferably within 24 hours, and no later than 48 hours after randomization. 
Patients will be treated until disease progression, unacceptable toxicity, withdrawal of consent, 
or death.  After disease progression (as per RECIST v1.1), patients should discontinue the 
study medication. After disease progression, patients will be treated at the discretion of the 
investigator according to local practice.  Information regarding the nature and the duration of 
subsequent therapies will be collected. 
In case of isolated asymptomatic CNS progression (e.g., new CNS oligometastases), a local 
therapy can be given (e.g., stereotactic radiotherapy or surgery) followed by continuation of 
either alectinib (in alectinib arm) or crizotinib (in crizotinib arm) until systemic disease 
progression and/or symptomatic CNS progression.  The decision to continue the treatment 
beyond isolated, asymptomatic CNS progression is at the investigator’s discretion for patients 
who can continue to benefit from respective treatment. 
Patients who discontinue treatment prior to disease progression (e.g., due to unacceptable 
toxicity or withdrawal of consent) will continue to be followed until disease progression and for 
OS regardless of whether they subsequently receive non-study anti-cancer therapy.  Data for 
subsequent therapy will be collected for the analysis of OS. 
Number of Patients 
Approximately 286 patients will be randomly assigned in a 1:1 allocation ratio to the two 
treatment arms via a block stratified randomization procedure and over a planned recruitment 
period of 24 months. 
Randomization will guard against systematic selection bias and should ensure the comparability 
of treatment groups.  To assist balance in important prognostic factors, randomization will be 
stratified by ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at baseline 
(yes vs. no). 
Target Population  
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not 
amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive 
as assessed by the Ventana IHC test.  Sufficient tumor tissue to perform ALK IHC and ALK 
FISH is required.  Both tests will be performed at designated central laboratories. 
• 
Age ≥ 18 years old 
• 
Life expectancy of at least 12 weeks 
• 
ECOG PS of 0−2 
• 
No prior systemic treatment for advanced or recurrent NSCLC (Stage IIIB not amenable for 
multimodality treatment) or metastatic (Stage IV) NSCLC 
• 
Adequate hematologic function: 
Platelet count ≥ 100 × 109/L 
ANC ≥ 1500 cells/μL 
Hemoglobin ≥ 9.0 g/dL 
• 
Adequate renal function: 
An estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet 
in Renal Disease equation of at least 45 mL/min/1.73 m2 
• 
Patients must have recovered from effects of any major surgery or significant traumatic 
injury at least 28 days before the first dose of study treatment. 
• 
Measurable disease (by RECIST v1.1) prior to the administration of study treatment 


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• 
Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed 
incidentally at study baseline).  Asymptomatic CNS lesions might be treated at the 
discretion of the investigator as per local clinical practice.  If patients have neurological 
symptoms or signs due to CNS metastasis, patients need to complete whole brain radiation 
or gamma knife irradiation treatment.  In all cases, radiation treatment must be completed at 
least 14 days before enrollment and patients must be clinically stable. 
• 
For all females of childbearing potential, a negative pregnancy test must be obtained within 
3 days before starting study treatment. 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus), agreement to remain abstinent or 
use single or combined contraceptive methods that result in a failure rate of  < 1% per year 
during the treatment period and for at least 3 months after the last dose of study drug.  
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  Examples of 
contraceptive methods with a failure rate of < 1% per year include tubal ligation, male 
sterilization, hormonal implants, established and proper use of combined oral or injected 
hormonal contraceptives, and certain intrauterine devices.  Alternatively, two methods 
(e.g., two barrier methods such as condom and cervical cap use) may be combined to 
achieve a failure rate < 1% per year.  Barrier methods must always be supplemented with 
the use of a spermicide.  
• 
For men, agreement to remain abstinent or use a condom plus an additional contraceptive 
method that together result in a failure rate of  < 1% per year during the treatment period 
and for at least 3 months after the last dose of study drug.  Abstinence is only acceptable if 
it is in line with the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.   
• 
Able and willing to provide written informed consent prior to performing any study-related 
procedures and to comply with the study protocol, including patients must be willing and 
able to use the electronic patient-reported outcome (ePRO) device. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients with a previous malignancy within the past 3 years are excluded (other than 
curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by 
endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered 
to have no impact in PFS and OS for the current NSCLC). 
• 
Any GI disorder that may affect absorption of oral medications, such as mal-absorption 
syndrome or status post-major bowel resection 
• 
Liver disease characterized by: 
ALT or AST > 3 × ULN (≥ 5 × ULN for patients with concurrent liver metastasis) 
confirmed on two consecutive measurements 
OR 
Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or other 
conditions of decompensated liver disease such as coagulopathy, hepatic 
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices 
OR 
Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis 
• 
National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) 
Grade 3 or higher toxicities due to any prior therapy such as radiotherapy (excluding 
alopecia), which have not shown improvement and are strictly considered to interfere with 
current study medication 
• 
History of organ transplant 


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• 
Co-administration of anti-cancer therapies other than those administered in this study 
• 
Patients with baseline QTc > 470 ms or symptomatic bradycardia 
• 
Administration of strong/potent cytochrome P450 (CYP) 3A inhibitors or inducers within 
14 days prior to the first dose of study treatment and while on treatment with alectinib or 
crizotinib 
• 
Administration of agents with potential QT interval prolonging effects within 14 days prior to 
the first administration of study drug for all patients and while on treatment through the end 
of the study for crizotinib-treated patients only (see protocol for details) 
• 
History of hypersensitivity to any of the additives in the alectinib drug formulation 
(see protocol for details)   
• 
History of hypersensitivity to any of the additives in the crizotinib drug formulation 
(see protocol for details) 
• 
Pregnant or lactating women  
• 
Known HIV positivity or AIDS-related illness 
• 
Any clinically significant concomitant disease or condition that could interfere with, or for 
which the treatment might interfere with, the conduct of the study or the absorption of oral 
medications or that would, in the opinion of the Principal Investigator, pose an unacceptable 
risk to the patient in this study 
• 
Any psychological, familial, sociological, or geographical condition potentially hampering 
compliance with the study protocol requirements and/or follow-up procedures; those 
conditions should be discussed with the patient before trial entry 
 
Length of Study 
The time from first patient screened to end of study, defined below, will be approximately 
43 months. 
End of Study 
This study is event driven, with a recruitment period of approximately 24 months.  The required 
number of events for the final analysis of the primary endpoint is expected approximately 
33 months after the first patient has been enrolled.  Patients are to be treated until disease 
progression, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.  
Follow-up for survival will continue until the survival follow-up analysis or the Sponsor decides to 
end the trial, whichever occurs first.  The study will formally end once the survival follow-up 
analysis is complete. 
A survival follow-up analysis will be performed once approximately 50% of patients 
(i.e., 143 patients) have died, which is estimated to occur approximately 42 months after the first 
patient has been enrolled. 
Outcome Measures 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
• 
PFS, which is defined as the time from randomization to the first documented disease 
progression, as determined by the investigators (primary endpoint) or IRC (secondary 
endpoint) using RECIST v1.1 or death from any cause, whichever occurs first.  Patients 
without an event will be censored at the last tumor assessment either during follow-up or 
during study treatment.  Patients with no post-baseline assessments will be censored at the 
date of randomization. 
• 
ORR, which is defined as the percentage of patients who attain complete response (CR) or 
partial response (PR); response, as determined by the investigators using RECIST v1.1.  
Patients without any assessments will be regarded as non-responders. 


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• 
Time to CNS progression, which is defined as the time from randomization to the first 
occurrence of disease progression in the CNS as determined by IRC using RECIST 
v1.1 and RANO (separate assessments and analyses), as well as C-ORR in patients with 
CNS metastases who have measurable disease in the CNS at baseline, C-DOR in patients 
who have a CNS Objective Response, and C-PR at 6, 12, 18, and 24 months 
• 
DOR, which is defined as the time from when response (CR or PR) was first documented to 
first documented disease progression or death (whichever occurs first).  This will only be 
calculated for patients who have a best overall response of CR or PR.  Patients who do not 
progress or die after they have had a response are censored at the date of their last tumor 
measurement. 
• 
OS, which is defined as the time from randomization to death from any cause.  Patients 
without an event will be censored at the last date known to be alive.  Patients without any 
follow-up information will be censored at the date of randomization. 
 
Safety Outcome Measures 
The secondary safety outcome measures for this study are as follows: 
• 
Serious and non-serious adverse events 
• 
Safety laboratory tests values 
• 
Vital signs (blood pressure, heart rate), ECG 
• 
Physical examination 
 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Sparse (pre-dose) PK samples for measurement of alectinib and its major metabolite(s) will 
be collected in all study patients receiving alectinib treatment 
• 
Serial/intensive PK sampling will be collected in a subset of consenting patients enrolled to 
receive alectinib treatment (approximately 10%−15%, at least approximately n = 20) 
• 
PK parameters will be determined as appropriate and where data allow: 
The pharmacokinetics of alectinib (and metabolite[s], if appropriate) will be described, 
and the between-patient variability will be estimated using a population PK approach.  
The potential influence of covariates that contribute significantly to the between-patient 
differences in PK parameters of alectinib will also be explored and quantified. 
Non-compartmental analysis may be conducted in patients undergoing serial/intensive 
PK sample collection, as appropriate and where data allow. 
 
Patient-Reported Outcome Measures 
The PRO measures for this study are as follows: 
• 
EORTC QLQ-C30 and the EORTC QLQ-LC13 to determine the impact of alectinib 
compared with crizotinib as measured by TTD in patient-reported lung cancer symptoms 
(e.g., cough, dyspnea [single item and multi-item scales], pain in chest, pain in 
arm/shoulder, fatigue) 
• 
The EORTC QLQ-C30 and EORTC QLQ-LC13 to measure PROs of HRQoL, patient 
functioning, and side effects of therapy compared between patients treated with alectinib 
and those treated with crizotinib 
 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
EQ-5D-3L to generate utility scores for use in economic models for the purpose of 
reimbursement 
• 
Total testosterone and free testosterone levels (either by direct measurement or by 
calculation using albumin and SHBG), FSH, and LH in blood to measure an onset of 
hypogonadism in adult men 


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• 
Results from the FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) to evaluate and 
compare efficacy in patients with treatment-naive NSCLC that is ALK-positive by FISH test 
• 
ALK fusion status in circulating tumor nucleic acids from plasma to evaluate and compare 
efficacy and safety in patients with treatment-naive NSCLC that is ALK-positive by plasma 
ALK tests (PCR and/or sequencing) for diagnostic purposes  
• 
Post-progression tumor mutation status to study molecular mechanisms of resistance to 
ALK inhibitors 
• 
ALK mutation status in plasma DNA to monitor efficacy and disease progression 
 
Investigational Medicinal Products 
Test Product 
Alectinib comes in a capsule dosage form containing the following active ingredient: 
[Chemical name] 9-Ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-6, 
11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride 
Each capsule contains 150 mg of alectinib (as free base) along with lactose monohydrate, 
carmellose calcium, hydroxypropyl cellulose, SLS, and magnesium stearate. 
Alectinib capsules should be stored in accordance with the storage instructions on the label. 
Alectinib capsules should be administered orally BID with food in the morning and evening. 
Comparator 
Crizotinib comes in a hard capsule dosage form.  Each capsule contains 250 mg or 200 mg 
crizotinib.  Crizotinib hard capsules should be stored in accordance with the storage instructions 
on the label.  Crizotinib capsules should be administered orally BID. 
For further details, see the local prescribing information for crizotinib (Xalkori®). 
Non-Investigational Medicinal Products 
Standard-of-care therapy administered to all patients in addition to test product or comparator. 
Statistical Methods 
Primary Analysis 
PFS is defined as the time from date of randomization to the date of first documented disease 
progression or death, whichever occurs first.  The primary endpoint of PFS will be determined 
on the basis of investigator assessment of progression using RECIST v1.1.  Patients who have 
not experienced disease progression or death at the time of analysis will be censored at the last 
tumor assessment date either during study treatment or during follow-up.  Patients with no 
post-baseline tumor assessment will be censored at the date of randomization. 
Patients who discontinue treatment prior to disease progression (e.g., due to toxicity) will 
continue on study and will be followed until disease progression and for OS regardless of 
whether they subsequently receive anti-cancer therapy. 
The treatment comparison of PFS will be based on a stratified log-rank test at the 5% level of 
significance (two-sided).  The stratification factors are the randomization stratification factors:  
ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at baseline (yes vs. no), 
as recorded on the eCRF.  Results from an unstratified log-rank test will also be presented. 
The Kaplan-Meier method will be used to estimate the median PFS for each treatment arm with 
95% confidence limits, and a Kaplan-Meier curve will be constructed to provide a visual 
description of the difference between the treatment arms.  A stratified Cox proportional 
regression model will be used including treatment in order to provide an estimate of the 
treatment effect expressed as a hazard ratio (HR) (alectinib vs. crizotinib), as well as a 95% CI. 
The difference between the two treatment groups will be assessed and tested for the following 
hypothesis:  the survival distribution function (SDF) of the alectinib treatment group is the same 
as for the crizotinib treatment group versus the alternative that the two distributions are different:  
H0:  SDF (alectinib) = SDF (crizotinib) 
versus 
H1:  SDF (alectinib) ≠ SDF (crizotinib) 
where SDF denotes the survival distribution function of the parameter PFS. 


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Determination of Sample Size   
The focus of this clinical trial is hypothesis testing, and the primary endpoint of PFS was used to 
determine the sample size of the study. 
At the time of initially writing the protocol, there were no Phase III data available on crizotinib in 
the first-line setting in ALK-positive patients.  The median PFS for crizotinib administered as 
second-line therapy from the global randomized Phase III PROFILE 1007 study was 7.7 months 
(95% CI: 6.0%, 8.8%).  From the Phase II single arm study of patients who had received ≥ 1 line 
of chemotherapy (with 85% patients having received ≥ 2 prior chemotherapy regimens), the 
median PFS was 8.5 months (95% CI: 6.2%, 9.9%).  The Phase III PROFILE 1014 study of 
crizotinib versus standard pemetrexed−platinum-based chemotherapy in previously untreated 
patients with ALK-positive non-squamous NSCLC reported a median PFS of 10.9 months for 
crizotinib. 
Thus, an initial assumption of median PFS of 9.8 months for the crizotinib arm has been 
reassessed based on data from the Phase III study PROFILE 1014 to 10.9 months.  An HR 
of 0.65 for alectinib versus crizotinib (i.e., an increase from 10.9 months median PFS to 
16.8 months) will be targeted. 
In this study, 286 patients will be enrolled in a 1:1 randomization allocation.  Enrollment will take 
approximately 24 months on the basis of an assumption of non-linear recruitment as follows: 
• 
Month 1:  1 patient per month 
• 
Month 2:  2 patients per month 
• 
Month 3:  4 patients per month 
• 
Month 4:  6 patients per month 
• 
Month 5:  8 patients per month 
• 
Month 6:  10 patients per month 
• 
Month 7:  12 patients per month 
• 
Months 8−12:  13 patients per month 
• 
Months 13−14:  14 patients per month 
• 
Month 15 onwards:  15 patients per month 
 
A total of 170 PFS events are required to achieve 80% power at a two-sided alpha level of 5%.  
This number of PFS events is estimated to occur approximately 33 months after the first patient 
has been enrolled. 
Interim Analyses 
No interim analysis for efficacy or futility is planned. 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
AUC 
area under the concentration−time curve 
BID 
twice daily 
Cmax 
maximum concentration 
C-DOR 
CNS duration of response 
C-ORR 
CNS objective response rate 
C-PR 
CNS progression rate 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DOT 
duration of treatment 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EGFR 
epidermal growth factor receptor 
EML4 
echinoderm microtubule-associated protein-like 4 
EORTC  
European Organization for the Research and Treatment of Cancer  
ePRO 
electronic patient-reported outcome 
EQ-5D-3L 
EuroQoL 5 Dimension 
FDA 
U.S. Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FSH 
follicle-stimulating hormone 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
HRQoL 
health-related quality of life 


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Abbreviation 
Definition 
ICH 
International Conference on Harmonisation 
iDMC 
independent Data Monitoring Committee 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITT 
intent-to-treat 
IxRS 
interactive voice or web-based response system 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
LH 
luteinizing hormone 
MET 
mesenchymal-epithelial transition factor 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCA 
non-compartmental analysis 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
not evaluable 
NSCLC 
non−small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
P-gp 
P-glycoprotein 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PRO 
patient-reported outcome 
PS 
Performance Status 
QLQ-C30 
Quality of Life Questionnaire−Core 
QLQ-LC13 
Quality of Life Questionnaire lung cancer module 
QTcF 
QT interval corrected using Fridericia’s formula 
RANO 
Revised Assessment in Neuro Oncology 
RCR 
Roche Clinical Repository 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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Abbreviation 
Definition 
RON 
recepteur d’origine nantais 
ROS1 
c-ros oncogene 1 
SAE 
serious adverse event 
SAP 
Safety Analysis Population 
SD 
stable disease 
SDF 
survival distribution function 
SHBG 
sex hormone-binding globulin  
SLS 
sodium lauryl sulfate 
TKI 
tyrosine kinase inhibitor 
TTD 
time to deterioration 
UGT 
uridine 5'-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 


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1. 
BACKGROUND 
1.1 
BACKGROUND ON ANAPLASTIC LYMPHOMA 
KINASE−POSITIVE NON−SMALL CELL LUNG CANCER 
Non−small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality 
worldwide.  Lung cancer was estimated to cause 160,340 deaths in the United States 
in 2012, accounting for 28% of all cancer-related deaths according to the report from the 
American Lung Association (Lung Cancer Fact Sheet).  There is an annual incidence of 
310,000 cases of NSCLC in men in Europe with a mortality of 276,000 deaths 
(GLOBOCAN 2008).  Among women in Europe, there is an annual incidence of 107,000 
cases and a mortality of 91,000 deaths.  In total, there are 417,000 cases of NSCLC and 
367,000 deaths in Europe each year, which represents a major health problem.  Survival 
rates for lung cancer tend to be much lower than other common cancers because of its 
late diagnosis and limited effective therapy in the advanced stage.  The expected 5-year 
survival rate for all patients in whom lung cancer is diagnosed is 16.3% compared with 
65.2% for colon cancer, 90.0% for breast cancer, and 99.9% for prostate cancer 
(Siegel et al. 2012).  Conventional anti-cancer therapies are far from satisfactory, and 
there is an unmet medical need for the development of new therapies for NSCLC. 
Recent progress in the identification of genetic mutations or chromosomal 
rearrangements in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral 
oncogene homolog (KRAS), mesenchymal-epithelial transition factor (MET), and other 
genes has provided new opportunities to use targeted therapeutic agents for the 
treatment of NSCLC, when the tumor is identified as having these mutations 
(Katayama et al. 2011; Doebele et al. 2012). 
Approximately 5% of NSCLC cases have been shown to harbor the echinoderm 
microtubule-associated protein-like 4 (EML4)−anaplastic lymphoma kinase (ALK) fusion 
gene as a result of a chromosomal inversion at 2p21 and 2p23 (Choi et al. 2010; 
Ou et al. 2012).  The formation of the resulting ALK fusion protein results in activation 
and dysregulation of the gene’s expression and signaling, which can contribute to 
increased cell proliferation and survival in tumors expressing these genes.  This is 
further supported by reports that the TFG and KIF5B genes can also serve as ALK 
fusion partners in some NSCLC patients.  Expression of these ALK fusion genes in 
mouse 3T3 fibroblasts causes their transformation and enhanced proliferation.  ALK 
gene alterations are generally in a mutually exclusive relationship with mutations in 
EGFR or KRAS (Soda et al. 2007; Inamura et al. 2008; Inamura et al. 2009; 
Wong et al. 2009), although EGFR mutations may develop as a resistance mechanism 
after treatment with crizotinib (Doebele et al. 2012).  Inhibition of ALK activity in Ba/F3 
cells transfected with the EML4-ALK fusion protein resulted in inhibition of cell growth 
(Ou et al. 2012), whereas a small molecule inhibitor of ALK demonstrated anti-tumor 
efficacy in two xenograft models in athymic mice, namely, the H3122 NSCLC and 
Karpas299 anaplastic large cell lymphoma models harboring the EML4-ALK and 


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nucleophosmin-ALK fusion proteins, respectively.  Hence, ALK appears to be a suitable 
therapeutic target for NSCLC with ALK gene rearrangements. 
Wild-type ALK is expressed at very low levels in most normal human tissues, but is 
expressed at higher levels in a few limited types of tissue such as developing and 
mature nervous system tissue (glial cells, neurons, endothelial cells, and pericytes) 
(Pulford et al. 1997).  By contrast, an aberrant ALK with constitutively active kinase 
results from the formation of the EML4-ALK fusion gene by chromosomal translocation. 
Currently, the only approved medicine for treatment-naive ALK-positive NSCLC is 
crizotinib (Xalkori®, Pfizer, Inc.), an inhibitor of receptor tyrosine kinases including ALK, 
hepatocyte growth factor receptor (HGFR, c-Met), recepteur d’origine nantais (RON), 
and c-ros oncogene 1 (ROS1) (Sahu et al. 2013).  
Crizotinib was first granted accelerated approval by the U.S. Food and Drug 
Administration (FDA) for the treatment of patients with locally advanced or metastatic 
NSCLC that is positive for ALK as detected by an FDA-approved test in August 2011. 
The approval was based on two single-arm trials.  The primary endpoint of both trials 
was objective response rate (ORR) as assessed by the investigator.  In one study, the 
ORR was 50% (95% CI: 42%, 59%) with a median response duration of 42 weeks, and, 
in the other study, the ORR was 61% (95% CI: 52%, 70%) with a median response 
duration of 48 weeks (Camidge et al. 2012; Kim et al. 2012).  In November 2013, the 
FDA granted regular approval for crizotinib on the basis of demonstrating superior 
progression-free survival (PFS) and ORR for crizotinib compared with chemotherapy in 
patients with ALK-positive NSCLC whose disease progressed after platinum-based 
doublet chemotherapy (PROFILE 1007 study).  An open-label active-controlled 
multinational randomized trial enrolled 347 patients with ALK-positive metastatic NSCLC.  
Patients were required to have disease progression following platinum-based 
chemotherapy.  The trial demonstrated significantly prolonged PFS with crizotinib 
treatment compared with chemotherapy (hazard ratio [HR] = 0.49 [95% CI: 0.37, 0.64], 
p < 0.0001).  Median PFS was 7.7 months for patients treated with crizotinib and 
3.0 months for patients treated with chemotherapy.  The ORR was significantly higher 
for patients treated with crizotinib (65% vs. 20%), with median response durations of 
7.4 months for patients treated with crizotinib and 5.6 months for patients treated with 
chemotherapy.  No difference in overall survival (OS) was noted between the two groups 
(HR = 1.02 [95% CI: 0.68%, 1.54%]) in a planned interim analysis (Shaw et al. 2013).  
Common adverse reactions in clinical trials with crizotinib, occurring at an incidence of 
25% or higher, included visual disorders, nausea, diarrhea, vomiting, constipation, 
edema, elevated transaminases, and fatigue (National Cancer Institute 2013).  These 
results showed that an ALK inhibitor is effective in patients with NSCLC harboring ALK 
fusion genes.  Crizotinib has subsequently been approved in other countries, such as 
Japan, Korea, Canada, and Switzerland.  In the European Union, crizotinib was 
conditionally approved in October 2012 for the treatment of adults with previously treated 
ALK positive NSCLC. 


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Although substantial benefit has been observed with crizotinib therapy, relapse remains 
the norm.  Studies with patients who had progression with crizotinib treatment revealed 
two main reasons for treatment failure: the development of resistance because of 
secondary (e.g., gatekeeper) mutations (predominantly in ALK or occasionally in other 
genes, such as EGFR, cKIT, or KRAS) (Katayama et al. 2011; Doebele et al. 2012; 
Kim et al. 2013) and CNS relapse (crizotinib has impaired control of brain metastases in 
comparison to other sites of systemic disease).  The CNS is the primary site of initial 
treatment failure in 46% of patients with ALK-positive NSCLC treated with crizotinib 
(Costa et al. 2011; Chun et al. 2012; Weickhardt et al. 2012).  Significant morbidity is 
associated with brain metastases as a function of brain involvement, and because of 
treatment (corticosteroids, surgery, and radiation) required for disease control. 
A new generation of ALK inhibitors will have the potential to overcome these two major 
limitations of crizotinib treatment and may offer patients a better chance of prolonged 
remission and minimize the development of CNS metastases and the attendant 
comorbidity. 
1.2 
BACKGROUND ON ALECTINIB 
Alectinib (also RO5424802 or CH5424802) is a newly developed small molecule, highly 
selective, and potent oral next-generation ALK inhibitor with a benzo[b]carbazole 
scaffold.  In enzyme inhibition assays performed in vitro, this compound has been shown 
to selectively inhibit ALK.  The compound also shows high antitumor activity both in vitro 
and in vivo against tumor cell lines with some types of ALK gene alteration, including 
NSCLC and anaplastic large cell lymphoma lines harboring an ALK translocation and a 
neuroblastoma line harboring amplified ALK gene. 
Nonclinical pharmacology studies showed that alectinib is efficacious in a model of 
tumors expressing an ALK fusion bearing the L1196M mutation, which is associated with 
resistance to crizotinib, and alectinib is effective in mouse NCI H2228 NSCLC xenografts 
that are already maximally suppressed by crizotinib.  Alectinib also prolongs survival in 
an intracerebral NCI H2228 implantation model, and it reduces tumor growth in an 
intracranial model monitored using bioluminescence. 
The clinical development program for alectinib, to date, comprises three ongoing 
Phase I/II studies in patients with ALK-positive NSCLC.  The ongoing Phase I/II studies 
are as follows:  Study AF-001JP, which is being conducted in Japan; 
Study NP28761/AF-002JG, which is being conducted in United States and Canada; and 
Study NP28673, which is being conducted globally. 
The first-in-human study AF-001JP is an open-label Phase I/II study being conducted in 
Japan.  This study is assessing the pharmacokinetics, safety, and efficacy of alectinib in 
patients with ALK-positive NSCLC who are crizotinib-naive and have disease 
progression after at least one line of chemotherapy.  This study has completed 
enrollment, but it is still ongoing.  A total of 70 patients were included (24 patients in the 


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Phase I portion and 46 patients in the Phase II portion of the study).  In the Phase I 
portion of the study, at the data cutoff date of 31 July 2012, 24 patients were treated at 
doses of 20−300 mg twice daily (BID).  No dose-limiting toxicities (DLTs) or adverse 
events of Grade 4 were noted up to the highest dose; thus, 300 mg BID was evaluated 
in the Phase II portion of the study without further escalating the dose.  In the Phase II 
portion of the study, 46 patients were treated with the highest evaluated dose of 300 mg 
BID, of whom 43 achieved an objective response (93.5%; 95% CI: 82.1%, 98.6%) and 
7 patients had a complete response (CR) on the basis of an independent radiological 
review in the 12-month follow-up analysis (data cutoff for response data: 18 April 2013).  
The median duration of treatment (DOT) in the study has not been achieved at that date 
because 86% of patients were still on treatment in the study, but the projected median 
DOT is more than 14 months as data mature. 
Figure 1 shows the waterfall plot of the best change from baseline in the size of target 
lesions by an independent radiological review.  Table 1 shows the ORR by time interval.  
The majority (86%) of patients had a time to response of within 6 weeks after 
administration of the first dose. 
Figure 1 Change in Size of Target Lesions as Assessed by the 
Independent Review Committee in Part 2 of Study AF-001JP 
Using RECIST v1.1 (Data Cutoff Date: 18 April 2013) 
 


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Two of 7 patients who were assessed as having a CR had lymph nodes as the target 
lesions.  Per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), 
the percent change from baseline for patients with CR can be less than 100% when 
lymph nodes are identified as the target lesions.  Therefore, they were assessed as 
having CR, although their tumor change from baseline was less than 100%. 
Table 1 
Overall Response Rates and Time to Response in Patients 
in Part 2 of Study AF-001JP 
Response (Data Cutoff Date: 18 April 2013) 
IRC Assessment (N = 46) 
Complete response 
7 
Partial response 
36 
Stable disease 
1 
Progressive disease 
0 
Not evaluable 
2 
Total response 
43 
Overall response rate (95% CI) 
93.5% (82.1%, 98.6%) 
Time to Response 
IRC Assessment (N = 43) 
0 to ≤ 3 weeks 
22 (51%) 
> 3 to ≤ 6 weeks 
15 (35%) 
> 6 to ≤ 9 weeks 
3 (7%) 
> 9 weeks 
3 (7%) 
IRC = Independent Review Committee. 
 
In Study NP28761/AF-002JG (crizotinib-failed ALK-positive NSCLC patients), the 
Phase I portion has completed enrollment.  Two ‘bridging’ cohorts of patients receiving 
alectinib using the 150-mg capsule at 600 and 900 mg BID were included in 
Study NP28761/AF-002JG to transition/facilitate the planned formulation for the Phase II 
trials.  A total of 47 patients were enrolled in Phase I (Part 1).  There does not appear to 
be any substantial difference in pharmacokinetics between the two formulations 
(20/40-mg capsule and the 150-mg capsule) at the 600-mg dose on the basis of 
available data. 
The radiological imaging analysis performed in 44 evaluable patients who had a baseline 
scan and at least one follow-up scan (data cutoff date: 12 September 2013) has shown 
that 2 of 7 patients in the 300-mg BID dosage cohort, 5 of 7 patients in the 460-mg BID 
dosage cohort, 4 of 10 patients in the 600-mg BID dosage cohort, and 4 of 13 patients 
(including 1 patient with CR) in the 900-mg BID dosage cohort have achieved a 
confirmed partial response (PR), as assessed by the investigator.  Three of 10 patients 
in the 600-mg BID dosage cohort, 2 of 7 patients in the 760-mg BID dosage cohort, and 
4 of 13 patients in the 900-mg BID dosage cohort have achieved a PR, as assessed by 
the investigator, which is still to be confirmed.  Three patients (all in the 600-mg BID 






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both systemic disease and CNS progression).  No patient discontinued because of CNS 
progression alone. 
In addition, 2 patients with leptomeningeal carcinomatosis received benefit from alectinib 
treatment.  One patient with leptomeningeal spread in Study NP28761/AF-002JG 
achieved PR after 6 weeks of treatment.  Another patient with leptomeningeal 
carcinomatosis but without systemic lesions was treated under a single-patient 
Investigational New Drug (IND) application because of ineligibility to enter either of the 
two Phase II alectinib studies (because of the high intake of dexamethasone for 
symptom control).  After 6 weeks of treatment, this patient achieved CR as 
demonstrated by complete disappearance of gadolinium enhancement on magnetic 
resonance imaging (MRI) and disappearance of positive CSF cytology.  This patient has 
been able to reduce corticosteroids to physiological replacement dose only. 
See the Alectinib Investigator's Brochure for additional details on nonclinical and clinical 
studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Over the past 10 years, the treatment of NSCLC has become increasingly focused on 
guiding treatment based on the presence or absence of an actionable mutation.  
Numerous oncogenes have now been identified in NSCLC, including mutations in the 
genes coding for EGFR, KRAS, phosphoinositide-3-kinase (specifically, the catalytic α 
polypeptide), and EGFR 2 (Pao and Girard 2011).  As described in previous sections, a 
translocation in the gene encoding the receptor tyrosine kinase ALK, leading to the 
expression of ALK fusion proteins, was identified as an oncogenic driver in a subset of 
patients with NSCLC (Soda et al. 2007).  ALK rearrangements are found in 
approximately 4.6% of unselected patients with NSCLC (Koivunen et al. 2008; 
Takeuchi et al. 2008; Boland et al. 2009; Wong et al. 2009; Bang 2011; Kim et al. 2011; 
Paik et al. 2011; Cardarella et al. 2012; Dai et al. 2012; Fukui et al. 2012;). 
Crizotinib is the first ALK inhibitor that has been approved and registered in multiple 
countries worldwide for the treatment of ALK-positive NSCLC.  Crizotinib is an oral 
small-molecule multitargeted tyrosine kinase inhibitor (TKI) targeting ALK, MET, RON, 
and ROS1 tyrosine kinases (Sahu et al. 2013, Shaw et al. 2013).  The previous clinical 
studies reported that the median PFS with crizotinib ranged from 7.7−9.7 months 
(Camidge et al. 2012, Kim et al. 2013, Shaw et al. 2013).  The PROFILE 1014 study, a 
Phase III study of crizotinib compared to standard pemetrexed-platinum-based 
chemotherapy, was presented at the ASCO 2014 congress (Mok et al. 2014).  The study 
met its primary objective of prolonging PFS in previously untreated patients with 
ALK-positive non-squamous NSCLC with median PFS of 10.9 and 7.0 months 
(HR: 0.454; 95% CI: 0.346, 0.596; p < 0.0001) for crizotinib and 
pemetrexed-platinum-based chemotherapy, respectively. 


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Although substantial benefit has been observed with crizotinib therapy, relapse 
eventually occurs.  Two major reasons for this are the development of resistance 
because of secondary (e.g., gatekeeper) mutations, or CNS relapse 
(Katayama et al. 2011; Doebele et al. 2012; Kim et al. 2013).  This could be due to the 
fact that crizotinib is a P-gp substrate and has a low penetration in the CNS.  Thus, 
ALK-positive NSCLC treated with crizotinib has impaired control of brain metastases 
relative to other sites of systemic disease, with 46% of progressions in patients treated 
with crizotinib involving the CNS (Costa et al. 2011; Weickhardt et al. 2012).  The CNS 
becomes a sanctuary site for ALK-positive NSCLC treated with crizotinib⎯a physiologic 
and anatomic mechanism of drug resistance. 
Alectinib is a highly selective and potent oral next generation ALK inhibitor.  Clinical data 
collection from the Phase II portion is still ongoing.  Study AF-001JP, assessing alectinib 
in patients with ALK-positive NSCLC who are crizotinib-naive and have disease 
progression after at least one line of chemotherapy, reported that the median treatment 
duration in the study had not been achieved as 86% of patients were still active on the 
study, but the projected median DOT is estimated to be at least 14 months at the final 
point of data collection (Inoue et al. 2013). 
Moreover, alectinib is a lipophilic drug and is not a P-glycoprotein (P-gp) substrate.  
Thus, it is able to penetrate the blood-brain barrier and has the potential to reach higher 
concentrations in the brain as compared to substrates of P-gp such as crizotinib.  This 
has been shown in the nonclinical setting on the basis of the prolongation of survival in a 
mouse model with implanted CNS lesions and in a tissue distribution study with a single 
oral dose of [14C]-alectinib at 1 mg/kg in albino rats (Ou et al. 2013).  Preliminary clinical 
data from the Phase I/II studies show consistent therapeutic efficacy of alectinib in brain 
metastases. 
The clinical efficacy data is compelling given the demonstrated activity for a longer 
progression-free interval with alectinib treatment and improved activity in the CNS.  This 
progression-free interval delays the impact of CNS metastases on neurologic function 
along with the morbidities associated with treatment like brain radiation, surgery and 
corticosteroid use required for disease control.  The currently available clinical safety 
data is supportive of an acceptable safety and tolerability profile with alectinib.  
Altogether, it would be important to compare alectinib to crizotinib as a therapeutic 
option for treatment-naive ALK-positive advanced NSCLC patients. 
Alectinib was granted approval in Japan on 04 July 2014 for treatment of ALK fusion 
gene-positive, unresectable, recurrent or advanced NSCLC. 
In this proposed Phase III study, treatment-naive patients with ALK-positive advanced 
NSCLC will be enrolled and will be randomized to receive either crizotinib or alectinib 
treatment.  The results of this study will determine whether alectinib treatment has 
superior efficacy compared to crizotinib. 


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The first Phase I dose-escalation study of alectinib (Study AF001-JP, conducted only in 
Japan) with a dose schedule of 20, 40, 80, 160, 240, and 300 mg BID orally showed that 
alectinib was generally well tolerated without major toxicities.  Of the 58 patients who 
received treatment with 300 mg BID alectinib in Study AF-001JP, 27 experienced 
Grade 3 adverse events and 9 experienced serious adverse events.  No deaths were 
reported during this study and up to 28 days after treatment discontinuation.  There were 
5 adverse events leading to treatment discontinuation in Part 2 (brain edema, sclerosing 
cholangitis, interstitial lung disease [ILD], ALT increased, and tumor hemorrhage).  
Alectinib was well tolerated at all doses investigated in this study.  Its adverse event 
profile was consistent with the one known to be associated with TKIs.  In the 
Phase II Study NP28761/AF-002JG, alectinib was well tolerated with no DLTs or 
treatment-related dose modifications up to 600 mg BID.  Two DLTs were reported at 
900 mg BID.  The recommended alectinib Phase II dosage of 600 mg BID was chosen 
as having the best balance between clinical safety, efficacy, and pharmacokinetic (PK) 
data as observed in the Phase I/II studies (see Section 3.3.1). 
On the basis of available preliminary data, the estimated benefits of alectinib treatment 
outweigh the risks.  Specifically: 
• 
Available nonclinical and clinical data demonstrate that alectinib is active in NSCLC 
in crizotinib-naive patients as well as after progression on prior crizotinib therapy. 
• 
Clinical safety data in humans up to 900 mg BID demonstrate that its safety profile 
is consistent to the one known to be associated with ALK inhibitors. 
 
Identified and potential risks associated with alectinib treatment will continue to be 
closely monitored throughout the clinical program.  Patient safety during the alectinib 
program is ensured by targeting the most appropriate patient population, stringent safety 
monitoring by the Sponsor and independent Data Monitoring Committee (iDMC), and by 
protocol-specified study drug interruption criteria. 
2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The primary efficacy objective for this study is: 
• 
To evaluate and compare the efficacy of alectinib compared to crizotinib in patients 
with treatment-naive ALK-positive advanced NSCLC, as measured by 
investigator-assessed PFS 
 
The secondary efficacy objectives for this study are: 
• 
To evaluate and compare the Objective Response Rate (ORR) and Duration of 
Response (DOR) 


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• 
To evaluate and compare the time to progression in the CNS on the basis of IRC 
review of radiographs by RECIST v1.1 and Revised Assessment in Neuro Oncology 
(RANO) criteria, as well as: 
To evaluate CNS objective response rate (C-ORR) in patients with CNS 
metastases who have measurable disease in the CNS at baseline  
To assess CNS duration of response (C-DOR) in patients who have a CNS 
Objective Response  
To assess CNS progression rates (C-PR) at 6, 12, 18, and 24 months on the 
basis of cumulative incidence  
• 
To evaluate and compare the PFS assessment by the IRC 
• 
To evaluate and compare the OS 
 
2.2 
SAFETY OBJECTIVES 
The secondary safety objective for this study is: 
• 
To evaluate the safety and tolerability of alectinib compared to crizotinib 
 
2.3 
PHARMACOKINETIC OBJECTIVES 
The secondary PK objective for this study is: 
• 
To characterize the pharmacokinetics of alectinib and metabolite(s) 
 
2.4 
PATIENT-REPORTED OUTCOME OBJECTIVES 
The secondary patient-reported outcome (PRO) objectives for this study are: 
• 
To evaluate and compare time to deterioration (TTD) in patient-reported lung cancer 
symptoms of cough, dyspnea (single item and multi-item subscales), chest pain, 
arm and shoulder pain, and fatigue as measured by the European Organization for 
the Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire−Core (QLQ-C30) and the supplemental lung cancer module 
(QLQ-LC13) as well as a composite of three symptoms (cough, dyspnea, chest pain) 
• 
To evaluate and compare PROs of health-related quality of life (HRQoL), patient 
functioning, and side effects of treatment as measured by the EORTC QLQ-C30 
and EORTC QLQ-LC13 
 
2.5 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are: 
• 
To evaluate and compare patient’s health status as assessed by the EuroQoL 5 
Dimension (EQ-5D-3L) questionnaire to generate utility scores for use in economic 
models for reimbursement 
• 
To evaluate and compare the onset of hypogonadism in adult men by measuring 
total testosterone and free testosterone (either by direct measurement or by 
calculation using albumin and sex hormone-binding globulin [SHBG]), 
follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels in blood 


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• 
To evaluate and compare efficacy in patients with treatment-naive ALK-positive 
NSCLC as assessed by the FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) 
• 
To evaluate and compare efficacy and safety in patients having treatment-naive 
ALK positive NSCLC as assessed by plasma ALK assays (polymerase chain 
reaction [PCR] and/or sequencing)  
• 
To determine the correlation between ALK status as assessed by plasma ALK PCR 
and/or plasma ALK sequencing tests, with ALK status obtained using the Ventana 
ALK IHC and FISH Vysis ALK Break Apart FISH Probe Kit (Abbott) 
• 
To investigate molecular mechanisms of resistance to ALK inhibitors. 
• 
To investigate detection of ALK mutations/fusions in plasma 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a randomized, active-controlled, multicenter Phase III open-label study in patients 
with treatment-naive ALK-positive advanced NSCLC.  All patients are required to provide 
pretreatment tumor tissue to confirm the presence of ALK rearrangement (by Ventana 
immunohistochemistry [IHC] test).  Patients will be randomized 1:1 into one of the two 
treatment arms to receive either alectinib or crizotinib. 
This study will comprise approximately 180 centers, in around 30 countries worldwide. 
The primary endpoint of the study is investigator-assessed PFS. 
Central randomization will be performed via an interactive voice or web-based response 
system (IxRS) using the following stratification factors:  Eastern Cooperative Oncology 
Group Performance Status (ECOG PS) (0/1 vs. 2), race (Asian vs. non-Asian), and CNS 
metastases at baseline (yes vs. no).  An IxRS manual containing relevant information 
will be provided to each study site. 
The experimental arm will receive alectinib at 600 mg orally BID, taken with food.  The 
control arm will receive crizotinib at 250 mg orally BID, taken with or without food.  The 
first dose of the study drug should be administered as soon as possible after 
randomization, preferably within 24 hours, and no later than 48 hours after 
randomization. 
Patients will be treated until disease progression, unacceptable toxicity, withdrawal of 
consent, or death.  After disease progression (as per RECIST v1.1), patients should 
discontinue the study medication.  After disease progression, patients will be treated at 
the discretion of the investigator according to local practice.  Information regarding the 
nature and the duration of subsequent therapies will be collected. 
In case of isolated asymptomatic CNS progression (e.g., new CNS oligometastases), 
local therapy can be given (e.g., stereotactic radiotherapy or surgery) followed by 


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continuation of either alectinib (in alectinib arm) or crizotinib (in crizotinib arm) until 
systemic disease progression and/or symptomatic CNS progression.  The decision to 
continue the treatment beyond isolated, asymptomatic CNS progression is at the 
investigator’s discretion for patients who can continue to benefit from their respective 
treatment. 
Patients who discontinue treatment prior to disease progression (e.g., due to 
unacceptable toxicity or withdrawal of consent) will continue to be followed until disease 
progression and for OS regardless of whether they subsequently receive non-study 
anti-cancer therapy.  Data for subsequent therapy will be collected for the analysis of OS. 
Approximately 286 patients (143 per treatment arm) will be enrolled into the study over a 
planned competitive recruitment period of 24 months.  Patients inappropriately 
randomized into the study will not be replaced.  The final analysis evaluating the primary 
endpoint of investigator-assessed PFS will occur when approximately 170 patients have 
progressed or died, which is expected to occur approximately 33 months after the first 
patient has been enrolled.  Data collection will continue for each patient until death or 
study closure, whichever occurs first. 
An iDMC will be established to monitor the progress of the study and ensure that the 
safety of patients enrolled in the study is not compromised as outlined in Section 9.4. 
A summary of the study design is shown in Figure 4. 
A schedule of assessments is provided in Appendix 1. 




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3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Alectinib Dosage 
Selection of the alectinib dose for the study is based on the clinical safety, efficacy, and 
PK data observed in the Phase I/II studies, AF-001JP and NP28761/AF-002JG, and the 
supportive nonclinical data for alectinib. 
The first-in-human study, AF-001JP evaluated escalating doses of alectinib in an 
accelerated titration scheme to rapidly identify the maximum tolerated dose (MTD).  All 
doses, including the highest evaluated dose in the study, 300 mg BID, were well 
tolerated with no DLTs observed at any dose.  The highest tested dose, 300 mg BID, 
was further evaluated in the Phase II portion of the study and demonstrated robust 
efficacy and good safety with an ORR by IRC of 93.5% (43/46 patients; 95% CI: 82.1%, 
98.6%). 
With no MTD determined in Study AF-001JP, dose escalation progressed in the North 
American Study NP28761/AF-002JG using a modified 3 + 3 design, where 3 patients 
were assessed for DLT evaluation whereas additional patients were enrolled for PK 
evaluation.  The starting dose in Study NP28761/AF-002JG was the highest dosage 
evaluated in Study AF-001JP, 300 mg BID.  Following multiple dosages of alectinib at 
300 mg BID in Study NP28761/AF-002JG, median alectinib exposure (area under the 
concentration-time curve [AUC] from 0 to 10 hours) appeared to be approximately 
two-fold lower compared with that in patients from Study AF-001JP, which demonstrated 
robust efficacy and safety.  Dose escalation progressed with evaluation of higher doses 
of alectinib up to 900 mg BID. 
In Study NP28761/AF-002JG, no DLTs were observed in the dose escalation cohorts up 
to dose-level of 900 mg BID.  However, 2 patients in the subsequent 900 mg BID 
bridging cohort experienced a DLT; 1 patient had Grade 3 headache and 1 patient had 
Grade 3 neutropenia, and both patients continued study treatment at a reduced dosage 
of 600 mg BID.  Overall, alectinib was well tolerated in the study population.   
Importantly, administration of 600 mg BID provides systemic exposures that meet or 
exceed exposures achieved in patients receiving 300 mg BID in Study AF-001JP, 
demonstrating its robust efficacy and safety in crizotinib-naive patients.  Furthermore, in 
Study NP28761/AF-002JG, the 600 mg BID regimen has demonstrated promising 
activity in crizotinib-resistant patients, including activity in patients with CNS metastases 
while being tolerated by patients.  On the basis of available preclinical data, 
administration of alectinib 600 mg BID provides systemic exposures within the expected 
range (on the basis of regression of available data) for tumor regression observed in 
mouse xenograft models. 
Thus, on the basis of nonclinical and clinical data, a dosing regimen of 600 mg BID of 
alectinib has been chosen as the optimal therapeutic dose level with the best balance 
between efficacy and safety. 


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Alectinib at 600 mg should be administered orally BID with food in the morning and 
evening. 
3.3.2 
Rationale for Patient Population 
The study population will comprise patients with non-resectable, locally advanced and 
metastatic NSCLC who have been shown to be ALK-positive by the Ventana IHC test 
performed at central laboratories specially designated for the study.  Patients should not 
have received any prior treatment for advanced NSCLC (treatment-naive). 
Both experimental (alectinib) and control (crizotinib) treatments are ALK-targeted 
therapies.  The clinical practice guidelines recommend targeted treatment for patients 
with metastatic, oncogene-driven disease as first-line systemic therapy 
(i.e., EGFR-inhibitors for EGFR-positive NSCLC and ALK-inhibitors for ALK-positive 
NSCLC) (NCCN 2014).  
To be eligible for the study, determination of ALK positivity will be performed centrally 
using the IHC assay (see Appendix 8) that is being developed by Ventana Medical 
Systems as a companion diagnostic to alectinib.  IHC may replace fluorescence in situ 
hybridization (FISH)-based identification of ALK rearrangement as the standard 
companion diagnostic in the future.  IHC is faster, easier to perform in local laboratories, 
and requires less equipment compared with the FISH assay.  In addition, IHC has high 
concordance with FISH and a lower false-negative rate (Kim et al. 2011). 
3.3.3 
Rationale for Control Group 
Targeted therapy (including ALK-targeted therapy) is likely to have a greater anti-tumor 
effect than standard chemotherapy, offering patients a higher response rate and longer 
durability of response with less toxicity compared with any potential chemotherapy 
options (Mok et al. 2009; Rosell et al. 2012; Sequist et al. 2013; Shaw et al. 2013). 
Crizotinib (Xalkori®) is an oral small-molecule multi-targeted TKI targeting ALK, MET, 
RON, and ROS1 tyrosine kinases (Sahu et al. 2013, Shaw et al. 2013).  It is the only 
first-generation ALK inhibitor that has been approved in multiple countries worldwide for 
the treatment of ALK-positive NSCLC. 
In the United States, in November 2013, crizotinib was granted a regular approval for the 
ALK-positive NSCLC setting regardless of treatment line (XALKORI® U.S. Package 
Insert), whereas in Europe, crizotinib is currently only approved conditionally for patients 
with previously treated ALK-positive NSCLC (Crizotinib SmPC). 
The National Comprehensive Cancer Network (NCCN) guidelines recommend crizotinib 
as a first-line therapy for patients with advanced ALK-positive NSCLC (NCCN 2014). 
The randomized Phase III PROFILE 1014 study was conducted to assess the efficacy of 
crizotinib versus standard platinum-based chemotherapy (pemetrexed plus cisplatin or 


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carboplatin) as first-line treatment for patients with ALK-positive, non-squamous NSCLC.  
The study met its primary objective of prolonging PFS in previously untreated patients 
with ALK-positive non-squamous NSCLC with median PFS of 10.9 and 7.0 months 
(HR: 0.454; 95% CI: 0.346, 0.596; p < 0.0001) for crizotinib and pemetrexed 
platinum-based chemotherapy, respectively (Mok et al. 2014).  The authors concluded 
that these findings support crizotinib as the standard of care for patients with previously 
untreated advanced ALK-positive non-squamous NSCLC (Mok et al. 2014). 
Crizotinib will be dosed as per standard dose recommendations from prescribing 
information; patients in the crizotinib arm will receive crizotinib at 250 mg orally BID with 
or without food until disease progression, unacceptable toxicity, withdrawal of consent, 
or death.  See Section 5.1.4 for criteria for dosing interruption and/or dose reduction for 
treatment with crizotinib.  
3.3.4 
Rationale for Open-Label Design 
An open-label study design is more appropriate for patients enrolled in this particular trial 
for a number of reasons described below, and with the ultimate goal to ensure patient 
compliance as much as possible. 
For a blinded study design, all enrolled patients would be required to take five large 
capsules twice per day.  This high pill count results from the difference in capsule size 
between crizotinib (size 0) and alectinib (size 1).  Each dose would comprise one 
250-mg capsule of crizotinib or matching placebo and four 150-mg capsules of alectinib 
or matching placebo.  In order to blind, crizotinib capsules must be over-encapsulated. 
That further increases the size of a capsule from size 0 to size 00.  Size 00 is usually the 
largest capsule size used orally for humans.  For some patients, size 00 capsules are 
too large to swallow.  This high pill count of large capsules is considered to be a 
significant burden to patients and increases the risk of non-compliance. 
Additionally, a blinded study would increase the complexity of standard dose reductions.  
Dose interruption or dose reduction may be required on the basis of individual safety and 
tolerability.  The standard dose reductions for crizotinib would be 200 mg BID (different 
capsule, size 1), followed by 250 mg QD.  Dose reductions for alectinib would occur in 
150-mg steps.  In a double-blind study, these multiple step dose reductions introduce a 
high level of complexity and potential for error. 
In order to avoid a significant burden to patients with high pill count, increased risk of 
non-compliance, and complexity of standard dose reductions, adequate steps have been 
taken to ensure the validity of the data in an open-label study design.  These include 
performing a supportive analysis of efficacy on the basis of determining progression by 
an IRC, performing sensitivity analyses to demonstrate the robustness of the primary 
endpoint, defining progression using established response evaluation criteria 
(RECIST v1.1), performing tumor assessment at the same frequency in both arms and 
adhering to protocol-defined schedules, and finalizing the strategy for the final analysis 


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of the primary endpoint before trial start, including developing predefined methods for 
handling missing data and censoring rules.  Efficacy analyses will only be performed at 
the pre-specified analysis timepoints in the protocol (final analysis once 170 PFS events 
have occurred and survival follow-up analysis at 143 events). 
3.3.5 
Rationale for Primary Endpoint Selection 
The investigator-assessed PFS (which will be supported by IRC-assessed PFS analysis, 
one of the secondary endpoints of the study) is the primary endpoint for this trial. 
PFS, as an endpoint, can reflect tumor growth and can be assessed before the 
determination of a survival benefit, and its determination is not generally confounded by 
subsequent therapies.  Whether an improvement in PFS represents a direct clinical 
benefit or a surrogate for clinical benefit depends on the magnitude of the effect and the 
risk-benefit of the new treatment compared to available therapies (Guidance for 
Industry 2007; European Medicines Agency 2012).  A PFS HR of 0.65 will be targeted, 
which constitutes a clinically meaningful benefit in this patient population as it will delay 
the use of platinum-based chemotherapy and will potentially reduce the frequency of 
CNS relapse and the morbidity associated with treating CNS metastases. 
The assumed median PFS of patients in the alectinib treatment arm is 16.8 months, and 
an OS of more than 30 months is expected, which equates to a post-progression 
survival of at least 13 months.  Patients with ALK-positive NSCLC treated with crizotinib 
in the second-line setting had a median PFS of 7.7 months and an interim median OS of 
20.3 months (Shaw et al. 2013), which equated to a post-progression survival of 
12.6 months.  This lengthy post-progression survival provides an opportunity for 
subsequent treatment with other ALK inhibitors, several additional lines of chemotherapy, 
or participation in additional clinical trials. 
Patients in both study arms who experience disease progression on study treatment will 
likely be treated with other subsequent treatment options, including ALK inhibitors.  
The availability of crizotinib on the market, as well as the likely availability of other 
next-generation ALK TKIs, and the availability of other investigational agents in clinical 
trials offer potential treatment options to patients in the study who will eventually have 
disease progression.  Subsequent therapies frequently confound the detection of an OS 
benefit, particularly in a setting with a long post-progression survival, such as 
ALK-positive NSCLC.  This has been observed in trials for EGFR TKIs, in which strong 
PFS benefits were observed without evidence of OS benefit (Rosell et al. 2009; 
Fukuoka et al. 2011). 
The long post-progression survival and the confounding effects of subsequent lines of 
therapy indicate that it would be difficult to detect an OS benefit in this setting.  
Nevertheless, OS is one of the study’s secondary endpoints.  The crossover from the 
crizotinib arm to alectinib will not be allowed in this study, with the aim of preserving the 
trial’s ability to potentially demonstrate some degree of treatment benefit of alectinib in 


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OS.  However, the study will not be powered to demonstrate any statistically significant 
difference in the secondary endpoint of OS. 
To ensure the validity of the PFS as the primary endpoint, a number of measures have 
been implemented: full IRC assessment to support the analysis of the primary endpoint, 
a substantial target magnitude of benefit (target HR = 0.65) and study assessments that 
will allow a robust evaluation of risk-benefit (standard RECIST criteria to define 
progression with fixed assessment intervals that are identical in both treatment arms and 
a robust definition of PFS and prospectively defined methods to assess, quantify, and 
analyze PFS, including censoring methods and sensitivity analyses). 
3.3.6 
Rationale for Secondary Endpoint of Time to CNS Progression 
Lung cancer is the most common type of cancer to spread to the brain, with at least 40% 
of people with lung cancer developing brain metastases at some point during their 
disease.  ALK-positive NSCLC has a propensity to metastasize to the brain, and 
crizotinib has impaired control of brain metastases in comparison to other sites of 
systemic disease (Chun et al. 2012). 
Delaying or preventing the development of CNS metastases would provide patients with 
clinically meaningful benefit by avoiding consequences of neurological deficits from brain 
metastasis or by delaying/preventing long-term side effects associated with steroid use 
and brain irradiation. 
Preliminary evidence of CNS benefit with alectinib has been observed in patients in the 
two ongoing Phase I/II studies.  See Section 1.2 and Alectinib Investigator's Brochure for 
additional details. 
Time to CNS progression is defined as the time from randomization until radiographic 
evidence of CNS progression is documented.  The aim of the pre-specified analysis will 
be to evaluate whether alectinib significantly delays or prevents the development of CNS 
metastases. 
Randomization of the Phase III study will be stratified by the presence or absence of 
CNS metastasis at baseline. 
Imaging analysis by consistently used uniform image acquisition technique (MRI scans) 
will be performed routinely at baseline and at subsequent follow-up assessments along 
with every systemic imaging tumor assessment or whenever clinically indicated 
(i.e., clinical suspicion of CNS metastasis) in order to achieve an accurate determination 
of time to CNS progression.  This ensures that early brain metastatic lesions are 
detected and that assessment bias between the two arms is avoided by having regularly 
scheduled scans. 


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An independent central radiological review will be performed for all patients and the 
analysis of time to CNS progression or response will be based on the data from the 
independent review.  The review will be based on the standard RECIST v1.1 criteria to 
assess the CNS lesions, and a second independent review on the basis of the RANO 
criteria, which are typically used to assess brain tumors (Wen et al. 2010), will be 
performed.  The assessment will be performed independently from the overall disease 
progression assessment. 
3.3.7 
Rationale for PK Sample Collection Schedule 
To date, the pharmacokinetics of alectinib have been characterized in 
chemotherapy-failed, crizotinib-naive patients with NSCLC in Study AF-001JP and in 
patients who have failed chemotherapy and crizotinib treatment in 
Study NP28761/AF-002JG and Study NP28673.  In order to better understand the 
pharmacokinetics of alectinib and to further support the development of a robust 
population PK model for alectinib in order to better understand, identify, and characterize 
variables which lead to changes in exposure, characterization of alectinib 
pharmacokinetics will be done in this study.  This study will include PK assessment of 
alectinib in ALK inhibitor treatment-naive patients with ALK-positive advanced NSCLC by 
collecting trough samples from all patients receiving alectinib.  Serial/intensive PK 
samples will be collected from a subset of patients (10%−15% [at least n = 20] of patients 
receiving alectinib) to facilitate the PK assessment.  The data that will be collected from 
this study will enable more robust understanding of alectinib pharmacokinetics in the 
global crizotinib-naive population including investigation and potential identification of 
sources of variability influencing alectinib pharmacokinetics and/or response to alectinib 
therapy.  Results from PK data collection in this study and analyses of PK data could 
help support optimal use of alectinib therapy. 
3.3.8 
Rationale for Biomarker Assessments 
Several molecular mechanisms of resistance to crizotinib have been reported in the 
literature: increased copy number of ALK gene, increased expression of ALK mRNA, 
secondary mutations in ALK (e.g., gatekeeper mutation), and changes (e.g., increased 
copy number, increased phosphorylation, or point mutations) in escape genes such as 
EGFR, cKIT, or KRAS (Katayama et al. 2011; Doebele et al. 2012; Kim et al. 2013).  In 
order to investigate molecular mechanisms of resistance to ALK inhibitors and ALK 
mutation status, tumor samples will be collected before treatment and at the time of 
disease progression with the goal of sequencing nucleic acids.  Two types of 
approaches will be used: 1) targeted sequencing of a panel of genes known to be 
involved in cancer and 2) unbiased genomic sequencing.  
Mutations in cancer genes appearing from drug resistance can be monitored in 
circulating nucleic acids in plasma (Forshew et al. 2012).  Tumor nucleic acids are shed 
into circulation in amounts that allow direct amplification by PCR and sequencing.  
Plasma samples will be collected before treatment and at certain timepoints during 


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treatment to monitor mutations in ALK and other genes involved in resistance to ALK 
inhibitors.  Information from mutated genes in the tumor will be correlated with mutations 
in plasma DNA. 
Determination of ALK positivity will be initially performed by Ventana IHC 
(see Appendix 8).  In addition, the Abbott Vysis FISH test will be used as an exploratory 
assay, after patients have been enrolled in this study.  Results from these analyses will 
be used to quantify the degree of correlation between FISH and IHC for the detection of 
ALK-positive NSCLC.  For exploratory purposes, other methods to determine ALK 
positivity (e.g., reverse transcription-PCR) may also be used.  Currently, ALK positivity 
for fusions can only be determined in tissue samples using assays such as FISH, IHC or 
PCR.  As tissue sampling is difficult and tissue biopsy sample sizes from lung cancer 
patients are very small, testing of several important biomarkers is challenging.  Many 
NSCLC patients may not have enough tumor tissue available and therefore cannot be 
tested for some biomarkers such as ALK.  Plasma ALK assays analyzing circulating 
tumor nucleic acids will enable more NSCLC patients to be tested for ALK fusions.  
Information from plasma ALK assays will be used to investigate the use of circulating 
tumor nucleic acids from plasma as a surrogate for tumor tissue for diagnostic purposes. 
3.3.9 
Rationale for PRO Assessments 
In the treatment of lung cancer, it is important to both increase survival and palliate 
symptoms because disease symptoms have negative impacts on HRQoL 
(Hyde and Hyde 1974; Hopwood and Stephens 1995; Sarna et al. 2008).  This is 
especially true for trials that use PFS as a primary endpoint, where it is important to 
translate the delay in disease progression into an endpoint that is meaningful to patients. 
Pain (chest; arm and shoulder), dyspnea, cough, and fatigue have been regarded as the 
most frequent and clinically relevant disease-related symptoms experienced by patients 
with NSCLC.  The BR.21 study (erlotinib vs. chemotherapy in second- or third-line 
NSCLC) demonstrated that longer TTD in the pain, dyspnea, and cough scales of the 
EORTC QLQ-C30 and QLQ-LC13 was consistent with superior PFS, OS, and 
quality-of-life benefits in the erlotinib arm as compared with the placebo arm 
(Aaronson et al. 1993; Bergman et al. 1994; Bezjak et al. 2006).  Additionally, patients 
in the crizotinib PROFILE 1005 trial reported clinically significant improvements 
(by 10 points) in the pain, cough, dyspnea, and fatigue symptom scales seen as early 
as 2 weeks on treatment (Crinò et al. 2011). 
The EORTC QLQ-C30 and QLQ-LC13 were used in the Phase III PROFILE 1007 study 
(second-line crizotinib vs. chemotherapy).  The study reported significantly greater 
overall reduction from baseline in the symptoms of alopecia, cough, dyspnea, fatigue, 
chest pain, arm or shoulder pain, and pain in other parts of the body with crizotinib than 
with chemotherapy (p < 0.001 for all comparisons, without adjustment for multiple testing).  
Patients treated with crizotinib also had a significantly greater delay in the worsening of 
symptoms.  There was also a significantly greater overall improvement from baseline in 


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the global quality of life among patients who received crizotinib treatment than among 
those who received chemotherapy (p < 0.001).  In all domains measuring function, 
except for the domain measuring cognitive function, there was a significantly greater 
overall improvement from baseline among patients in the crizotinib group than among 
patients in the chemotherapy group (Shaw et al. 2013). 
Therefore, to assess the quality of life of patients in this trial, PRO data will be collected 
from patients enrolled in this study using the validated questionnaires EORTC 
QLQ-C30 and QLQ-LC13. 
3.4 
OUTCOME MEASURES 
3.4.1 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
• 
PFS, which is defined as the time from randomization to the first documented 
disease progression, as determined by the investigators (primary endpoint) or IRC 
(secondary endpoint) using RECIST v1.1 or death from any cause, whichever 
occurs first.  Patients without an event will be censored at the last tumor 
assessment either during follow-up or during study treatment.  Patients with no 
post-baseline assessments will be censored at the date of randomization. 
• 
ORR, which is defined as the percentage of patients who attain CR or PR; response, 
as determined by the investigators using RECIST v1.1.  Patients without any 
assessments will be regarded as non-responders. 
• 
Time to CNS progression, which is defined as the time from randomization to the 
first occurrence of disease progression in the CNS as determined by IRC using 
RECIST v1.1 and RANO (separate assessments and analyses), as well as C-ORR 
in patients with CNS metastases who have measurable disease in the CNS at 
baseline, C-DOR in patients who have a CNS Objective Response, and C-PR at 
6, 12, 18, and 24 months. 
• 
DOR, which is defined as the time from when response (CR or PR) was first 
documented to first documented disease progression or death (whichever occurs 
first).  This will only be calculated for patients who have a best overall response of 
CR or PR.  Patients who do not progress or die after they have had a response are 
censored at the date of their last tumor measurement. 
• 
OS, which is defined as the time from randomization to death from any cause.  
Patients without an event will be censored at the last date known to be alive.  
Patients without any follow-up information will be censored at the date of 
randomization. 
 
3.4.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Serious and non-serious adverse events 
• 
Safety laboratory tests values 


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• 
Vital signs (blood pressure, heart rate), ECG 
• 
Physical examination 
 
3.4.3 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Sparse (pre-dose) PK samples for measurement of alectinib and its major 
metabolite(s) will be collected in all study patients receiving alectinib treatment.  
See Appendix 1 and Appendix 2 for PK sampling times. 
• 
Serial/intensive PK sampling will be collected in a subset of consenting patients 
enrolled to receive alectinib treatment (approximately 10%−15%, at least 
approximately n = 20).  See Appendix 1 and Appendix 2 for PK sampling times. 
• 
PK parameters will be determined as appropriate and where data allow: 
The pharmacokinetics of alectinib (and metabolite[s], if appropriate) will be 
described, and the between-patient variability will be estimated using a 
population PK approach.  The potential influence of covariates that contribute 
significantly to the between-patient differences in PK parameters of alectinib will 
also be explored and quantified. 
Non-compartmental analysis (NCA) may be conducted in patients undergoing 
serial/intensive PK sample collection, as appropriate and where data allow. 
 
3.4.4 
Patient-Reported Outcome Measures 
The PRO measures included for this study are as follows and will be administered to 
patients every 4 weeks until disease progression and during post-progression on 
treatment in case of isolated, asymptomatic CNS progression; at the post-treatment visit 
(4 weeks after permanent treatment discontinuation); and every follow-up visit (every 
8 weeks) after post-treatment visit for 6 months: 
• 
The EORTC QLQ-C30 and EORTC QLQ-LC13 to determine the impact of alectinib 
compared with crizotinib as measured by TTD in patient-reported lung cancer 
symptoms (e.g., cough, dyspnea [single item and multi-item scales], pain in chest, 
pain in arm/shoulder, fatigue). 
• 
The EORTC QLQ-C30 and EORTC QLQ-LC13 to measure PROs of HRQoL, 
patient functioning, and side effects of therapy compared between patients treated 
with alectinib and those treated with crizotinib. 
 
For patients who discontinue treatment for reasons other than disease progression and 
who progress within the first 6 months of survival follow-up, PRO measures will be 
administered every 4 weeks until disease progression and then decreased to every 
8 weeks until 6 months post-treatment. 
For patients who discontinue treatment for reasons other than disease progression and 
have not yet progressed at 6 months post treatment, PRO measures will be 
administered every 4 weeks until disease progression and will no longer be required 
thereafter.  


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3.4.5 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
EQ-5D-3L to generate utility scores for use in economic models for the purpose of 
reimbursement 
• 
Total testosterone and free testosterone levels (either by direct measurement or by 
calculation using albumin and SHBG), FSH, and LH in blood to measure the onset 
of hypogonadism in adult men 
• 
Results from the FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) to evaluate 
and compare efficacy in patients with treatment-naive NSCLC that is ALK-positive 
by FISH test  
• 
ALK fusion status in circulating tumor nucleic acids from plasma to evaluate and 
compare efficacy and safety in patients with treatment-naive NSCLC that is 
ALK-positive by plasma ALK tests (PCR and/or sequencing) for diagnostic purposes  
• 
Post-progression tumor mutation status to study molecular mechanisms of 
resistance to ALK inhibitors 
• 
ALK mutation status in plasma DNA to monitor efficacy and disease progression 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
The target population is patients with treatment-naive, ALK-positive, non-resectable, 
locally advanced and metastatic NSCLC. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Histologically or cytologically confirmed diagnosis of advanced or recurrent 
(Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) 
NSCLC that is ALK-positive as assessed by the Ventana IHC test.  Sufficient tumor 
tissue to perform ALK IHC and ALK FISH is required.  Both tests will be performed 
at designated central laboratories. 
• 
Age ≥ 18 years old 
• 
Life expectancy of at least 12 weeks 
• 
ECOG PS of 0−2 
• 
No prior systemic treatment for advanced or recurrent NSCLC (Stage IIIB not 
amenable to multimodality treatment) or metastatic (Stage IV) NSCLC 
• 
Adequate hematologic function: 
Platelet count ≥ 100 × 109/L 
ANC ≥ 1500 cells/μL 
Hemoglobin ≥ 9.0 g/dL 


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• 
Adequate renal function: 
An estimated glomerular filtration rate (eGFR) calculated using the Modification 
of Diet in Renal Disease equation of at least 45 mL/min/1.73 m2 
• 
Patients must have recovered from effects of any major surgery or significant 
traumatic injury at least 28 days before the first dose of study treatment. 
• 
Measurable disease (by RECIST v1.1) prior to the administration of study treatment 
• 
Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed 
incidentally at study baseline).  Asymptomatic CNS lesions might be treated at the 
discretion of the investigator as per local clinical practice.  If patients have 
neurological symptoms or signs due to CNS metastasis, patients need to complete 
whole brain radiation or gamma knife irradiation treatment.  In all cases, radiation 
treatment must be completed at least 14 days before enrollment and patients must 
be clinically stable. 
• 
For all females of childbearing potential, a negative pregnancy test must be 
obtained within 3 days before starting study treatment. 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus), agreement to 
remain abstinent or use single or combined contraceptive methods that result in a 
failure rate of < 1% per year during the treatment period and for at least 3 months 
after the last dose of study drug.  Abstinence is only acceptable if it is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.  Examples of contraceptive methods with a 
failure rate of < 1% per year include tubal ligation, male sterilization, hormonal 
implants, established and proper use of combined oral or injected hormonal 
contraceptives, and certain intrauterine devices.  Alternatively, two methods 
(e.g., two barrier methods such as condom and cervical cap use) may be combined 
to achieve a failure rate of < 1% per year.  Barrier methods must always be 
supplemented with the use of a spermicide.  
• 
For men, agreement to remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of < 1% per year during the 
treatment period and for at least 3 months after the last dose of study drug.  
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception. 
• 
Able and willing to provide written informed consent prior to performing any 
study-related procedures and to comply with the study protocol, including patients 
must be willing and able to use the electronic patient-reported outcome (ePRO) 
device. 
 


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4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients with a previous malignancy within the past 3 years are excluded (other than 
curatively treated basal cell carcinoma of the skin, early gastrointestinal [GI] cancer 
by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is 
considered to have no impact in PFS and OS for the current NSCLC). 
• 
Any GI disorder that may affect absorption of oral medications, such as 
mal-absorption syndrome or status post-major bowel resection 
• 
Liver disease characterized by: 
ALT or AST > 3 × ULN (≥ 5 × ULN for patients with concurrent liver metastasis) 
confirmed on two consecutive measurements 
OR 
Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or 
other conditions of decompensated liver disease such as coagulopathy, hepatic 
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal 
varices 
OR 
Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis 
• 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy 
such as radiotherapy (excluding alopecia), which have not shown improvement and 
are strictly considered to interfere with current study medication 
• 
History of organ transplant 
• 
Co-administration of anti-cancer therapies other than those administered in this 
study 
• 
Patients with baseline QTc > 470 ms or symptomatic bradycardia 
• 
Administration of strong/potent cytochrome P450 (CYP)3A inhibitors or inducers 
within 14 days prior to the first dose of study treatment and while on treatment with 
alectinib or crizotinib (see Appendix 3)  
• 
Administration of agents with potential QT interval prolonging effects within 14 days 
prior to the first administration of study drug for all patients and while on treatment 
through the end of the study for crizotinib-treated patients only (see Section 4.4.2 
for further details) 
• 
History of hypersensitivity to any of the additives in the alectinib drug formulation 
(see Section 4.3.1.1 for further details) 
• 
History of hypersensitivity to any of the additives in the crizotinib drug formulation 
(see Section 4.3.1.2 for further details) 
• 
Pregnant or lactating women 
• 
Known HIV positivity or AIDS-related illness 


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• 
Any clinically significant concomitant disease or condition that could interfere with, 
or for which the treatment might interfere with, the conduct of the study or the 
absorption of oral medications or that would, in the opinion of the Principal 
Investigator, pose an unacceptable risk to the patient in this study 
• 
Any psychological, familial, sociological, or geographical condition potentially 
hampering compliance with the study protocol requirements and/or follow-up 
procedures; those conditions should be discussed with the patient before trial entry 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label trial, for which the rationale is described in Section 3.3.4. 
Approximately 286 patients will be randomly assigned in a 1:1 allocation ratio to the two 
treatment arms via a block-stratified randomization procedure and over a planned 
recruitment period of 24 months. 
Randomization will guard against systematic selection bias and should ensure the 
comparability of treatment groups.  To assist balance in important prognostic factors, 
randomization will be stratified by ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and 
CNS metastases at baseline (yes vs. no). 
Central randomization and drug pack number allocations will be performed and 
managed by an IxRS.  Further details will be provided in an IxRS manual. 
The independent review of scans for the secondary endpoints of PFS and time to CNS 
progression on the basis of IRC will be performed in a blinded fashion. 
4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Alectinib 
Alectinib comes in a hard capsule dosage form containing the following active ingredient: 
[Chemical name] 9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-6,11-
dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride 
Each capsule contains 150 mg of alectinib (as free base) along with lactose 
monohydrate, carmellose calcium, hydroxypropyl cellulose, sodium lauryl sulfate (SLS), 
and magnesium stearate as excipients. 
Alectinib capsules should be stored in accordance with the storage instructions on the 
label. 
Alectinib capsules should be administered orally BID with food in the morning and 
evening. 


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The formulation contains SLS as an excipient.  This excipient is known to be potentially 
associated with GI adverse events such as nausea, vomiting, diarrhea, and abdominal 
pain. 
For further details, see the alectinib Investigator's Brochure. 
4.3.1.2 
Crizotinib 
Crizotinib comes in a hard capsule dosage form.  Each capsule contains 250 mg or 
200 mg crizotinib.  Crizotinib hard capsules should be stored in accordance with the 
storage instructions on the label.  Crizotinib capsules should be administered orally BID. 
For further details, see the local prescribing information for crizotinib (XALKORI® U.S. 
Package Insert). 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Alectinib 
Alectinib 600 mg (four 150-mg capsules) should be administered orally BID with food in 
the morning and evening. 
If a patient misses a dose, it can be taken within 6 hours of the scheduled time.  If the 
time is greater than 6 hours, or if the patient vomits the dose, the patient should wait until 
the next scheduled time and take the next scheduled dose.  Patients should not take 
two doses at the same time to make up for a missed dose. 
Guidelines for dosage modifications and treatment interruptions or discontinuation due to 
specified adverse events are provided in Section 5.1.3. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF. 
4.3.2.2 
Crizotinib 
Crizotinib at 250 mg (one 250-mg capsule) should be administered orally BID with or 
without food (in the morning and evening). 
If a dose is missed, then it should be taken as soon as the patient remembers unless it is 
less than 6 hours until the next dose, in which case the patient should not take the 
missed dose.  Patients should not take 2 doses at the same time to make up for a 
missed dose.  If vomiting occurs after taking a dose of crizotinib, the next dose should be 
taken as scheduled.  
If dose reduction is necessary, then the dose of crizotinib should be reduced to 200 mg 
taken BID.  If further dose reduction is necessary, then the dose should be modified to 


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250 mg taken once daily.  Guidelines for dosage modification and treatment interruption 
or discontinuation are provided in Section 5.1.4. 
Any overdose or incorrect administration of crizotinib should be noted on the crizotinib 
Administration eCRF.  Adverse events associated with an overdose or incorrect 
administration of crizotinib should be recorded on the Adverse Event eCRF. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(alectinib and crizotinib) will be provided by the Sponsor where required by local health 
authority regulations.  The study site will acknowledge receipt of IMPs and confirm the 
shipment condition and content.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Post-Trial Access to Alectinib 
The Sponsor will offer post-trial access to the study drug alectinib free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive study drug after the end of the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or would not 
otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for ALK-positive NSCLC 


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• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for ALK-positive NSCLC 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy 
Concomitant medication includes any medication (e.g., prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used 
by a patient from screening to the study completion/discontinuation visit.  All concomitant 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
All therapy and/or medication administered to manage adverse events should be 
recorded on the Adverse Event eCRF. 
The medications and/or treatments below are permitted: 
• 
Anticoagulants and antithrombotic agents (i.e., coumadin-derived anticoagulants, 
unfractionated heparin or low-molecular heparins, aspirin (≤ 325 mg/day), and 
clopidogrel) 
• 
Acetaminophen up to 2 g/day 
• 
Gastric pH elevating medications (such as proton pump inhibitors, H2 blockers, or 
antacids) 
• 
Local therapy (e.g., stereotactic radiotherapy or surgery) may be given to patients 
with isolated asymptomatic CNS progression (e.g., new CNS oligometastases). 
 
Caution should be exercised when the following are co-administered with alectinib: 
• 
For medications that are substrates of P-gp transporter or breast cancer resistance 
protein transporter, the investigator should use caution and monitoring when 
considering concomitant use of alectinib.  Alectinib has been shown to have 
potential for inhibition of these transporters.  Substrates with a narrow therapeutic 
index (e.g., methotrexate, digoxin) should be avoided.  If co-administration cannot 
be avoided, it is recommended that drug levels and/or signs for toxicity are carefully 
monitored (see Appendix 3). 
 
Caution should be exercised when the following are co-administered with crizotinib: 
• 
Crizotinib has been shown to be a moderate inhibitor of CYP3A.  Dose reduction 
may be needed for co-administered drugs that are predominantly metabolized by 


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CYP3A in patients receiving crizotinib.  Concurrent use of CYP3A substrates with 
narrow therapeutic indices should be avoided (see Appendix 3). 
• 
On the basis of an in vitro study, crizotinib is predicted to inhibit intestinal P-gp.  
Therefore, administration of crizotinib with medicinal products that are substrates of 
P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin) may increase their 
therapeutic effect and adverse reactions (see Appendix 3).  Close clinical 
surveillance is recommended when crizotinib is administered with these medicinal 
products. 
• 
Bradycardia has been reported during clinical studies; therefore, avoid using 
crizotinib in combination with other agents known to cause bradycardia 
(e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and 
digoxin) to the extent possible 
• 
In vitro studies in human hepatocytes indicated that crizotinib may induce 
pregnane X receptor and constitutive androstane receptor-regulated enzymes 
(e.g., CYP3A4, CYP2B6, CYP2C8, CYP2C9, UGT1A1).  However, there was no 
observed induction in vivo when crizotinib was coadministered with the CYP3A 
probe substrate midazolam.  Caution should be exercised in administering crizotinib 
in combination with medicinal products that are predominantly metabolized by these 
enzymes.  Of note, the effectiveness of concomitant administration of oral 
contraceptives may be altered. 
• 
In vitro studies indicated that crizotinib is an inhibitor of CYP2B6.  Therefore, 
crizotinib may have the potential to increase plasma concentrations of 
coadministered drugs that are metabolized by CYP2B6 (e.g., bupropion, efavirenz). 
 
4.4.2 
Prohibited Therapy 
Use of the following therapies (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) is prohibited during the study and for at 
least 14 days prior to initiation of study treatment (either alectinib or crizotinib), unless 
otherwise specified below.  Exceptions to restrictions of the concomitant therapies listed 
below (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) may be made if the rationale is discussed and documented 
between the investigator and the Sponsor’s Clinical Pharmacologist. 
• 
Potent inducers of CYP3A (e.g., rifampin, rifabutin, phenobarbital, phenytoin, 
carbamazepine, and St. John’s wort [Hypericum perforatum]) within 2 weeks or 
5 half-lives (whichever is longer) before the first dose of study drug treatment and 
while on treatment with study drugs (see Appendix 3). 
• 
Potent inhibitors of CYP3A (e.g., ketoconazole) within 2 weeks or 5 half-lives 
(whichever is longer) before the first dose of study drug treatment and while on 
treatment with study drug (see Appendix 3). 
• 
Any concomitant medications known to affect QT interval duration, including but not 
limited to the following drugs:  amiodarone, cisapride, clarithromycin, methadone, 
and quinidine, within 2 weeks before the first dose of study drug treatment for all 


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patients and while on treatment through the end of the study for crizotinib-treated 
patients only 
• 
Systemic immunosuppressive drugs, cytotoxic or chemotherapeutic agents 
(other than study drug treatment), ergot derivatives, probenecid, and bile 
acid-binding resins while on study treatment. 
• 
Systemic chemotherapy. 
• 
Radiotherapy/radionuclide therapy except for palliative radiotherapy to bone lesions 
or for pain control.  If palliative radiation is indicated for bone metastases, palliative 
radiation may start within 24 hours of the last dose of alectinib, unless, in the 
judgment of the investigator, patient safety will require a longer washout period prior 
to palliative therapy.  Dosing of alectinib may resume with the resolution of any 
radiation toxicity to ≤ Grade 1. 
• 
Additional investigational drug (except for during the follow-up period) 
 
The list of medications provided above is not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication 
as well as the Internet references provided below when determining whether a certain 
medication strongly inhibits or induces CYP3A.  In addition, the investigator should 
contact the Medical Monitor if questions arise regarding medications not listed above. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM292362.pdf 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx (for P450 drug interactions) 
 
4.4.3 
Prohibited Food 
Use of grapefruit or grapefruit juice should be avoided during the study and for at least 
14 days prior to the initiation of study treatment (either alectinib or crizotinib) because it 
is a potent CYP3A inhibitor and may increase plasma concentration of either alectinib or 
crizotinib. 
4.5 
STUDY ASSESSMENTS 
See Appendix 1 for the schedule of assessments performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 


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4.5.2 
Medical History and Demographic Data 
Medical history includes a record of clinically significant diseases, surgeries, cancer 
history (including prior cancer therapies and procedures), reproductive status, smoking 
history, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 28 days prior 
to the screening visit. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Corticosteroid Use for CNS Metastases 
For patients with CNS metastases requiring corticosteroid use, the corticosteroid intake 
should be captured at all tumor assessment visits and compared to the corticosteroid 
intake at the time of the last disease assessment.  The changes will be recorded as 
Increased, Unchanged, or Decreased.  Increases and decreases in corticosteroid intake 
should be clinically justified.  Increases in corticosteroid dose for reasons other than for 
CNS metastases control do not need to be taken into consideration when making this 
comparison. 
4.5.4 
Physical Examinations 
A complete physical examination at screening and baseline should include an evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, GI, genitourinary, and neurological systems as well as 
height and weight.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
Note:  for patients with known CNS metastases, a neurological examination must be 
performed at each tumor assessment visit and compared to the neurological 
examination performed at the time of the last disease assessment.  Definition of clear 
neurological worsening is difficult to describe because progression in the CNS can 
present in numerous ways.  Accordingly, evaluation of neurological function at each 
disease assessment will be based purely on the investigator’s assessment of the 
patient’s neurological state compared to the neurological function at the time of the last 
disease assessment.  Neurological status will be recorded as Improved, Stable, or 
Worsened. 
4.5.5 
Vital Signs 
Vital signs will include measurements of respiratory rate, oxygen saturation, pulse rate, 
and systolic and diastolic blood pressure while the patient is in a seated position, and 
temperature. 


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4.5.6 
ECOG Performance Status 
Performance Status (PS) will be measured using the ECOG PS Scale (see Appendix 5).  
It is recommended, where possible, that a patient’s PS be assessed by the same person 
throughout the study. 
4.5.7 
Tumor and Response Evaluations 
Disease burden must be documented at screening and re-assessed at each subsequent 
tumor evaluation.  Response will be assessed by the investigator on the basis of physical 
examinations.  Clinical lesions will be documented by color photography (with caliper 
measurement for measurable lesions), computed tomography (CT) scans, and other 
modalities (e.g., MRI, brain scans), using RECIST v1.1 (see Appendix 4).  For assessing 
response in patients with measurable disease, the preferred radiologic tumor response 
assessment is CT scan with intravenous contrast.  If intravenous contrast is 
contraindicated, a non-contrast-enhanced chest CT scan will be acceptable for chest 
lesions, and MRI can be used for non-chest lesions.  If contrast-enhanced MRI is 
contraindicated, then non-contrast-enhanced MRI will suffice.  Positron emission 
tomography (PET) scan, bone scan, and ultrasound cannot be used to measure lesion as 
per RECIST v1.1 (see Appendix 4).   
The same radiographic procedure used to define measurable disease sites at screening 
must be used throughout the study (e.g., the same contrast protocol for CT scans).  
Assessments should be performed by the same evaluator to ensure internal consistency 
across visits. 
CT/MRI scans of chest and abdomen, and MRI scans of the brain should be performed 
for all patients as described in Schedule of Assessments (see Appendix 1) at screening, 
then every 8 weeks subsequently until disease progression and during post-progression 
on treatment in case of isolated, asymptomatic CNS progression and at the 
post-treatment visit (4 weeks after permanent treatment discontinuation).  CT/MRI scans 
of the neck bone and pelvis should be included if clinically indicated.  At the investigator’s 
discretion, CT/MRI scans may be repeated at any time if PD is suspected. 
Note: Brain imaging should be performed using MRI with the following image acquisition 
requirements. 
• 
Minimum sequences required: 
Pre-contrast T1, T2/FLAIR 
Post-contrast T1, with two orthogonal planes (or a volume acquisition) 
recommended 
• 
Recommended slice thickness ≤ 5 mm with no gap 
 
Patients with known or suspected bone metastases should undergo radionuclide bone 
scan at screening.  Bone scan, PET scan, or plain films are not considered adequate 
imaging techniques to measure bone lesions and do not need to be repeated routinely 


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but can be used to confirm the presence or disappearance of bone lesions.  Lytic bone 
lesions or mixed lytic-blastic lesions, with identifiable soft tissue components that can be 
evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
measurable lesions of the soft tissue component and meet the definition of measurability 
and should be followed by cross-sectional imaging. 
4.5.8 
Laboratory, Biomarker, and Other Biological Sample 
4.5.8.1 
Laboratory Assessments 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Hematology (hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
absolute differential count [neutrophils, eosinophils, lymphocytes, monocytes, 
basophils, other cells]) 
• 
Coagulation (PT [or INR], and aPTT) 
• 
Serum chemistry (sodium, potassium, chloride, bicarbonate, fasting glucose, BUN 
or urea, creatinine [including calculated eGFR using the Modification of Diet in 
Renal Disease formula, see Appendix 7]; CPK; gamma-glutamyl transferase [GGT]; 
calcium; total and direct bilirubin; total protein; albumin; ALT; AST; alkaline 
phosphatase [ALP]; phosphorus; magnesium; thyroid-stimulating hormone; and total 
testosterone and free testosterone [either by direct measurement or by calculation 
using, albumin and SHBG], FSH, and LH [for male patients only]) 
• 
Urinalysis.  Urine samples will be collected according to the schedule of 
assessments (Appendix 1)(first morning urine sample for baseline and end of 
treatment visit, spot urine for rest of visits).  Urine protein will be measured by 
dipstick test. 
• 
Pregnancy test.  All women who are not postmenopausal (≥ 12 months of 
non-therapy-induced amenorrhea) or surgically sterile will have a serum pregnancy 
test at screening, within 3 days of dosing.  Urine pregnancy tests will be performed 
anytime during the course of the study, as per investigator’s discretion.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
 
4.5.8.2 
Pre-Treatment Tumor Samples (Mandatory) 
Mandatory pre-treatment tumor samples will be collected to centrally examine ALK 
status by Ventana IHC (eligibility criteria) and Vysis FISH.  Tumor blocks (formalin-fixed, 
preferred 10% neutral-buffered formalin) are the preferred source, but if blocks are not 
available, unstained slides (ten to fifteen 5-µm slides cut less than 3 months before 
screening) are also accepted.  Remaining tumor blocks will be returned to the sites; 
slides will not be returned. 
For fresh tumor biopsies (guided by ultrasound or CT scan), acceptable methods include 
core biopsies for lung and liver lesions and bronchoscopic biopsies for lung lesions.  The 
minimum size for the biopsy needle recommended is 20G. 


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Central ALK testing to determine or confirm patient ALK status will be performed at a 
Sponsor designated central laboratory.  After completion of ALK testing for enrollment 
with a pre-specified ALK test by Ventana IHC (Appendix 8), patient samples will also be 
centrally tested by FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott).  Additionally, 
other ALK assays may be used for testing patient samples to establish performance 
characteristics of these assays for diagnostic development.  Testing may be performed 
on all screened patients (screen- failed and enrolled).  These additional testing data will 
have no impact on eligibility, and testing will be performed only after eligibility is 
established for each patient.  In addition, local ALK test information, baseline 
demographic, and disease-related characteristic data for all screened patients may be 
collected in order to support potential registration of a companion diagnostic assay for 
alectinib. 
The tumor sample may also be tested for the presence of EGFR mutations, if requested 
by the investigator. 
Pre-treatment tumor samples may be used, after proper informed consent is obtained, 
for genomic sequencing. 
For sample handling procedures, storage conditions and shipment instructions, see the 
laboratory manual. 
4.5.8.3 
Pre- and Fresh Post-Treatment Tumor Biopsies (Optional) 
Pre-treatment tumor samples (preferably formalin-fixed blocks but if not available a 
minimum of 10-15 unstained 5 µm slides) for ALK testing is a mandatory requirement for 
this study.  Optional additional pre-treatment tumor samples and fresh post-treatment 
tumor biopsy at disease progression or permanent treatment discontinuation (at the last 
treatment or post-progression visit) may be collected, with proper informed consent.  
These samples will be used to help to understand molecular mechanisms of resistance 
to ALK inhibitors by genomic sequencing.  Remaining tumor blocks will be returned to 
the sites, slides will not be returned. 
The remaining mandatory (Section 4.5.8.2) and optional specimens (Section 4.5.8.3) will 
be destroyed within 5 years after the date of final closure of the clinical database.  Other 
residual tissue material (slides, extracts, etc.) will be destroyed within 5 years after the 
date of final closure of the clinical database. 
On the basis of continuous analysis of the data in this study and other studies, or on the 
basis of data from literature, collection of optional tumor biopsies with exploratory 
purposes may be stopped at any time if the data from the samples collected do not 
produce useful information. 


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4.5.8.4 
Blood and Plasma Samples 
Mandatory plasma samples will be obtained to determine: 
• 
Mutation status in ALK and other escape genes (e.g., EGFR, KRAS).  It will require 
20 mL of blood (2 tubes of 10 mL each) to be collected at baseline, at the 
Visit 3 (Week 16) treatment, and subsequently at every second treatment visit 
(every 16 weeks) (see Appendix 1 for detailed information) until disease progression, 
and during post-progression on treatment in case of isolated, asymptomatic CNS 
progression.  For sample handling procedures, storage conditions and shipment 
instructions, see the laboratory manual.  These samples will not be taken in 
countries where regulatory agency or Institutional Review Board (IRB) does not 
allow genetic testing. 
• 
ALK rearrangement in plasma.  This will require 20 mL of blood (2 tubes of 10 mL 
each) to be collected at baseline. 
 
Mandatory blood samples will be obtained to determine: 
• 
All patients who are randomized in alectinib arm will also participate in retrospective 
pharmacogenomic research to understand inter-individual variability of safety and 
pharmacokinetics of alectinib.  For this purpose, a 3-mL blood sample will be drawn 
at baseline (see Section 4.5.8.4.1). 
 
Optional blood samples will be collected to obtain: 
• 
Plasma.  Centrally ALK negative tested patients (by Ventana ALK IHC) who agree 
to donate 10 ml plasma will be assessed by plasma ALK assays (PCR and/or 
Sequencing) for the development of a plasma ALK diagnostic test 
• 
A source of healthy tissue for patients who agreed to participate in the optional 
genomic sequencing assessment.  For patients in the crizotinib arm, a 3-mL blood 
sample will be drawn at baseline.  For patients in the alectinib arm, a source of 
healthy tissue will be used as a portion of the sample for the pharmacogenomics 
research (see Section 4.5.8.4.1) 
• 
A portion of this blood sample will also be used as a source of healthy tissue for the 
patients on alectinib treatment who agree to participate in the optional genomic 
sequencing research. 
 
For biomarkers, a maximum of 43 mL of blood will be collected at baseline (20 mL of 
blood for plasma purification and determination of mutation status in ALK and other 
escape genes, 20 mL of blood for plasma purification and detection of ALK 
rearrangements, and 3 mL blood for pharmacogenomics research.  Twenty mL of blood 
(for plasma purification and determination of mutation status in ALK and other escape 
genes) will be collected at Visit 3 (Week 16) and subsequently at every second visit 
(every 16 weeks), and 20 mL will be collected at disease progression (CNS and/or 
systemic disease progression) for plasma purification, for determination of mutation 
status in ALK and other escape genes. 


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Details of sample handling procedures, sample storage, and shipment will be described 
in a separate laboratory manual. 
On the basis of continuous analysis of the data in this study and other studies, or on the 
basis of data from literature, collection of plasma with exploratory purposes may be 
stopped at any time if they are deemed not informative. 
4.5.8.4.1 
Samples for Pharmacogenomic Assessments 
One sample (approximately 3 mL of whole blood) will be collected from all patients on 
alectinib treatment.  Samples will be used for the evaluation of genetic polymorphisms of 
drug metabolic enzymes including but not limited to CYP2C9, CYP3A4/5, and UGT1A1, 
and transporters (e.g., organic anion transporter polypeptide 1B1) and for genetic 
variants that could contribute to potentially drug-related liver safety assessments 
(including but not limited to human leukocyte antigen, see Appendix 9 for more details). 
For sample handling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Only in circumstances where there is concern for collection of this 
genetic material for above evaluations can this assessment be considered not 
mandatory as part of study assessments in this study.  Results of any analyses from 
these samples will be reported outside the clinical study report. 
4.5.8.5 
Samples for Pharmacokinetic Assessments 
PK samples will be collected in all patients on alectinib treatment, as indicated in 
Appendix 1 and Appendix 2 for the analysis of alectinib and its major metabolite(s) 
(RO5468924, RO5507197, and/or others, if applicable and if appropriate, and if assays 
are available).  Residual samples following PK analysis may be used to evaluate 
profiling for alectinib metabolite(s). 
All trough/pre-dose PK samples should be collected within 2 hours BEFORE the 
morning doses of study medications.  
Serial/intensive samples will be collected in a subset of patients (10%–15% [at least 
approximately n = 20] of patients receiving alectinib) on Visit 0 (baseline, after the first 
dose) and Visit 1 (Week 4) at the timepoints specified in Appendix 2. 
Plasma concentrations for alectinib and its metabolite(s), if applicable, will be measured 
by specific and validated liquid chromatography tandem mass spectrometry methods. 
For each sample, approximately 2 mL of venous blood will be collected for alectinib PK 
analysis at the timepoints specified in the PK schedule in Appendix 1 and Appendix 2. 
Patients who permanently discontinue from study drugs will also discontinue from all PK 
assessments.  The procedures for the collection, handling, storage, and shipping of 
plasma samples for the PK analysis are specified in the Laboratory Manual.  


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These samples will be destroyed when the final Clinical Study Report is complete. 
On the basis of continuous analysis of the data in this study and other studies, any 
sample type collection may be stopped at any time if the data from the samples collected 
do not produce useful information or at the discretion of the Sponsor. 
4.5.9 
Electrocardiograms 
An ECG will be recorded at specified timepoints as outlined in the schedule of 
assessments (Appendix 1) at screening, Visit 0 (baseline), Visit 1 (Week 4), 
Visit 4 (Week 24), Visit 8 (Week 56), and at the last treatment visit and as clinically 
indicated throughout the study.  All ECG recordings must be performed using a standard 
high-quality, high-fidelity digital electrocardiograph machine equipped with 
computer-based interval measurements.  All ECGs are to be obtained prior to other 
procedures scheduled at that same time (e.g., vital sign measurements, blood draws, 
study drug administration) as well as prior to meals.  Circumstances that may induce 
changes in heart rate, including environmental distractions (e.g., television, radio, 
conversation), should be avoided during the pre-ECG resting period and during ECG 
recording. 
Patients must have been in a supine or semi-supine position for at least 5 minutes prior 
to the recording being taken.  The same recording position (supine or semi-supine) and 
the same equipment should be used for each patient throughout the study.  The ECG 
printout must be (1) reviewed by a medically qualified member of the study team at the 
site, (2) annotated to indicate any clinical finding, and (3) dated and signed by this 
person and filed in the patient notes.  ECG parameters will be entered on the ECG 
eCRF.  The following parameters should be captured on the eCRF: heart rate, RR, PQ, 
QRS and QT duration, and QT interval corrected using Fridericia’s formula (QTcF). In 
the event that the ECG machine does not directly provide results for RR and/or QTcF, 
these parameters can be derived using the formulae provided in Appendix 10. 
If any ECG abnormality is associated with an adverse event, it must be recorded and 
managed as described in Section 5.   
If considered appropriate by the Sponsor, ECGs may be analyzed retrospectively at a 
central laboratory.   
4.5.10 
Patient-Reported Outcomes 
PROs (EORTC QLQ-C30, QLQ-L13, and EQ-5D) will be collected to more fully 
characterize the clinical profile of alectinib.  The instruments will be translated as 
required in the local language.  To ensure instrument validity and that data standards 
meet health authority requirements, the PROs scheduled for administration during a 
clinic visit (EORTC QLQ-C30, QLQ-L13, and EQ-5D) should be completed prior to the 
performance of non-PRO assessments and the administration of study treatment. 


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Patients will use an ePRO device to capture PRO data and maintain a diary of daily drug 
intake (crizotinib arm) or drug intake with food (alectinib arm).  The ePRO device and 
instructions for completing the PRO questionnaires and diaries electronically will be 
provided by the investigator staff.  The data will be transmitted via pre-specified 
transmission method (e.g., web or wireless) automatically after entry to a centralized 
database at the ePRO vendor.  The data can be accessed by appropriate study 
personnel securely via the Internet. 
4.5.11 
Samples for Roche Clinical Repository 
4.5.11.1 
Overview of the Roche Clinical Repository 
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future. 
Specimens for the RCR will be collected from patients who give specific consent to 
participate in optional research.  RCR specimens will be used to achieve the following 
objectives: 
• 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.11.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's IRB or Ethics Committee (EC) and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval for RCR sampling, 
this section of the protocol (Section 4.5.11) will not be applicable at that site. 
4.5.11.3 
Sample Collection 
For RCR purposes, 10 mL of blood will be collected.  Any remaining tissue samples from 
study-related or non-study related procedures that are performed during the study may 
also be collected for RCR purposes.  For all samples, date of consent should be 
recorded on the associated RCR page of the eCRF.  For sampling procedures, storage 
conditions, and shipment instructions, see the laboratory manual. 


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RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below. 
4.5.11.4 
Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
4.5.11.5 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 


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objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether the patient has given consent to participate 
by completing the RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research. 
4.5.11.6 
Withdrawal from the Roche Clinical Repository 
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study BO28984 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study BO28984. 
4.5.11.7 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 


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• 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients who withdraw consent for treatment should continue to be 
followed for tumor assessments until progression and for OS, provided they have not 
withdrawn consent for the study.  However, patients will not be followed for any reason 
after consent for the study has been withdrawn.  Patients who withdraw from the study 
will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Pregnancy 
• 
Inability to tolerate study medication on the basis of the investigator judgment 
See guidelines for managing adverse events and for comprehensive guidance on study 
drug discontinuation in Section 5.1.3. 
Patients who discontinue study drug prematurely will be asked to return to the clinic for 
tumor assessments until progression as per study schedule (see Appendix 1). 
The primary reason for premature study drug discontinuation should be documented on 
the appropriate eCRF.  Patients who discontinue study drug prematurely will not be 
replaced. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 


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5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
5.1.1 
Adverse Events Collection 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events (SAEs) caused by a protocol-mandated intervention should be 
reported (e.g., SAEs related to invasive procedures such as biopsies).  After the first 
dose of study treatment and up to the 4-week follow-up after the last dose of study 
treatment, all adverse events (AEs) regardless of seriousness, causality assessment, or 
actions taken reported by the investigator or designated medically qualified study site 
personnel will be collected as described below.  At each visit, the investigator or 
designated medically qualified study personnel will ask the patient if any untoward 
medical event occurred since the last visit.  It is the investigator’s responsibility to record 
all AEs in the source patient’s medical records. 
All SAEs and non-SAEs will be reported on the standard AE/SAE eCRF. 
5.1.2 
Adverse Events Relating to ALK Inhibitors and/or the Tyrosine 
Kinase Inhibitor Class and Alectinib Data 
Events described in Section 5.1.2.1 through Section 5.1.2.10 will be closely monitored 
and represent selected AEs for this study. 
A more detailed safety profile of alectinib is provided in the alectinib Investigator's 
Brochure. 
5.1.2.1 
Interstitial Lung Disease 
TKIs, including ALK inhibitor crizotinib, have been associated with the occurrence of 
treatment-related ILD (including fatalities). 
See Section 5.1.3 for management and follow-up. 
5.1.2.2 
Hepatotoxicity 
Hepatobiliary findings were observed in both the rat and monkey 4- and 13-week toxicity 
studies with alectinib, and findings in the 13-week studies were similar to those of the 
4-week studies.  The findings were at or close to clinically relevant exposures.  
Hepatobiliary effects included increased hepatic ALP, direct bilirubin, GGT and liver 
weight, vacuolation/degeneration/necrosis of bile duct epithelium, inflammatory cell 
infiltration in Glisson’s sheath, enlargement/focal necrosis of hepatocytes, and 
enlargement of Kupffer cells. 
Abnormal hepatobiliary laboratory test values, such as increased ALT, AST, or bilirubin 
levels, have been observed after alectinib administration.  AST, ALT, and total bilirubin 
levels temporarily increased in the initial stages of treatment and then improved.  In 
patients with Grade 3−4 AST/ALT elevations, documented drug-induced liver injury 
by liver biopsy was reported with uncommon frequency in alectinib pivotal clinical 


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trials.  Concurrent elevations in ALT or AST greater than or equal to three times the 
ULN and total bilirubin greater than or equal to two times the ULN, with normal 
alkaline phosphatase, occurred with uncommon frequency in patients treated in 
alectinib clinical trials. 
In patients treated with other tyrosine kinase ALK inhibitor drugs, abnormal liver function 
tests and drug-induced hepatotoxicity, including cases with fatal outcome, have been 
reported. 
See Section 5.1.3 for management and follow-up. 
5.1.2.3 
Anemia 
Hematologic findings were observed in both the rat and monkey 4- and 13-week toxicity 
studies with alectinib, and findings in the 13-week studies were similar to those of the 
4-week studies.  Findings were at or close to clinically relevant exposures.  Hematologic 
adverse effects such as anemia, thrombocytopenia, bleeding, and neutropenia have 
been observed with most TKIs, including ALK inhibitor crizotinib. 
Cases of anemia have been reported in patients treated with alectinib; the majority of 
the events were Grade 1 or 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.4 
Gastrointestinal Disorders 
GI disorders such as nausea, vomiting, constipation, and diarrhea have been reported 
with alectinib.  Similar GI disorders have been observed with other TKIs, including ALK 
inhibitor crizotinib. 
SLS (sodium lauryl sulfate, syn. sodium dodecyl sulfate) is a surfactant excipient in the 
clinical formulation at a concentration of 50% (w/w SLS to active pharmaceutical 
ingredient).  This excipient is a known GI irritant and may be associated with GI AEs 
including nausea, vomiting, diarrhea, and abdominal pain.  Of note, GI tract toxicity as 
the safety determinant of SLS is not because of systemic toxicity, but a consequence of 
local irritation to the GI tract.  In general, when mixed with diet, higher levels of SLS⎯a 
known GI tract mucosal irritant⎯are tolerated versus gavage administrations. 
See Section 5.1.3 for management and follow-up. 
5.1.2.5 
Skin Disorders 
Results of an in vitro phototoxicity study indicated that alectinib may have phototoxic 
potential. 
Skin rash has been reported with majority of TKIs including those targeting the ALK 
receptor (Hartmann et al. 2009). 


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Cases of skin rash and photosensitivity have been reported with alectinib and were 
generally Grade 1 or 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.6 
Vision Disorders 
In the rat quantitative whole body autoradiography study, tissue radioactivity 
disappeared over time, following a time course comparable to that of plasma 
radioactivity, except for melanin-containing tissues such as uveal tract of eyes, which 
had much higher and more sustained exposure in pigmented rats.  This is consistent 
with what is commonly observed for lipophilic basic drugs. 
Vision disorders, including diplopia, photopsia, blurred vision, visual impairment, and 
vitreous floaters, have been reported with several TKIs, including ALK inhibitors 
(crizotinib) (Shaw et al. 2013). 
Vision disorders, such as dry eye, blepharitis, conjunctivitis, blurred vision, and vision 
impaired, have been reported with alectinib and were generally Grades 1 and 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.7 
Edema 
Most TKIs, including ALK inhibitor crizotinib, have been associated with edema.  Events 
of edema have been reported with alectinib, mostly Grade 1 or 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.8 
Bradycardia 
In the monkey telemetry study, there were no effects on the ECG, any of the other 
cardiovascular parameters or body temperature at doses up to 15 mg/kg (mean 
maximum concentration [Cmax]: 279 ng/mL). 
In a preliminary non-Good Laboratory Practice telemetry study in conscious cynomolgus 
monkeys, a slight hypotensive effect (approximately 10 mmHg) was seen when alectinib 
was administered at 20 and 60 mg/kg orally with no effects on ECG or heart rate.  The 
hypotensive effect of alectinib observed in monkeys was considered to likely be caused 
by vasodilatation induced by L-type Ca2+ channel inhibition. 
Events of bradycardia have been reported with alectinib.  Preliminary heart rate data 
(based on ECG and pulse measurements) from the ongoing alectinib clinical trials show 
a decrease in heart rate during alectinib treatment, which is mainly asymptomatic.  In 
patients treated with other ALK inhibitors (crizotinib and ceritinib), bradycardia adverse 
events, as well as decreases in heart rate based on ECG and pulse measurements, 
have also been reported (XALKORI® U.S. Package Insert; ZYKADIA™ U.S. Package 
Insert).  


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In case of bradycardia, concomitant medications must be evaluated to identify those that 
are known to cause bradycardia, as well as anti-hypertensive medications; and 
discontinuation or dose reduction of these concomitant medications must be considered. 
See Section 5.1.3 for management and follow-up. 
5.1.2.9 
Abnormal Renal Function 
In the 2-week non-human primate study at 60 mg/kg, an increase in creatinine was 
observed but no changes were observed in histopathology.  In all other non-human 
primate studies, no changes in creatinine were observed. 
Serum creatinine increases have been reported with alectinib treatment and were 
generally Grades 1 and 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.10 
Severe Myalgia and CPK Elevations 
Postmarketing experience with some TKIs includes reports of myopathy and 
rhabdomyolysis (Hohenegger 2012). 
Blood CPK increases, generally Grades 1 and 2, and muscular AEs have been reported 
with alectinib treatment.  Grade 3 myalgia and CPK elevations have been reported with 
alectinib treatment and were reversible upon dose reduction and interruption. 
See Section 5.1.3 for management and follow-up and Table 2 for guidelines for 
managing AEs. 


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5.1.3 
Management of Specific Adverse Events with Alectinib 
Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib 
Event 
Action to Be Taken 
Interstitial lung disease 
• 
Patients should be monitored for pulmonary symptoms 
indicative of pneumonitis.  
• 
Study drug should be permanently discontinued in patients 
diagnosed with interstitial lung disease. 
Hepatotoxicity 
 
Liver test laboratory abnormalities are to be reported as AEs only if 
fulfilling the criteria listed in Section 5.3.5.4 and Section 5.3.5.6. 
• 
If ALT or AST  > 3 × baseline, repeat testing of ALT, AST, ALP, 
and total bilirubin within 48–72 hours, with inquiry about 
symptoms.  If upon repeat testing the transaminases 
remain  > 3 × baseline, but are not  > 5 × baseline or not 
accompanied with bilirubin increases or do not match any other 
rule for permanent discontinuation, then monitoring can 
continue as per investigator judgment, and dose modification is 
not necessary. 
• 
At any time during the study treatment, if symptoms compatible 
with liver injury are observed, liver enzymes should be 
measured as soon as possible.  
• 
Study drug treatment has to be permanently discontinued if 
any of the following occurs: 
First observation of ALT or AST  > 8 × ULN 
ALT or AST > 5 × ULN for more than 2 weeks 
First observation of ALT or AST > 3 × ULN and total 
bilirubin > 2 × ULN  
First observation of ALT or AST > 3 × ULN and the 
appearance of jaundice or signs of hepatic dysfunction or 
other symptoms (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or 
eosinophilia [> 5%]). 
• 
Following study drug discontinuation, weekly monitoring of 
laboratory values should continue until the abnormal values 
have normalized to pre-treatment levels and/or an adequate 
explanation of the abnormal value is found. 
• 
Resumption of study drug is not allowed in patients 
discontinuing because of any of the above criteria. 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
Gastrointestinal tract AEs 
(e.g., nausea, vomiting, 
diarrhea) 
The events are expected to be minimized by taking the study drug 
with meal.  In case GI events occur, appropriate measures should 
be taken in accordance with local clinical practice guidelines.  If GI 
toxicities are observed and not tolerable, treatment with study drug 
should be temporarily interrupted until recovery to Grade 1 or lower.
Skin disorder AEs 
(e.g., phototoxicity, rash) 
Patients should be advised to avoid prolonged sun exposure while 
taking alectinib and for at least 5 days after study drug 
discontinuation.  Patients should also be advised to use a 
broad-spectrum sun screen and lip balm of at least SPF 50 to help 
protect against potential sunburn 
Vision disorders 
Investigators should consider referring the patients for an 
ophthalmological evaluation according to local clinical practice 
guidelines, if vision disorders persist or worsen in severity, and to 
advise patients to exercise caution when driving or operating 
machinery due to the risk of developing a vision disorder. 
Edema 
Physical examinations will be performed routinely in clinical trials.  
In case edema events occur, appropriate measures should be taken 
in accordance with local clinical practice guidelines 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
Abnormal kidney function 
AEs 
Kidney function laboratory abnormalities are to be reported as AEs 
only if fulfilling the criteria listed in Section 5.3.5.4. 
• 
If, at any time during the study treatment, eGFR decreases 
by > 50% of the baseline visit value, the patient has to be 
carefully monitored.  All of the underlying factors that may have 
acutely impacted serum creatinine levels need to be evaluated 
and corrected (e.g., dehydration, recent exposure to contrast 
media, increased amount of cooked meat in diet, concomitant 
medications affecting renal function as appropriate, etc.). 
• 
Any eGFR decrease by > 50% of the baseline visit value 
requires repeat testing. 
If, at the repeat test, the eGFR decrease is still > 50% of 
the baseline visit value, the treatment with alectinib should 
be interrupted. 
• 
Alectinib treatment may be resumed with caution if the eGFR 
value has increased to approximately the baseline visit value. 
Severe myalgia and CPK 
elevations 
CPK laboratory abnormalities are to be reported as AEs only if 
fulfilling the criteria listed in Section 5.3.5.4. 
• 
Myopathy should be considered in any patient with diffuse 
myalgia, muscle tenderness or weakness, and/or marked 
elevations of CPK levels.  Patients should promptly report 
unexplained muscle pain, tenderness, or weakness, 
particularly if accompanied by malaise or fever.  CPK levels 
should be assessed in patients reporting these symptoms. 
• 
At the first occurrence of any of asymptomatic CPK values 
(> 10 × ULN, symptomatic CPK > 5 × ULN, or in the presence of 
severe muscular symptoms with CPK > ULN but  ≤ 5 × ULN) at 
any time during the study treatment, the patient requires 
monitoring of the CPK values until they are normalized to 
pre-treatment levels or a reasonable explanation for the CPK 
elevation and the symptoms is established. 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
Other AEs (including 
bradycardia, anemia, and 
CPK elevation) or 
laboratory abnormalities: 
• 
Grade 3 or 4: 
Temporarily interrupt alectinib for a maximum of 3 weeks. 
If improvement to Grade ≤ 1 or baseline does not occur 
within 3 weeks, permanently discontinue alectinib. 
First episode:  If improvement to Grade ≤ 1 or baseline 
within 21 days, decrease the current dose of alectinib by 
150 mg (1 capsule) BID (450 mg BID).  
Second episode:  If improvement to Grade ≤ 1 or baseline 
within 21 days, decrease the current dose of alectinib by 
another 150 mg (1 capsule) BID (300 mg BID). 
Third episode:  Permanently discontinue alectinib. 
• 
Grade 2 (except any symptoms and signs that can be 
corrected with supportive care): 
Temporarily interrupt alectinib and resume if recovering to 
Grade ≤ 1 or baseline if clinically indicated. 
First episode:  If improvement to Grade ≤ 1 or baseline 
within 10 days, continue same dose of alectinib.  If 
improvement occurs after 10 days, decrease the current 
dose of alectinib by 150 mg (1 capsule) BID when 
resuming treatment (450 mg BID). 
Second episode:  If improvement to Grade ≤ 1 or baseline 
within 10 days, decrease the current dose of alectinib by 
150 mg (1 capsule) BID (450 mg BID or 300 mg BID if 
after first episode dose was reduced to 450 mg BID).  If 
improvement occurs after 10 days, decrease the current 
dose of alectinib by 300 mg (2 capsules) when resuming 
treatment (300 mg BID or 150 mg BID if after first episode 
dose was reduced to 450 mg BID). 
Third episode:  Permanently discontinue alectinib. 
• 
Grade 1:  no action required 
ANC = absolute neutrophil count; eGFR = estimated glomerular filtration rate.  
Note:  Diarrhea, nausea, and vomiting should be handled with best supportive care first before 
considering dose modification.  Preexisting pleural effusion will not be considered as an adverse 
event. 
 
5.1.4 
Safety of Crizotinib and Management of Adverse Events  
Dosing interruption and/or dose reduction may be required on the basis of individual 
safety and tolerability.  If dose reduction is necessary, then the dose of crizotinib should 
be reduced to 200 mg taken BID.  If further dose reduction is necessary, then the dose 
should be modified to 250 mg taken once daily on the basis of individual safety and 
tolerability (XALKORI® U.S. Package Insert; Crizotinib SmPC).  Dose reduction 
guidelines for hematologic and non-hematologic toxicities are provided in Table 3 and 
Table 4. 


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Table 3 
Crizotinib Dose Modification⎯Hematologic Toxicities (Except 
Lymphopenia) 
CTCAEa Grade 
Crizotinib Dosing 
Grade 3 
Withhold until recovery to Grade ≤ 2, then resume at 
the same dose schedule 
Grade 4 
Withhold until recovery to Grade ≤ 2, then resume at 
200 mg twice dailyb 
a National Cancer Institute Common Terminology Criteria for Adverse Events 
b In case of second episode, dosing should be withheld until recovery to Grade ≤ 2, then dosing 
should be resumed at 250 mg once daily.  Crizotinib must be permanently discontinued in case 
of a third episode of Grade 4 hematologic toxicity. 
 


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Table 4 
Crizotinib Dose Modification⎯Non-Hematologic Toxicities 
Criteria 
Crizotinib Dosing 
ALT or AST elevation  > 5 × ULN with total 
bilirubin  ≤ 1.5 × ULN 
Withhold until recovery to baseline or 
≤ 3 × ULN, then resume at reduced dose.  
Crizotinib must be permanently discontinued in 
case of recurrence. 
ALT or AST elevation > 3 × ULN with 
concurrent total bilirubin elevation  > 1.5 × ULN 
(in the absence of cholestasis or hemolysis) 
Permanently discontinue 
Any grade drug-related ILD/pneumonitis 
Permanently discontinue 
QTc > 500 ms on at least 2 separate ECGs 
Withhold until recovery to baseline or < 481 ms, 
then resume at reduced dose.  Crizotinib must 
be permanently discontinued in case of 
recurrence (i.e., QTc > 500 ms on at least 
2 separate ECGs). 
QTc > 500 ms or ≥ 60 ms change from baseline 
with torsade de pointes or polymorphic 
ventricular tachycardia or signs/symptoms of 
serious arrhythmia 
Permanently discontinue 
Bradycardia (heart rate < 60 bpm, symptomatic, 
may be severe and medically significant, 
medical intervention indicated) 
Withhold until recovery to asymptomatic 
bradycardia or to a heart rate ≥ 60 bpm.  
Evaluate concomitant medications known to 
cause bradycardia, as well as anti-hypertensive 
medications.  If a contributing concomitant 
medication is identified and discontinued, or its 
dose is adjusted, resume crizotinib at previous 
dose upon recovery to asymptomatic 
bradycardia or to a heart rate ≥ 60 bpm. 
If no contributing concomitant medication is 
identified, or if contributing concomitant 
medication is identified but not discontinued or 
its dose was not modified, resume crizotinib at 
reduced dose upon recovery to asymptomatic 
bradycardia or to a heart rate of ≥ 60 bpm. 
Bradycardia (heart rate < 60 bpm, 
life-threatening consequences, urgent 
intervention indicated) 
Permanently discontinue if no contributing 
concomitant medication is identified. 
If contributing concomitant medication is 
identified and discontinued, or its dose is 
adjusted, resume at 250 mg once daily upon 
recovery to asymptomatic bradycardia or to a 
heart rate of ≥ 60 bpm, with frequent 
monitoring.  
Crizotinib must be permanently discontinued in 
case of recurrence. 
 
Gastrointestinal events were commonly reported with crizotinib in clinical trials.  Nausea, 
diarrhea, vomiting, and constipation were the most commonly reported gastrointestinal 


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events and were primarily Grade 1 in severity.  Supportive care for gastrointestinal 
events may include standard antiemetic and/or antidiarrheal or laxative medicinal 
products.  In clinical studies with crizotinib, events of gastrointestinal perforations were 
reported (XALKORI® U.S. Package Insert; Crizotinib SmPC). 
Blood counts and liver function tests including ALT, AST, and total bilirubin should be 
monitored as per local prescribing information for crizotinib. 
See local prescribing information for further crizotinib safety information. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
non-SAEs of special interest, performing protocol-specified safety laboratory 
assessments, measuring protocol-specified vital signs, and conducting other 
protocol-specified tests that are deemed critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical occurrence in a clinical investigation where a patient is administered a 
pharmaceutical product, regardless of causal attribution.  An AE can therefore be any of 
the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition). 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as 
biopsies) 
 


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5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
An SAE is any AE that meets any of the following criteria: 
• 
Is fatal (i.e., the AE actually causes or leads to death) 
• 
Is life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death) 
This does not include any AE that had it occurred in a more severe form or was 
allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an AE (e.g., rated as mild, moderate, or severe, or according to National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] criteria; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF. 
SAEs are required to be reported by the investigator to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2 for reporting 
instructions). 
5.2.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-SAEs of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2 for reporting instructions).  AEs of special interest for this study are the 
following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.6) 


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• 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs (see Section 5.2.1 for definition) 
are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Sections 5.4−5.6.  For each AE recorded 
on the Adverse Event eCRF, the investigator will make an assessment of seriousness 
(see Section 5.2.2 for seriousness criteria), severity (see Section 5.3.3), and causality 
(see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on AEs at each patient contact.  All AEs, whether 
reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
SAEs caused by a protocol-mandated intervention (e.g., invasive procedures such as 
biopsies, discontinuation of medications) should be reported (see Section 5.4.2 for 
instructions for reporting SAEs). 
After initiation of study drug, all AEs will be reported until 4 weeks after the last dose 
of study drug.  After this period, the investigator should report any SAEs that are 
believed to be related to study drug treatment (see Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient evaluation timepoints.  Examples of non-directive questions 
include the following: 
• 
"How have you felt since your last clinic visit?" 
• 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The AE severity grading scale for the NCI CTCAE (v4.0) will be used for assessing AE 
severity.  Table 5 will be used for assessing severity for AEs that are not specifically 
listed in the NCI CTCAE. 


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Table 5 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in the NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  On the basis of the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
AE is considered to be related to the study drug, indicating "yes" or "no" accordingly.  
The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 


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5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology and concepts when recording AEs 
on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 
5.3.5.1 
Diagnosis Versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported AEs based on 
signs and symptoms should be nullified and replaced by one AE report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events that are Secondary to Other Events 
In general, AEs that are secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events.  A medically significant secondary AE that is separated in 
time from the initiating event should be recorded as an independent event on the 
Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation timepoints.  Such events should only be recorded once on the Adverse Event 
eCRF.  The initial severity (intensity or grade) of the event will be recorded at the time 
the event is first reported.  If a persistent AE becomes more severe, the most extreme 
severity should also be recorded on the Adverse Event eCRF.  If the event becomes 


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serious, it should be reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 
to "serious," providing the date that the event became serious, and completing all data 
fields related to SAEs. 
A recurrent AE is one that resolves between patient evaluation timepoints and 
subsequently recurs.  Each recurrence of an AE should be recorded as a separate event 
on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE.  A laboratory test result must be 
reported as an AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
Note: For oncology trials, certain abnormal values may not qualify as AEs. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5 times the ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the AE.  For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent AEs).  


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5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported 
as an AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment 
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded one on the Adverse Event eCRF (see Section 5.3.5.3 for details 
on recording persistent adverse events). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an AE the occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as an SAE or a non-SAE of special interest (see Section 5.4.2). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified AE reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of NSCLC should be recorded only on the Study 
Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and 


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immediately reported to the Sponsor (see Section 5.4.2).  An independent monitoring 
committee will monitor the frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. 
During survival follow-up, deaths attributed to progression of NSCLC should be recorded 
only on the Survival eCRF. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such 
events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., "more 
frequent headaches"). 
5.3.5.9 
Lack of Efficacy or Worsening of Non-Small Cell Lung Cancer 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs.  These data will be captured as 
efficacy assessment data only.  In most cases, the expected pattern of progression will 
be based on RECIST criteria v1.1 (Appendix 4).  In rare cases, the determination of 
clinical progression will be based on symptomatic deterioration.  However, every effort 
should be made to document progression using objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an AE. 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization (i.e., in-patient admission to a hospital) or 
prolonged hospitalization should be documented and reported as an SAE (per the 
definition of SAE in Section 5.2.2), except as outlined below. 


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The following hospitalization scenarios are not considered to be AEs: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
The patient has not experienced an AE. 
• 
Hospitalization due solely to progression of the underlying cancer 
 
5.3.5.11 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an AE, but it may result in an AE.  All AEs associated with an overdose or incorrect 
administration of study drug should be recorded on the Adverse Event eCRF.  If the 
associated AE fulfills seriousness criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.3.5.12 
Patient-Reported Outcome Data 
AE reports will not be derived from PRO data by the Sponsor, and safety analyses will 
not be performed using PRO data.  However, if any PRO responses suggestive of a 
possible AE are identified during site review of the PRO data, the investigator will 
determine whether the criteria for an AE have been met and, if so, will report the event 
on the Adverse Event eCRF. 
5.3.5.13 
Adverse Events in Individuals Not Enrolled in the Study 
If an AE inadvertently occurs in an individual not enrolled in the study, the Adverse Event 
Form provided to investigators should be completed and submitted to Roche or its 
designee, either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
SAEs 


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• 
Non-SAEs of special interest 
• 
Pregnancies 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting SAEs to the local 
health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor (Roche Medical Responsible) Contact Information 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk as 
well as Medical Monitor contact information will be distributed to all investigators. 
This list can be generated using contact numbers found at the following link: 
http://gcpcenter.roche.com/synergy/portal/view/pdq-spi/gcpcenter/34-64711453. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
5.4.2.1 
Events That Occur Prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported.  The Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to Roche or its designee immediately (i.e., no more than 
24 hours after learning of the event), either by faxing or by scanning and emailing the 
form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur After Study Drug Initiation 
After initiation of study drug, SAEs and non-SAEs of special interest will be reported until 
4 weeks after the last dose of study drug.  Investigators should record all case details 
that can be gathered immediately (i.e., within 24 hours after learning of the event) on the 
Adverse Event eCRF and submit the report via the electronic data capture (EDC) system.  


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A report will be generated and sent to Roche Safety Risk Management by the EDC 
system. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to Roche or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system. 
Instructions for reporting post-study AEs are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 3 months after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Roche Safety Risk Management.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any SAEs associated 
with the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF. 
In the event that the EDC system is unavailable, the Clinical Trial Pregnancy Reporting 
Form provided to investigators should be completed and submitted to Roche or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Once the EDC system is available, all information will 
need to be entered and submitted via the EDC system. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
3 months after the last dose of study drug.  A Pregnancy Report eCRF should be 
completed by the investigator immediately (i.e., no more than 24 hours after learning of 
the pregnancy) and submitted via the EDC system.  Attempts should be made to collect 
and report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  The pregnant partner will need to sign an Authorization 
for Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy.  Once the authorization has been signed, the investigator will update the 


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Pregnancy Report eCRF with additional information on the course and outcome of the 
pregnancy.  An investigator who is contacted by the male patient or his pregnant partner 
may provide information on the risks of the pregnancy and the possible effects on the 
fetus, to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 
5.4.3.3 
Abortions 
Any abortion should be classified as an SAE (as the Sponsor considers abortions to be 
medically significant), recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2). 
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as an SAE, recorded on the Adverse Event eCRF, and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or 
the patient withdraws consent.  Every effort should be made to follow all SAEs considered 
to be related to study drug or trial-related procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.5.2 
Sponsor Follow-Up 
For SAEs, non-SAEs of special interest, and pregnancies, the Sponsor or a designee 
may follow up by telephone, fax, electronic mail, and/or a monitoring visit to obtain 
additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 


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5.6 
POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the investigator becomes aware of any SAE that 
occurs after the end of the AE reporting period (defined as 4 weeks after the last dose of 
study drug), if the event is believed to be related to study drug treatment.  
The investigator should report these events directly to Roche or its designee, either by 
faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all SAEs and non-SAEs of special interest against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators, IRBs, ECs, and applicable health authorities based on 
applicable legislation. 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference documents: 
• 
Alectinib Investigator's Brochure 
• 
Local prescribing information for crizotinib 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The primary analysis population for efficacy is the intent-to-treat (ITT) population defined 
as all randomized patients.  Patients will be assigned to the treatment group to which 
they were randomized. 
The primary analysis population for safety is the Safety Analysis Population (SAP) 
defined as all patients who received at least one dose of study medication.  Patients will 
be assigned to treatment groups as treated, and all patients who received any dose of 
alectinib will be included in the alectinib treatment arm. 
A secondary analysis population for efficacy is the FISH Positive Population (FPP).  This 
is defined as all patients in the ITT population who were ALK-positive using the Vysis 
FISH assay.  Patients will be assigned to the treatment group to which they were 


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randomized.  This analysis population will be used to perform a supportive analysis of 
the study data based on the Vysis FISH assay. 
An analysis of the primary endpoint of investigator-assessed PFS based on the FPP will 
be performed at the time of the primary analysis.  A major discrepancy between the 
Ventana IHC assay and the Vysis FISH assay may necessitate a follow-up analysis of 
the primary endpoint based on 170 PFS events observed in the FPP to ensure 80% 
power of the log-rank test under the assumption of a hazard ratio of 0.65 in this 
secondary population. 
The final analysis of the primary endpoint of PFS will occur when 170 PFS events have 
occurred, on the basis of the investigators’ assessments.  On the basis of the 
assumptions outlined in Section 6.1, this is estimated to occur approximately 33 months 
after the first patient has been enrolled.  A survival follow-up analysis will be performed 
once approximately 50% of patients (i.e., 143 patients) have died, which is estimated to 
occur approximately 42 months after the first patient has been enrolled. 
Hypothesis tests will be two-sided with a significance level of 5% unless otherwise 
indicated. 
The baseline value of any variable will be defined as the last available value recorded 
prior to the first administration of alectinib or crizotinib. 
Further details of all analyses will be provided in the Statistical Analysis Plan. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The focus of this clinical trial is hypothesis testing (Section 6.4.1), and the primary 
endpoint of PFS was used to determine the sample size of the study. 
At the time of initially writing the protocol, there were no Phase III data available on 
crizotinib in the first-line setting in ALK-positive patients.  The median PFS for crizotinib 
administered as second-line therapy from the global randomized Phase III PROFILE 
1007 study was 7.7 months (95% CI: 6.0%, 8.8%).  From the Phase II single arm study 
of patients who had received ≥ 1 line of chemotherapy (with 85% patients having 
received ≥ 2 prior chemotherapy regimens), the median PFS was 8.5 months 
(95% CI: 6.2%, 9.9%).  The Phase III PROFILE 1014 study of crizotinib versus standard 
pemetrexed-platinum-based chemotherapy in previously untreated patients with 
ALK-positive non-squamous NSCLC reported a median PFS of 10.9 months for 
crizotinib (Mok et al. 2014). 
Thus, an initial assumption of median PFS of 9.8 months for the crizotinib arm has been 
reassessed based on data from the Phase III study PROFILE 1014 to 10.9 months.  An 
HR of 0.65 for alectinib versus crizotinib (i.e., an increase from 10.9 months median PFS 
to 16.8 months) will be targeted. 


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In this study, 286 patients will be enrolled in a 1:1 randomization allocation.  Enrollment 
will take approximately 24 months on the basis of an assumption of non-linear 
recruitment as follows: 
• 
Month 1:  1 patient per month 
• 
Month 2:  2 patients per month 
• 
Month 3:  4 patients per month 
• 
Month 4:  6 patients per month 
• 
Month 5:  8 patients per month 
• 
Month 6:  10 patients per month 
• 
Month 7:  12 patients per month 
• 
Months 8−12:  13 patients per month 
• 
Months 13−14:  14 patients per month 
• 
Month 15 onwards:  15 patients per month 
 
A total of 170 PFS events are required to achieve 80% power at a two-sided alpha level 
of 5%.  This number of PFS events is estimated to occur approximately 33 months after 
the first patient has been enrolled. 
No interim analysis for efficacy or futility is planned. 
A survival follow-up analysis will be performed once approximately 50% of patients 
(i.e., 143 patients) have died.  The median OS in the crizotinib arm is assumed to be 
24 months, and the expected median OS in the alectinib treatment arm is 30 months, 
equating to an HR of 0.83.  On the basis of the sample size (N = 286), the trial will not be 
powered to demonstrate any statistically significant difference in OS of this magnitude.  
At the time of the final analysis of the primary endpoint of PFS, on the basis of the above 
assumptions, 106 OS events are expected to have occurred.  The survival follow-up 
analysis is expected to occur approximately 42 months after the first patient has been 
enrolled. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Study enrollment, study treatment administration, reasons for discontinuation from study 
treatment, and reasons for study termination will be summarized by treatment arm for all 
randomized patients.  Violations of inclusion and exclusion criteria, on the basis of 
information captured on the eCRF, will be reported and summarized by treatment arm. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Summaries of treatment group comparability will be based on the ITT population. 
Demographic, baseline disease characteristics and lung cancer history will be 
summarized by treatment arm for all randomized patients, including the randomization 


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stratification factors.  Descriptive baseline summaries of continuous data will present the 
group mean, standard deviation, median, minimum, and maximum.  Descriptive 
summaries of discrete data will present the category counts as frequency and 
percentages. 
Previous and concomitant cancer therapy will also be summarized, as well as 
anti-cancer subsequent therapy.  Previous and concurrent diseases and medications will 
also be summarized. 
6.4 
EFFICACY ANALYSES 
The primary population for all primary and secondary efficacy analyses will be the ITT 
population. 
6.4.1 
Primary Efficacy Endpoint 
PFS is defined as the time from date of randomization to the date of first documented 
disease progression or death, whichever occurs first.  The primary endpoint of PFS will 
be determined on the basis of investigator assessment of progression using 
RECIST v1.1.  Patients who have not experienced disease progression or death at the 
time of analysis will be censored at the last tumor assessment date either during study 
treatment or during follow-up.  Patients with no post-baseline tumor assessment will be 
censored at the date of randomization. 
Patients who discontinue treatment prior to disease progression (e.g., due to toxicity) will 
continue on study and will be followed until disease progression and for OS regardless 
of whether they subsequently receive anti-cancer therapy. 
The treatment comparison of PFS will be based on a stratified log-rank test at the 5% 
level of significance (two-sided).  The stratification factors are the randomization 
stratification factors:  ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS 
metastases at baseline (yes vs. no), as recorded on the eCRF.  Results from an 
unstratified log-rank test will also be presented. 
The Kaplan-Meier method will be used to estimate the median PFS for each treatment 
arm with 95% confidence limits, and a Kaplan-Meier curve will be constructed to provide 
a visual description of the difference between the treatment arms.  A stratified Cox 
proportional regression model will be used including treatment in order to provide an 
estimate of the treatment effect expressed as an HR (alectinib vs. crizotinib), as well as 
a 95% CI. 


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The difference between the two treatment groups will be assessed and tested for the 
following hypothesis:  the survival distribution function (SDF) of the alectinib treatment 
group is the same as for the crizotinib treatment group versus the alternative that the two 
distributions are different:  
H0:  SDF (alectinib) = SDF (crizotinib) 
versus 
H1:  SDF (alectinib) ≠ SDF (crizotinib) 
where SDF denotes the survival distribution function of the parameter PFS. 
6.4.2 
Secondary Efficacy Endpoints 
If the primary endpoint of PFS is statistically significant at a two-sided 5% significance 
level, the following secondary endpoints will be tested in the following sequential order, 
each at a two-sided 5% significance level: 
• 
PFS by IRC 
• 
Time to CNS progression 
• 
ORR 
• 
OS 
 
PFS by IRC 
An analysis of PFS on the basis of the IRC assessments will be performed using the 
same methodology as specified for PFS on the basis of investigator assessment. 
Time to CNS Progression 
Time to CNS progression is defined as the time from randomization until radiographic 
evidence of CNS progression.  An independent central radiological review will be 
performed for all patients, and the analysis of CNS progression or response will be on 
the basis of the data from the independent review.  All patients will be included in the 
analysis regardless of their baseline status of CNS metastases.  CNS progression is 
defined as progression due to newly developed CNS lesions and/or progression of 
preexisting baseline CNS lesions.  On the basis of RECIST v1.1, this is defined as a new 
post-baseline CNS/brain lesion(s) and/or an increase of ≥ 20% in the sum of longest 
diameters of the measurable baseline CNS lesions compared to nadir and/or 
unequivocal progression of non-measurable baseline CNS lesions. 
In order to account for the competing risks inherent in such an analysis, HRs, including 
statistical inference on the basis of a two-sided log-rank test, to compare the risk of CNS 
progression between the alectinib and crizotinib treatment groups, will be computed on 
the basis of cause-specific hazard functions. 
The probability of CNS progression, non-CNS progression, and death will each be 
estimated using cumulative incidence functions. 


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For descriptive purposes, estimates of the CNS progression rates over time with 
95% CIs on the basis of cumulative incidence functions will be presented.  A Gray’s test 
to compare the risk of CNS progression between alectinib and crizotinib will also be 
performed as a supportive analysis. 
An exploratory analysis of CNS Time to Progression on the basis of RANO criteria will 
also be performed on the basis of the IRC assessments. 
In the subgroup of patients with measurable CNS lesions at baseline, an exploratory 
analysis of C-ORR defined as the percentage of patients who achieve a best overall 
response of CR or PR (defined by RECIST v1.1 as a 30% decrease in the sum of 
longest diameters of measurable CNS lesions referencing baseline) will also be 
performed.  Duration of CNS response will be listed and may be analyzed if there are a 
sufficient number of CNS responses.  Similar analyses will be performed in the 
subgroup of patients with measurable and/or non-measurable CNS lesions at baseline.  
An exploratory analysis of these endpoints will also be performed on the basis of RANO 
criteria assessed by the IRC. 
Objective Response Rate 
ORR, on the basis of investigator assessment, is defined as the percentage of patients 
who attain a CR or PR.  Per RECIST v1.1, confirmation of objective response is not 
required for this secondary endpoint.  Patients without a post-baseline tumor 
assessment will be considered non-responders, as will patients with a best overall 
response of stable disease (SD), PD, or NE (not evaluable). 
An estimate of ORR and its two-sided 95% CI will be calculated using the 
Clopper-Pearson method for each treatment arm.  Response rates in the treatment 
groups will be compared using a stratified Mantel-Haenszel test on the basis of the 
randomization stratification factors.  The difference in ORR between the two treatment 
arms will be presented together with a two-sided 95% CI on the basis of a normal 
approximation to the binomial distribution. 
DOR 
For patients who have experienced an objective response (CR or PR) during the study 
as assessed by the investigator, DOR is defined as the duration from the first tumor 
assessment that supports the patient’s objective response (CR or PR, whichever is first 
recorded) to first documented disease progression or death due to any causes, 
whichever occurred first.  Patients who have not progressed or died at the time of 
analysis will be censored at the last tumor assessment date.  Because the determination 
of DOR is based on a non-randomized subset of patients, formal hypothesis testing will 
not be performed.  DOR will be estimated using Kaplan-Meier methodology and an HR 
on the basis of a Cox proportional regression model will be calculated. 


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Overall Survival 
OS is defined as the time from the date of randomization to the date of death due to any 
cause.  Patients who are not reported as having died at the time of analysis will be 
censored at the date when they were last known to be alive.  Patients who do not have 
post-baseline information will be censored at the date of randomization.  OS will be 
analyzed using the same methodology as specified for the primary endpoint.  A survival 
follow-up will be performed based on more mature data. 
6.4.2.1 
Sensitivity Analyses 
The following sensitivity analyses will be performed on the primary endpoint of PFS: 
• 
The effect of non−protocol-specified anti-cancer therapy prior to progression will be 
assessed by censoring patients at the last adequate tumor assessment prior to the 
start of non−protocol-specified anti-cancer therapy. 
• 
The effect of missing tumor assessments will be assessed if the number of missing 
assessments in either arm is > 5%.  For patients with progression determined 
following one or more missing tumor assessments, the progression will be 
backdated to the first missing tumor assessment. 
• 
The effect of loss to follow-up will be assessed depending on the number of patients 
who are lost to follow-up.  If > 5% of patients are lost to follow-up for PFS in either 
treatment arm, a “worst-case” analysis will be performed in which patients who are 
lost to follow-up will be considered to have progressed at the last date they were 
known to be progression-free. 
 
6.4.2.2 
Subgroup Analyses 
Subgroup analyses of PFS will be performed for patients with baseline CNS metastases 
and for patients without baseline CNS metastases.  In addition, a subgroup analysis of 
Time to CNS Progression will be performed, excluding patients who had pre-treatment 
radiation therapy for CNS lesions. 
All other subgroup analyses will be specified in the SAP. 
6.5 
SAFETY ANALYSES 
The primary population for all safety analyses will be the SAP as defined in Section 6. 
All safety parameters will be summarized in tables to evaluate and compare the safety 
profile of patients treated with alectinib versus crizotinib in terms of: 
• 
Adverse events including adverse events leading to dose modifications or 
interruptions, study drug withdrawal, and death  
• 
Severe, serious, and selected adverse events 
• 
Deaths 
• 
Laboratory parameters and abnormalities 
• 
Vital signs 


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• 
ECGs 
• 
ECOG PS 
 
Adverse events will be coded using MedDRA and summarized by mapped term and 
appropriate thesaurus level.  All adverse events and routine laboratory parameters will 
be assessed according to the NCI CTCAE v4.0 grading system.  For adverse events, the 
most extreme severity will be used for reporting.  Adverse events will be described by 
individual listings and by body system, as well as by severity.  In tables showing the 
overall incidence of adverse events, patients who experienced the same event on more 
than one occasion are counted only once in the calculation of the event frequency. 
Laboratory values will be summarized by treatment arm including summary tables for the 
shifts in grades from baseline to the worst grade observed during treatment.  In order to 
evaluate and compare hypogonadism in the two treatment arms, testosterone levels in 
the blood will be summarized for males by treatment arm over time (for details, 
see Section 6.8). 
Descriptive summary tables of change from baseline over time will be provided for vital 
signs and descriptive statistics will be tabulated for ECOG PS.  ECG findings over time 
will be summarized. 
Study drug administration will be summarized by duration and cumulative dose.  In 
addition, treatment exposure will be summarized including the number of doses received, 
dose intensity, and the percentage of planned dose. 
Subgroup analyses will be performed to evaluate the safety profile within the subgroups 
of patients including by sex, age (< 65 vs. ≥ 65 years), and race (non-Asian vs. Asian). 
An iDMC will review the safety data collected during the conduct of the study.  Safety 
monitoring will be performed periodically.  Further details will be outlined in the iDMC 
Charter. 
6.6 
PHARMACOKINETIC ANALYSES 
Standard NCA may be conducted for PK data collected from patients participating in 
serial/intensive PK collections for relevant analytes, as data allow, as appropriate, and if 
needed.  PK parameters, including but not limited to AUC, Cmax, and time to maximum 
concentration (Tmax), will be calculated on the basis of the available data as appropriate 
and where data allow.  Additional PK parameters may be calculated as deemed 
appropriate. 
Individual and mean plasma concentrations at each sampling timepoint and/or PK 
parameters for alectinib and metabolite(s) will be listed, as appropriate. 


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Summary statistics (e.g., means, standard deviation, coefficient of variation %, 
geometric means, medians and ranges) for plasma concentrations and/or PK 
parameters for alectinib and metabolite(s) will be presented by treatment and nominal 
collection times (plasma concentrations only), as appropriate.  Additional plots or 
summary statistics may be constructed or calculated, as appropriate. 
Results of PK and/or any PK/pharmacodynamic analyses may be reported outside the 
clinical study report. 
Nonlinear mixed-effects modeling (with software NONMEM) (Beal et al. 1999) will be 
used to analyze the sparse and/or serial/intensive plasma concentration-time data for 
alectinib.  The PK data from this study may be pooled with data from other studies.  
Population and individual PK parameters will be estimated and the influence of various 
covariates (such as age, gender, and body weight) on these parameters will be 
investigated. 
Exploratory analyses will be conducted to investigate the relationship between alectinib 
PK exposure and efficacy/safety parameters. 
Details of the mixed-effects modeling and exploratory analyses will be reported in a 
document separate from the clinical study report. 
6.7 
PATIENT-REPORTED OUTCOME ANALYSES 
The following PRO endpoints will be analyzed and PRO data will be presented 
separately from adverse event data. 
6.7.1 
Time to Deterioration of Patient-Reported Lung Cancer 
Symptoms 
TTD from baseline will be assessed at every study visit (Week 4, Week 8, and then after 
every 4 weeks) until disease progression and during post-progression on treatment in 
case of isolated, asymptomatic CNS progression; at post-treatment Visit (4 weeks after 
permanent treatment discontinuation); and at subsequent 8-weekly survival follow-up 
visits for 6 months, for the following lung cancer symptoms: cough (Question 31 on the 
QLQ-LC13), dyspnea single item (Question 8 on the QLQ-C30), dyspnea multi-item 
subscale (Questions 33-35 on the QLQ-LC13), chest pain (Question 40 on the 
QLQ-LC13), arm/shoulder pain (Question 41 on the QLQ-LC13) and fatigue multi-item 
subscale (Questions 10, 12, and 18 on the QLQ-C30) for patients in each arm.  
Completion and compliance rates will be summarized at each timepoint by treatment 
arm with reasons for missing data.  TTD will be analyzed for the ITT population.  If a 
baseline or post-baseline PRO evaluation is not available, TTD will be censored at the 
date of randomization. If they have not deteriorated, patients will be censored at the last 
time when they completed an assessment for cough, dyspnea (single item), dyspnea 
(subscale items), chest pain, arm/shoulder pain, and fatigue. 


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6.7.2 
Additional Patient-Reported Outcomes 
PROs of HRQoL, lung cancer−related symptoms, and health status will be measured 
using the EORTC QLQ-C30 and EORTC QLQ-LC13. 
Summary statistics (mean, standard deviation, median, and range) of linear transformed 
scores will be reported for all the items and subscales of the EORTC 
QLQ-C30 questionnaire, and the QLQ-LC13 according to the EORTC scoring manual 
guidelines.  Completion and compliance rates will be summarized at each timepoint by 
treatment arm with reasons for missing data.  Only patients with a baseline assessment 
and at least one post-treatment assessment will be included in the analyses. 
6.8 
EXPLORATORY ANALYSES 
The EQ-5D-3L is a generic PRO instrument that is used for across diseases and 
indications cost-effectiveness analyses.  This instrument quantifies the QoL of various 
health outcomes and is applicable to a wide range of health states.  Analyses of this 
outcome will be exploratory and will generate utility scores for use in economic models 
for reimbursement purposes only.  The PRO will be administered every 4 weeks until 
disease progression and during post-progression on treatment in case of isolated, 
asymptomatic CNS progression; at the post-treatment visit (4 weeks after permanent 
treatment discontinuation); and every follow-up visit (every 8 weeks) after post-treatment 
visit for 6 months (see Appendix 1).  
It has been reported that crizotinib therapy triggers rapid suppression of testosterone 
levels in men causing rapid-onset hypogonadism.  It is unknown if reductions in 
testosterone reflect an effect of crizotinib on ALK or on some combination of the drug’s 
targets (i.e., c-MET) (Weickhardt et al. 2012; Weickhardt et al. 2013).  Total testosterone 
and free testosterone levels (either by direct measurement or by calculation using 
albumin and sex hormone-binding globulin [SHBG] calculator:  
http://www.issam.ch/freetesto.htm) and FSH and LH levels in blood will be measured 
(see Appendix 1) in male patients enrolled in the study for exploratory analysis of an 
onset of hypogonadism.  The recommended time of day to have a blood sample taken 
for this test is between 7 a.m. and 10 a.m. 
The Abbott Vysis FISH test will be used as an exploratory assay after patients have 
been enrolled in this study.  Results from these analyses will be used to quantify the 
degree of correlation between Vysis FISH and Ventana IHC for the detection of 
ALK-positive NSCLC. 
ALK plasma assays (PCR and/or sequencing) will be used as exploratory assays for 
ALK positive and consented ALK negative patients.  Results from these analyses will be 
used to quantify the degree of correlation between ALK plasma tests and Ventana IHC 
and Vysis FISH for the detection of ALK positive NSCLC.  The ALK plasma assay 
population may be used for exploratory efficacy and safety analysis.  This analysis 
population will be used to support diagnostic development.  Assays from this population 


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may be used for the registration of a plasma assay as a companion diagnostic. This 
analysis will be dependent on the successful technical development of a plasma ALK 
assay.  Results of analyses related to those alternative diagnostic tests and exploratory 
analyses on post-progression tumor samples to measure molecular mechanisms of 
resistance to ALK inhibitors and plasma samples to measure ALK rearrangements in 
circulating tumor cells will be communicated outside the main clinical study report. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC using eCRFs.  
Sites will be responsible for data entry into the EDC system.  In the event of discrepant 
data, the Sponsor will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data. Central laboratory data or other electronic 
data will be sent directly to the Sponsor, using the Sponsor’s standard procedures to 
handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
ePRO data will be collected through use of an electronic device provided by an ePRO 
vendor.  The device is designed for entry of data in a way that is attributable, secure, 
and accurate, in compliance with the FDA regulations for electronic records (21 CFR 
Part 11).  The ePRO device data are available for view access only via secure access to 
a web server.  Only identified and trained users may view the data, and their actions 
become part of the audit trail.  The Sponsor will have view access only.  System 
backups for data stored by the Sponsor and records retention for the study data will be 
consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 


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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
Patients will use an ePRO device to capture PRO data.  The data will be transmitted via 
pre-specified transmission method (e.g., web or wireless) automatically after entry to a 
centralized database at the ePRO vendor.  The data can be reviewed by site staff via 
secure access to a web server. 
Once the study is complete, the ePRO data, audit trail, and trial and system 
documentation will be archived.  The investigator will receive patient data for the site in 
both human- and machine-readable formats on an archival-quality compact disc that 
must be kept with the study records as source data.  Acknowledgement of receipt of the 
compact disc is required. In addition, the Sponsor will receive all patient data in a 
machine-readable format on a compact disc. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 


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7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a United States 
IND application will comply with FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the European Union or European Economic Area will comply 
with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 


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submission.  The final IRB/EC−approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient before his or her 
participation in the study.  The case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC−approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 


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8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  In 
addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 


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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, which includes an audit trail containing a complete record of all changes 
to data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
Steering Committee is established to provide the study Sponsor with recommendations 
related to any aspect of the trial, specifically study design, data interpretation, 
exploratory analyses, or alternate changes to the trial that may assist in patient accrual, 
data collection, analysis, and interpretation of the study results.  The Sponsor is 
ultimately responsible for all decisions regarding the study. 
The test for the study inclusion criteria of ALK-positive NSCLC will be performed at 
Sponsor’s designated central laboratories and assessed by Ventana IHC test. 
An iDMC will be established to monitor the progress of the study and ensure that the 
safety of patients enrolled in the study is not compromised.  Details of the composition, 
roles, and responsibilities, and processes of the iDMC are documented in a separate 
iDMC charter.  The iDMC will review safety data and can make recommendations to the 
Sponsor to stop or amend the study on the basis of safety findings.  The frequency of 
these reviews as well as the data to be reviewed will be agreed with the iDMC and 
outlined in the separate iDMC charter.  No stopping for early proof of efficacy will result 
from any of these regular safety reviews.  iDMC review meetings will be held in a blinded 
manner to the Sponsor. 


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An IRC will review the tumor assessments to determine the secondary endpoints of the 
overall disease PFS and time to CNS progression, both on the basis of RECIST v1.1.  In 
addition to the secondary endpoint of time to CNS progression together with C-ORR, 
C-DOR, and CNS progression rate at 6, 12, 18, and 24 months, an IRC will review the 
tumor assessments on the basis of RANO criteria. 
The independent review of MRI and CT scans will NOT determine either eligibility OR 
patient treatment.  All treatment decisions will be made by the investigator using local 
assessments. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 


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Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


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10. 
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Costa DB, Kobayashi S, Pandya SS, et al. CSF Concentration of the anaplastic 
lymphoma kinase inhibitor crizotinib. J Clin Oncol 2011;29:e443−5. 
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Crizotinib SmPC [resource on Internet]. [cited 2014 Jan 20]. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
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Dai Z, Kelly JC, Meloni-Ehrig A, et al. Incidence and patterns of ALK FISH abnormalities 
seen in a large unselected series of lung carcinomas. Mol Cytogenet. 2012;5:44. 
Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in 
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Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK fusion is linked to histological 
characteristics in a subset of lung cancers. J Thorac Oncol 2008;3:13−17. 


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Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK lung cancers are characterized by 
rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. 
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selective ALK inhibitor CH5424802/RO5424802 in ALK- rearranged advanced 
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NCCN 2014. Clinical Practice Guidelines in Oncology. Non−small Cell Lung Cancer 
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Appendix 1  
Schedule of Assessments 
Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) 
Until PD, 
Death, or 
Withdrawal 
from Study 
prior to PD a 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
 
 
 
 
 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation)a 
 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D) a 
Informed consent 
x 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
Pregnancy test b 
 
x 
To be repeated as necessary 
 
 
 
Physical 
examination c 
x 
 
x 
x 
x 
x 
x 
 
 
Vital signs 
x 
 
x 
x 
x 
x 
x 
 
 
ECOG PS 
x 
 
x 
x 
x 
x 
x 
 
 
ECG d 
x 
 
x e 
x 
 
x 
 
 
 
Hematology, 
Coagulation 
x 
 
x e 
x 
x 
x 
x 
 
 
Biochemistry 
x 
 
x e 
x 
x 
x 
x 
 
 
Urinalysis 
x 
 
x e 
x 
x 
x 
x 
 
 


Clinical Study Report: RO5424802 - F. Hoffmann-La Roche Ltd
Protocol BO28984     Report Number 1078196
2219
Appendix 1  
Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
117/Protocol BO28984, Version 4 
Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) 
Until PD, 
Death, or 
Withdrawal 
from Study 
prior to PD a 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
 
 
 
 
 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation)a 
 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D) a 
Concomitant 
medications 
x 
 
x 
x 
x 
x 
x 
 
 
Mandatory tumor 
sample for ALK 
testing f 
x 
 
 
 
 
 
 
 
 
Optional plasma 
sample from 
centrally confirmed 
ALK negative 
patients 
(20 ml of blood) 
x 
 
 
 
 
 
 
 
 
Optional tumor 
sample 
 
 
x g 
 
 
x h 
x h 
 
 


Clinical Study Report: RO5424802 - F. Hoffmann-La Roche Ltd
Protocol BO28984     Report Number 1078196
2220
Appendix 1  
Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
118/Protocol BO28984, Version 4 
Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) 
Until PD, 
Death, or 
Withdrawal 
from Study 
prior to PD a 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
 
 
 
 
 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation)a 
 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D) a 
Plasma sample for 
ALK fusion 
detection in nucleic 
acids (20 mL of 
blood) 
 
 
x i 
 
 
 
 
 
 
Plasma for 
detection of ALK 
mutation status 
(20 mL of blood) 
 
 
x 
 
 
x j 
x j 
 
 
Blood sample for 
pharmacogenomics 
research at 
pre-dose (3 mL of 
blood) k 
 
 
x 
 
 
 
 
 
 


Clinical Study Report: RO5424802 - F. Hoffmann-La Roche Ltd
Protocol BO28984     Report Number 1078196
2221
Appendix 1  
Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
119/Protocol BO28984, Version 4 
Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) 
Until PD, 
Death, or 
Withdrawal 
from Study 
prior to PD a 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
 
 
 
 
 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation)a 
 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D) a 
Tumor assessmentl 
x m 
 
x m 
 
x 
x n 
x 
x o 
 
MRI scan of the 
brain 
x m 
 
x m 
 
x 
x n 
x 
x o 
 
PK samples (2 mL 
blood) p 
 
 
x 
x 
x 
x 
 
 
 
PRO (EORTC 
QLQ-C30/LC13); 
EQ-5D q 
 
 
x 
x 
x 
x 
x 
x 
x r 
Total testosterone, 
(either by direct 
measurement or by 
calculation using 
albumin and 
SHBG), FSH, and 
LH s 
 
 
x 
x 
x 
x 
 
 
 
Adverse events t 
x 
x 
x 
x 
x 
x 
x 
x 
 


Clinical Study Report: RO5424802 - F. Hoffmann-La Roche Ltd
Protocol BO28984     Report Number 1078196
2222
Appendix 1  
Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
120/Protocol BO28984, Version 4 
Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) 
Until PD, 
Death, or 
Withdrawal 
from Study 
prior to PD a 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
 
 
 
 
 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation)a 
 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D) a 
Subsequent 
therapy for NSCLC 
 
 
 
 
 
 
x 
x 
xr 
Drug dispensing 
and accountability u 
 
 
x 
x 
x 
x 
x 
x (accountability 
only) 
 
Blood Sample for 
Roche Clinical 
Repository (10 mL) 
 
 
x 
 
 
 
 
 
 
ALK = anaplastic lymphoma kinase; ALP = alkaline phosphatase;  CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse 
Events; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30 = European Organization for the Research and 
Treatment of Cancer Quality of Life Questionnaire−Core; EQ-5D = EuroQoL 5 Dimension; FSH = follicle-stimulating hormone; LH = luteinizing 
hormone; MRI = magnetic resonance imaging; NCI = National Cancer Institute; NSCLC = non−small cell lung cancer; PD = progressive disease; 
PK = pharmacokinetic; PRO = patient-reported outcome; ULN = upper limit of normal. 
Notes: First dose of study drug to be taken as soon as patient has been randomized and appropriate drug has been provided–within ≤ 24 hours.  
Post-baseline assessments are to be performed within ± 1 week for the first two 4 weekly and subsequent 8 weekly assessments. 
a  For details on assessments when patient permanently discontinues from study treatment, see flowchart in Figure 1. 
b Urine or serum, to be repeated as necessary. 
c Including an ophthalmologic examination if clinically indicated. 


Clinical Study Report: RO5424802 - F. Hoffmann-La Roche Ltd
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Appendix 1  
Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
121/Protocol BO28984, Version 4 
d At screening, Visit 0 (baseline), Visit 1 (Week 4), Visit 4 (Week 24), Visit 8 (Week 56), last treatment visit, and as clinically indicated throughout 
the study. 
e Screening laboratory assessment done within 3 days can be counted as the baseline assessment. 
f Preferably blocks fixed in neutral buffered formalin; if blocks are not available, a minimum of 10 to 15 unstained 5-µm slides are required.  Tumor 
ALK status will be assessed by central laboratory before randomization. 
g Optional tumor sample could be taken from the tumor block obtained at screening. 
h At the time of disease progression from progressive lesions. 
i Mandatory blood sample (20 mL) for detection of ALK rearrangements in nucleic acids in plasma collected at baseline only. 
j Blood sample (20 mL) to obtain plasma for exploratory biomarkers will be collected at Visit 0 (baseline), during the study every second visit (i.e., 
every 16 weeks) until disease progression and during post-progression on treatment in case of isolated, asymptomatic CNS progression. 
k This sample is required in all patients in alectinib arm, and in those patients in the crizotinib arm who wish to participate in optional genomics 
sequencing. 
l Tumor assessment consists at minimum of a CT/MRI scan of chest and abdomen (for imaging of liver and adrenal glands).  Patients who are 
known to have bone metastasis or who display clinical or laboratory signs (e.g., serum ALP >1.5 × ULN) of bone metastasis should undergo 
radionuclide bone scan.  Clinical lesions should be assessed with caliper measurement and documented by color photography, including a ruler 
to estimate the size of the lesion. Post-baseline assessments are to be performed within ±1 week for the 8 weekly assessments.  If there is 
suspicion of disease progression on the basis of clinical or laboratory findings, a tumor assessment should be performed as soon as possible 
before the next scheduled evaluation. 
m Screening tumor assessment done within 14 days will be counted as the baseline assessment. 
n Tumor assessment can be performed whenever clinically indicated.  Brain assessment scans should be performed at every systemic imaging 
tumor assessment.  Tumor assessment should continue until disease progression if a patient discontinues treatment prior to PD, regardless of 
whether they subsequently receive non-study, anti-cancer therapy.  
o If treatment was permanently discontinued due to disease progression. 
p Pre-dose PK (2 mL) sampling for all patients on alectinib treatment will be performed at each visit during the treatment period and at the final 
study visit.  The pre-dose PK samples should be taken immediately before (within 2 hours) intake of study medication at all study visits. Remind 
the patient not to take a daily dose at home on the day of scheduled study visit.  For a subset of patients on alectinib treatment (10%−15%, or at 
least approximately n = 20) participating in serial/intensive PK sample collection, additional PK will be collected on Visits 0 (baseline) and 1 
(Week 4) at pre-dose (within 2 hours before intake of study medication), 1, 2, 4, 6, and 8 hours post-dose. 


Clinical Study Report: RO5424802 - F. Hoffmann-La Roche Ltd
Protocol BO28984     Report Number 1078196
2224
Appendix 1  
Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
122/Protocol BO28984, Version 4 
q PRO questionnaires are to be completed every 4 weeks until disease progression and during post-progression on treatment in case of isolated, 
asymptomatic CNS progression; at the post-treatment visit (4 weeks after permanent treatment discontinuation); and every follow up visit (every 
8 weeks) after post-treatment visit for 6 months..  Further guidelines on PRO questionnaire administration will be provided in the study manual. 
r Performed every 8 weeks after post-treatment visit during the first 6 months and then every 12 weeks.  The PRO assessments should be 
performed during the first 6 months.  For patients who discontinue treatment for reasons other than disease progression and who progress within 
the first 6 months of survival follow-up, PRO measures will be administered every 4 weeks until disease progression and then decreased to 
every 8 weeks until 6 months post treatment. For patients who discontinue treatment for reasons other than disease progression and have not 
yet progressed at 6 months post treatment, PRO measures will be administered every 4 weeks until disease progression and will no longer be 
required thereafter.  
s Male patients only, using institutional standard assay. The recommended time of day to have a blood sample taken for this test is between 7 a.m. 
and 10 a.m.  Albumin and SHBG measurements are not required when a direct assessment of free testosterone is available.  If free testosterone 
level cannot be directly assessed, it will be calculated from albumin and SHBG using a free testosterone calculator: 
http://www.issam.ch/freetesto.htm. 
t Graded according to NCI CTCAE (version 4.0).  Serious adverse events collection must start from first study-specific procedure. 
u For details on drug dispensing and accountability, see Section 4.3.3. 




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Alectinib—F. Hoffmann-La Roche Ltd 
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Appendix 2  
Schedule of Alectinib Pharmacokinetic Assessments 
Visit 
Timepoint 
Visit 0 (baseline) 
Pre-dose (within 2 hours before intake of alectinib)
Visit 1 (Week 4) 
Pre-dose (within 2 hours before intake of alectinib)
Visit 2 (Week 8) 
Pre-dose (within 2 hours before intake of alectinib)
All subsequent visits (every 
8 weeks) until PD or 
death/withdrawal from study prior to 
PD 
Pre-dose (within 2 hours before intake of alectinib)
Visit 0 (baseline) and Visit 1 
(Week 4)a 
Pre-dose (within 2 hours before intake of 
alectinib), 1, 2, 4, 6, and 8 hours post-dose 
PD = progressive disease; PK = Pharmacokinetic. 
a For patients participating in the serial/intensive PK sample collection only. 


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Alectinib—F. Hoffmann-La Roche Ltd 
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Appendix 3  
List of Substrates, Inhibitors, and Inducers of Drug-Metabolizing 
Enzymes and Transporters 
This representative list is not intended to be an exhaustive list.  Each patient’s 
concomitant medications should be carefully considered by the investigator with regard 
to the risk-benefit for the particular patient and appropriate monitoring, including any 
concomitant medication, dose adjustment, or therapeutic alternatives, which should be 
determined by the investigator caring for the patient. 
CYP3A Potent Inducers 
CYP3A Potent Inhibitors 
avasimibe, barbiturates, carbamazepine, 
efavirenz, ethosuximide, garlic supplements, 
modafinil, nevirapine, oxcarbazepine, 
phenobarbital, phenytoin, pioglitazone, 
primidone, rifabutin, rifampin, rifapentine, St. 
John’s wort, troglitazone 
aprepitant, atazanavir, boceprevir, 
ciprofloxacin, clarithromycin, conivaptan, 
diltiazem, erythromycin, fluconazole, grapefruit 
juice, indinavir, itraconazole, ketoconazole, 
lopinavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, troleandomycin, verapamil, 
voriconazole 
 
P-gp 
Substrates 
 
Inducers 
aliskiren, ambrisentan, 
colchicine, dabigatran, 
digoxin, everolimus, 
fexofenadine, imatinib, 
lapatinib, maraviroc, nilotinib, 
posaconazole, pravastatin, 
ranolazine, saxagliptin, 
sirolimus, sitagliptin, talinolol, 
tolvaptan, topotecan 
 
avasimibe, carbmazepine, 
phenytoin, rifampin, St John’s 
wort, tipranavir 
Dual UGT1A1/CYP3A 
Substrates 
Inhibitors 
Inducers 
buprenorphine, raltegravir 
atazanavir 
rifampin 
 Levien TL, and Baker DE Cytochrome P450 Drug Interactions. Therapeutic Research Center 
Pharmacist’s Letter/Prescriber’s Letter [resource on the Internet]. 2003. Available from: 
www.pharmacistsletter.com and www.prescribersletter.com. 
 Zhang L. Transporter Mediated Drug-Drug Interactions. FDA. Clinical Pharmacology Advisory 
Committee Meeting Topic 4: Transporter-Mediated Drug-Drug Interactions Atlanta, GA, March 
17, 2010. 
 
This information in this appendix is adapted from Levien and Baker 20031, Zhang 20102, 
and FDA Guidance on Drug-Drug Interactions. 
                                            
 
 


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Appendix 3  
List of Substrates, Inhibitors, and Inducers of Drug-Metabolizing 
Enzymes and Transporters (cont.) 
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126/Protocol BO28984, Version 4 
Also see: 
• 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dr
ugInteractionsLabeling/ucm080499.htm  
• 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
 
Potent inhibitors of CYP3A are those considered to be “strong CYP3A inhibitors” 
previously shown to result in a ≥ 5-fold increase in the AUC of a concomitantly 
administered CYP3A substrate.  These are based on the available published literature 
and, thus, are not considered exhaustive or inclusive.  See FDA Guidance on Drug-Drug 
Interactions for further detail. 


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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1: Excerpt from Original Publication 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1,1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2 
MEASURABILITY OF TUMOR AT BASELINE 
DEFINITIONS 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below. 
Measurable tumor lesions 
Tumor lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 
• 
10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater than 
5 mm) 
• 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
• 
20 mm by chest X-ray 
Malignant lymph nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
≥ 15 mm in the short axis when assessed by CT scan (CT scan slice thickness is 
recommended to be no greater than 5 mm).  At baseline and follow-up, only the short 
axis will be measured and followed.  See also notes below on “Baseline Documentation 
of Target and Non-Target Lesions” for information on lymph node measurement. 
Non-Measurable tumor lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 
                                            
1  Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors:  revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47. 
2  For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made. 


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Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
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Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone lesions 
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions.  However, these techniques 
can be used to confirm the presence or disappearance of bone lesions. 
Lytic bone lesions or mixed lytic−blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques, such as CT or MRI, can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
Blastic bone lesions are non-measurable. 
Cystic lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
TARGET LESIONS: SPECIFICATIONS BY METHODS OF MEASUREMENTS  
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
Method of assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 


Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
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Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
clinical lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is required. 
Chest X-Ray 
Chest CT is preferred over chest X-Ray, particularly when progression is an important 
endpoint, because CT is more sensitive than X-Ray, particularly in identifying new 
lesions.  However, lesions on chest X-Ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 
CT, MRI 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  This guideline has defined measurability of lesions on CT 
scan on the basis of the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable.  
If, prior to enrollment, it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease and should be 
optimized to allow for comparison with the prior studies if possible.  Each case should be 
discussed with the radiologist to determine if the substitution of these other approaches 
is possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of non-target disease or new lesions because the same lesion may 
appear to have a different size using a new modality. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. 
Endoscopy, laparoscopy, tumor markers, cytology, histology 
The utilization of these techniques for objective tumor evaluation cannot generally be 
advised. 
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Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
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TUMOR RESPONSE EVALUATION 
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least one 
measurable lesion, as detailed above. 
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions, up to a 
maximum of five lesions total and a maximum of two lesions per organ, representative of 
all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be recorded as non-measurable lesions (even if the size is > 10 mm by CT scan).   
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but, in addition, the lesions 
should lend themselves to reproducible repeated measurements.  It may be the case 
that, on occasion, the largest lesion does not lend itself to reproducible measurement, in 
which circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT this is 
almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or 
coronal).  The smaller of these measures is the short axis.  For example, an abdominal 
node that is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node.  In this example, 20 mm should be recorded as the 
node measurement.  All other pathological nodes (those with short axis ≥ 10 mm but 
< 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
< 10 mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
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into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
All other lesions or sites of disease, including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression”. 
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). 
RESPONSE CRITERIA 
Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
• 
CR:  Disappearance of all target lesions 
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm. 
• 
PR:  At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum of diameters. 
• 
PD:  At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (nadir), including baseline. 
In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered progression. 
• 
SD:  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum on study. 
 
Special notes on the assessment of target lesions 
Lymph nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to < 10 mm on study.  This means that when 
lymph nodes are included as target lesions, the sum of lesions may not be zero even if 
CR criteria are met, since a normal lymph node is defined as having a short axis of 
< 10 mm. 
Target lesions that become too small to measure 
During the study, all lesions (nodal and non-nodal) recorded at baseline should have 
their actual measurements recorded at each subsequent evaluation, even when very 
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small (e.g., 2 mm).  However, sometimes lesions or lymph nodes that are recorded as 
target lesions at baseline become so faint on the CT scan that the radiologist may not 
feel comfortable assigning an exact measure and may report them as being too small to 
measure.  When this occurs, it is important that a value be recorded on the CRF, as 
follows:   
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
If the lesion is believed to be present and is faintly seen but is too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should be 
ticked.  (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such as 
in the retroperitoneum; however, if a lymph node is believed to be present and is faintly 
seen but is too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well and BML should also be ticked). 
To reiterate:  If the radiologist is able to provide an actual measure, this 
measurement should be recorded, even if it is below 5 mm, and, in that case, BML 
should not be ticked. 
Lesions that split or coalesce on treatment 
When non-nodal lesions fragment, the longest diameters of the fragmented portions 
should be added together to calculate the target lesion sum.  Similarly, as lesions 
coalesce, a plane between them may be maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion.  If the lesions have truly coalesced 
such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximum longest diameter for the coalesced lesion. 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  Whereas some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the protocol. 
• 
CR:  Disappearance of all non-target lesions 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• 
Non-CR/Non-PD:  Persistence of one or more non-target lesions 
• 
PD:  Unequivocal progression of existing non-target lesions 
The appearance of one or more new lesions is also considered progression. 
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Response Evaluation Criteria in Solid Tumors (RECIST) 
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Special notes on assessment of progression of non-target disease 
When the patient also has measurable disease 
In this setting, to achieve unequivocal progression on the basis of the non-target 
disease, there must be an overall level of substantial worsening in non-target disease in 
a magnitude that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy.  A modest increase 
in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or PR of target disease will 
therefore be extremely rare. 
When the patient has only non-measurable disease 
This circumstance arises in some Phase III trials when it is not a criterion of study entry 
to have measurable disease.  The same general concepts apply here as noted above; 
however, in this instance, there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden.  Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly 
non-measurable), a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden on the 
basis of the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease, that is, an 
increase in tumor burden representing an additional 73% increase in volume (which is 
equivalent to a 20% increase in diameter in a measurable lesion).  Examples include an 
increase in a pleural effusion from “trace” to “large” or an increase in lymphangitic 
disease from localized to widespread.  Examples may be described in protocols as 
“sufficient to require a change in therapy”.  If unequivocal progression is seen, the 
patient should be considered to have had overall PD at that point.  Though it would be 
ideal to have objective criteria to apply to non-measurable disease, the very nature of 
that disease makes it impossible to do so; therefore, the increase must be substantial. 
New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(e.g., some “new” bone lesions may be simply healing or flare of preexisting lesions).  
This is particularly important when the patient’s baseline lesions show PR or CR (e.g., 
necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, 
which it is not). 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
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If a new lesion is equivocal (e.g., because of its small size) continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan. 
EVALUATION OF RESPONSE 
Timepoint response (overall response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used. 
Table 1 
Timepoint Response: Patients with Target Lesions (with or 
without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
 


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Table 2 
Timepoint Response: Patients with Non-Target Lesions Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised. 
 
Missing assessments and not-evaluable designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned timepoint response.  This would be most likely 
to happen in the case of PD (e.g., if a patient had a baseline sum of 50 mm with three 
measured lesions and during the study only two lesions were assessed, but those gave 
a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution 
of the missing lesion).  
If one or more target lesions were not assessed either because the scan was not done 
or because the scan could not be assessed due to poor image quality or obstructed 
view, the response for target lesions should be “unable to assess” since the patient is 
not evaluable.  Similarly, if one or more non-target lesions are not assessed, 
the response for non-target lesions should be “unable to assess”, except where there is 
clear progression.  Overall response would be “unable to assess” if either the target 
response or the non-target response is “unable to assess”, except where this is clear 
evidence of progression, as this equates with the case being not evaluable at that 
timepoint. 


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Response Evaluation Criteria in Solid Tumors (RECIST) 
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Table 3 
Best Overall Response When Confirmation Is Required 
Overall Response at First 
Timepoint 
Overall Response at 
Subsequent Timepoint 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR a 
CR 
SD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
CR 
PD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
CR 
NE 
SD, provided minimum 
duration for SD was met; 
otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
PR 
NE 
SD, provided minimum 
duration for SD was met; 
otherwise, NE 
NE 
NE 
NE 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even 
disease meeting PR criteria relative to baseline, qualifies as PD at that point (since disease 
must have reappeared after CR).  Best response would depend on whether the minimum 
duration for SD was met.  However, sometimes CR may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR, at the 
first timepoint.  Under these circumstances, the original CR should be changed to PR and the 
best response is PR. 
 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (< 10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
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progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Table 1 to Table 3. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes, or necrosis in existing lesions), treatment may continue until the 
next scheduled assessment.  If at the next scheduled assessment, progression is 
confirmed, the date of progression should be the earlier date when progression was 
suspected. 
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or non-target lesion.


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Appendix 5  
Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework or 
office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about > 50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair > 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair 
5 
Dead 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires 
 
 
 
 
 
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.) 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 
 


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Appendix 7  
Modification of Diet in Renal Disease (MDRD) Formula 
The estimating glomerular filtration rate (eGFR) will be calculated on the basis of the 
following formula: 
eGFR [mL/min/1.73 m2] = 175 × SCRT -1.154 × AGE -0.203 [× 0.742 if 
female] [× 1.212 if African American] (conventional units) 
 
where SCRT =  serum creatinine in conventional units, i.e. mg/dL. The following 
conversion factor should be used in case the serum creatinine value is provided by the 
lab in μmol/L units:  
Serum creatinine [mg/dL] = Serum creatinine [μmol/L] × 0.0113 
 
 
References:  
Miller WG. Estimating glomerular filtration rate. Clin Chem Lab Med 2009;47(9):1017−9. 
Heil W., Koberstein R, Zawta B. Reference Ranges for Adults and Children−Pre-
Analytical Considerations. Roche Diagnostics GmbH 2014, 8th edition, p.159.  


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Appendix 8  
Anaplastic Lymphoma Kinase (ALK) Immunohistochemistry 
Overview 
The VENTANA anti-ALK (D5F3) Rabbit Monoclonal Primary Antibody (VENTANA 
anti-ALK [D5F3]) IHC assay will be used to determine anaplastic lymphoma kinase (ALK) 
IHC status and to select patients with positive ALK for enrollment in Study BO28984.  
The anti-ALK (D5F3) rabbit monoclonal antibody IHC assay is currently being developed 
by Ventana Medical Systems as a companion diagnostic to Roche’s ALK inhibitor, 
alectinib.  For Study BO28984, the VENTANA anti-ALK (D5F3) assay will be used for 
investigational purposes only. 
VENTANA anti-ALK (D5F3) is intended for laboratory use in the detection of the ALK 
protein in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) 
tissue stained with using a VENTANA automated slide stainer.  It is indicated as an aid 
in identifying patients eligible for treatment with alectinib. 
Device Description 
The VENTANA anti-ALK (D5F3) IHC assay is an automated IHC staining assay system 
comprising a pre-diluted, ready to-use anti-ALK (D5F3) rabbit monoclonal primary 
antibody, the BenchMark® automated slide staining platform, OptiView DAB detection kit, 
OptiView Amplification kit, Rabbit Monoclonal Negative Control Ig, and VENTANA 
anti-ALK 2-in-1 cell line control slides or other appropriate system run control. 
Scoring System 
The IHC scoring system evaluates specific VENTANA anti-ALK (D5F3) staining in 
NSCLC tumor cells by the presence of a strong, granular, cytoplasmic staining pattern.  
Pathologists must rely on the Negative Reagent Control (NRC) slides to distinguish 
non-specific staining from specific ALK positivity.  Samples must be assessed for 
morphological damage and the presence of viable tumor versus necrosis.  Light, 
granular, cytoplasmic stippling in alveolar macrophages can occur on anti-ALK (D5F3) 
and/or NRC slides as an artifact of the detection system.  This staining artifact should be 
noted on the Slide Evaluation Form comment field but should NOT be interpreted as 
ALK-positive staining.  Some background staining has also been observed on normal 
mucosa in NSCLC specimens, as well as in necrotic tumor areas; this staining also 
should not be interpreted as ALK-positive staining.  Case slide sets failing to show 
specific staining of the case tissue with VENTANA anti-ALK (D5F3) cannot be 
considered ALK-positive.  Refer to VENTANA ALK Scoring Interpretation Guide for 
non-small cell lung carcinoma (NSCLC) for additional information. 
 


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Appendix 9  
Drug Metabolism Enzymes, Transporters (DMET), and Liver Injury Polymorphisms 
ABCB1 
CHST13 
CYP3A5 
HNMT 
SLC22A3 
UGT1A4 
ADRB3 
HSP90AA1 
STAT6 
ABCB11 
CHST2 
CYP3A7 
MAOA 
SLC22A4 
UGT1A5 
ALG10B 
IGF1 
TNF 
ABCB4 
CHST3 
CYP46A1 
MAOB 
SLC22A5 
UGT1A6 
APOA1 
IGF2 
TNFRSF1B 
ABCB7 
CHST4 
CYP4A11 
MAT1A 
SLC22A6 
UGT1A7 
APOC3 
IL10 
TXNIP 
ABCC1 
CHST5 
CYP4B1 
METTL1 
SLC22A7 
UGT1A8 
ARHGAP24 
IL22 
UBC 
ABCC2 
CHST6 
CYP4F11 
NAT1 
SLC22A8 
UGT1A9 
ATF3 
IL4 
UCP1 
ABCC3 
CHST7 
CYP4F12 
NAT2 
SLC25A27 
UGT2A1 
ATIC 
IL4R 
VDR 
ABCC4 
CHST8 
CYP4F2 
NNMT 
SLC28A1 
UGT2B11 
BIRC2 
IL6 
 
ABCC5 
CHST9 
CYP4F3 
NQO1 
SLC28A2 
UGT2B15 
BIRC3 
IL8 
 
ABCC6 
COMT 
CYP4F8 
NR1I2 
SLC28A3 
UGT2B17 
C3orf38 
INSR 
 
ABCC8 
CROT 
CYP4Z1 
NR1I3 
SLC29A1 
UGT2B28 
CALCA 
IRS1 
 
ABCC9 
CYP11A1 
CYP51A1 
NR3C1 
SLC29A2 
UGT2B4 
CASP9 
IRS2 
 
ABCG1 
CYP11B1 
CYP7A1 
ORM1 
SLC5A6 
UGT2B7 
CD33 
IRS4 
 
ABCG2 
CYP11B2 
CYP7B1 
ORM2 
SLC6A6 
UGT8 
CD36 
ITPA 
 
ABP1 
CYP17A1 
CYP8B1 
PGAP3 
SLC7A5 
VKORC1 
CD44 
JAK1 
 
ADH1A 
CYP19A1 
DCK 
PNMT 
SLC7A7 
XDH 
CDK4 
JUN 
 
ADH1B 
CYP1A1 
DPYD 
PON1 
SLC7A8 
 
CDK6 
KCNIP4 
 
ADH1C 
CYP1A2 
EPHX1 
PON2 
SLCO1A2 
 
CEBPB 
KRT18 
 
ADH4 
CYP1B1 
EPHX2 
PON3 
SLCO1B1 
 
CEP44 
KRT8 
 
ADH5 
CYP20A1 
FAAH 
POR 
SLCO1B3 
 
CES1 
LEP 
 
ADH6 
CYP21A2 
FMO1 
PPARD 
SLCO2B1 
 
CTLA4 
LEPR 
 
ADH7 
CYP24A1 
FMO2 
PPARG 
SLCO3A1 
 
CYP3A 
LMX1A 
 
AHR 
CYP26A1 
FMO3 
PPP1R9A 
SLCO4A1 
 
EGFR 
LPL 
 


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Appendix 9  
Drug Metabolism Enzymes, Transporters (DMET), and Liver Injury Polymorphisms (cont.) 
 
AKAP9 
CYP26C1 
FMO4 
PRSS53 
SLCO5A1 
 
ETNK2 
MCTP2 
 
ALB 
CYP27A1 
FMO5 
PTGIS 
SPG7 
 
FASLG 
MT-CO2 
 
ALDH1A1 
CYP27B1 
FMO6 
QPRT 
SPN 
 
FMOD 
MTHFR 
 
ALDH2 
CYP2A13 
G6PD 
RALBP1 
SULT1A1 
 
FOS 
NFE2L2 
 
ALDH3A1 
CYP2A6 
GSTA1 
RPL13 
SULT1A2 
 
FPGS 
NOS2 
 
ALDH3A2 
CYP2A7 
GSTA2 
RXRA 
SULT1A3 
 
GGH 
NOS3 
 
AOX1 
CYP2B6 
GSTA3 
SERPINA7 
SULT1B1 
 
GPNMB 
OR5H2 
 
APOA2 
CYP2B7P1 
GSTA4 
SLC10A1 
SULT1C2 
 
GPT 
PARD3B 
 
ARNT 
CYP2C18 
GSTA5 
SLC10A2 
SULT1C4 
 
GPX1 
PRKCZ 
 
ARSA 
CYP2C19 
GSTM1 
SLC13A1 
SULT1E1 
 
GPX3 
RASGRP1 
 
ATP7A 
CYP2C8 
GSTM2 
SLC15A1 
SULT2A1 
 
GPX4 
RB1 
 
ATP7B 
CYP2C9 
GSTM3 
SLC15A2 
SULT2B1 
 
GYS1 
RDH5 
 
CA5P 
CYP2D6 
GSTM4 
SLC16A1 
SULT4A1 
 
GYS2 
RIPK1 
 
CBR1 
CYP2E1 
GSTM5 
SLC19A1 
TBXAS1 
 
HCP5 
SOCS3 
 
CBR3 
CYP2F1 
GSTO1 
SLC22A1 
TPMT 
 
HGF 
SOD1 
 
CDA 
CYP2J2 
GSTP1 
SLC22A11 
TPSG1 
 
HLA-A 
SOD2 
 
CES2 
CYP2S1 
GSTT1 
SLC22A12 
TYMS 
 
HLA-B 
SPP1 
 
CHST1 
CYP39A1 
GSTT2 
SLC22A13 
UGT1A1 
 
HLA-DQA1 
SQSTM1 
 
CHST10 
CYP3A4 
GSTZ1 
SLC22A14 
UGT1A10 
 
HLA-DQB1 
ST6GAL1 
 
CHST11 
CYP3A43 
HMGCR 
SLC22A2 
UGT1A3 
 
HLA-DRB1 
STAT1 
 
 


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Appendix 10  Formulae for the Calculation of QTcF and RR  
 
QtcF  − Fridericia’s correction for QTc measurement (if not provided directly by the ECG machine): 
 
 
 
RR Interval Formula (if not provided directly by the ECG machine): 
RR (ms) = 60000/heart rate (bpm) 
 
 
 
 
 
 
 
 
 


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Title
14-May-2015 20:45:15
Date and Time (UTC)
Company Signatory
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 3 
PROTOCOL 
TITLE: 
RANDOMIZED, MULTICENTER, PHASE III, 
OPEN-LABEL STUDY OF ALECTINIB VERSUS 
CRIZOTINIB IN TREATMENT-NAIVE ANAPLASTIC 
LYMPHOMA KINASE-POSITIVE ADVANCED 
NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: BO28984 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2013-004133-33 
IND NUMBER: 
111723 
UTN NUMBER: 
 
TEST PRODUCT: 
Alectinib (RO5424802) 
MEDICAL MONITOR: 
 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  10 February 2014 
DATE AMENDED: 
Version 2:  08 October 2014 
Version 3:  See electronic date stamp below 


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2 
PROTOCOL AMENDMENT, VERSION 3: 
RATIONALE 
Protocol BO28984 has been amended to incorporate the latest pre-clinical and safety 
information.  Changes include those to the specific timing of dose administration, 
pharmacokinetic objectives, concomitant therapy, and exploratory objectives. 
The major changes to the protocol are as follows: 
Both observed clinical PK data and simulations from models support the rationale for 
removal of timing of dose administration with respect to meal timing.  Physiologically 
based PK (PBPK) model simulations were conducted to evaluate the impact of 
variations in dose administration relative to meal timing.  Results from the PBPK 
modeling support the clinical observation that drug levels seen following dosing after 
meal administration are not sensitive to slight variations in dosing times.  Notably, 
simulated steady state concentrations of alectinib following administration at 
approximately 2 hours after a meal compared to those following administration 
immediately after a meal were within 20% of each other.  These PBPK simulations are 
further supported by results from the Japanese BE Study JP28927 showing that steady 
state alectinib plasma concentrations following a 300-mg dose in Japanese patients with 
ALK positive NSCLC were not substantially different when alectinib was administered 
within 30 minutes after a meal compared with administration after fasting 2 hours before 
and 1 hour after alectinib intake.  The results of the simulations along with the clinical PK 
data support administration of alectinib under fed conditions but not specifically linked to 
the timing of meals. 
This study includes PK sample collection to fulfill the PK objective of characterizing 
alectinib and its major active metabolite(s) in the crizotinib naive patient population.  The 
scheduled PK sampling times have been amended to facilitate optional participation in 
the intensive PK sampling.  Specifically, PK samples scheduled at the 10 and 12 hr 
timepoints from the intensive/serial sample timepoint will be removed as these latest 
timepoints are considered a limiting factor for the patients’ participation in the intensive 
PK sampling.  On the basis of available PK data derived from previous studies 
(AF001JP, NP28761 and NP28673), removing the 10 and 12 hr timepoints will still 
enable adequate characterization of the pharmacokinetics of alectinib and its major 
metabolite(s) and will still enable the PK objectives of the study to be met.  Thus, this 
amendment will remove the 10 and 12 hr samples from the intensive PK sampling. 
Recommendations for CYP3A, CYP2C8 and P-gp substrates have been modified to 
reflect updated data, as follows: 
• 
In in-vitro experiments, alectinib and its major active metabolite (M4) showed weak 
time-dependent inhibition of CYP3A and a small CYP3A induction.  On the basis of 
these findings, a clinical drug-drug interaction study (Study NP28763) has been 
recently conducted to evaluate the effect of alectinib on the pharmacokinetics of 
midazolam, a probe CYP3A substrate.  Results from this study demonstrated that 


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alectinib and M4 have no influence on midazolam exposure, with a geometric mean 
ratio (midazolam+alectinib versus midazolam alone) of 0.971 (90% Confidence 
Interval [CI]: 0.717−1.315) for AUCinf and 0.919 (90% CI: 0.648−1.305) for Cmax of 
midazolam.  Similarly, the pharmacokinetics of alpha-hydroxymidazolam and the 
metabolic ratio were not affected by multiple doses of alectinib.  Thus, because this 
substudy demonstrated no effect of alectinib on CYP3A metabolism, CYP3A 
substrates may be allowed as concomitant treatments for patients enrolled in the 
study. 
• 
In in-vitro experiments alectinib, but not M4, showed competitive inhibition of 
CYP2C8 (Ki=1.98 μM).  A physiologically based PBPK model was used to predict 
possible interaction of alectinib with repaglinide, an in vivo probe CYP2C8 substrate.  
Results from the PBPK model indicate that multiple doses of alectinib would have 
no effect on the pharamcokinetics of repaglinide.  Therefore, at clinically relevant 
concentrations, alectinib does not have the potential to increase plasma 
concentrations of co-administered substrates of CYP2C8.  Thus, CYP2C8 
substrates may be allowed as concomitant treatments for patients enrolled in the 
study.  
• 
Based on in vitro data, alectinib is not a substrate of P-gp, but M4 is a P-gp 
substrate.  Because alectinib inhibits P-gp, it is not expected that co-medication with 
P-gp inhibitors will have an effect on M4 exposure.  Thus, P-gp inhibitors may be 
allowed as concomitant treatments for patients enrolled in the study. 
 
Exploratory objectives have been amended to reflect the following: 
• 
Blood sampling for the collection of Circulating Tumor Cells (CTCs) will be 
discontinued.  CTCs are cells shed by the tumor to the blood stream.  Because they 
originate in tumors, they have the potential to be considered as a surrogate for a 
tumor biopsy.  Published studies have shown promising results demonstrating that 
ALK rearrangement can be detected accurately in CTCs.  Therefore, we decided to 
investigate the value of CTCs for use in a diagnostic test of ALK rearrangement.  
However, after preliminary analyses of a subset of patients in ALEX, we failed to 
demonstrate an accurate correlation between the ALK fusion status in tissue and 
the ALK fusion status in CTCs. 
• 
Information from plasma ALK assays will be used to investigate the use of 
circulating tumor nucleic acids from plasma as a surrogate of tumor tissue for 
diagnostic purposes.  Currently, ALK positivity for fusions can only be determined in 
tissue samples using assays such as FISH, IHC or PCR.  As tissue sampling from 
lung cancer patients may be difficult and lung cancer tissue biopsy samples are in 
general very small, testing of several important biomarkers from tumor tissue is 
challenging.  In the last few years, various molecular markers with predictive and 
prognostic significance in lung cancer have evolved and molecular subtyping of lung 
cancer have become important.  Many NSCLC patients may not have enough tumor 
tissue available and can therefore not be tested for all relevant biomarkers, 
especially low prevalence markers such as ALK and others.  A plasma ALK assay 
analyzing circulating tumor nucleic acids will enable more NSCLC patients to be 
tested for ALK fusions. 


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Additional, minor changes have been made to improve clarity and consistency.  This 
amendment represents cumulative changes to the original protocol. 


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PROTOCOL AMENDMENT, VERSION 3: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 2.5: EXPLORATORY OBJECTIVES 
• 
To evaluate and to calculate free testosterone and compare the onset of 
hypogonadism in adult men by measuring total testosterone and free testosterone 
(either by direct measurement or by calculation using, albumin and sex hormone-
binding globulin (SHBG) follicle-stimulating hormone (FSH) and luteinizing hormone 
(LH) levels in blood 
• 
To evaluate and compare efficacy and safety in patients having treatment-naïve 
ALK positive NSCLC as assessed by plasma ALK assays (PCR and/or sequencing)  
• 
To determine the correlation between ALK status as assessed by plasma ALK PCR 
and/or plasma ALK sequencing tests, with ALK status obtained using the Ventana 
ALK IHC and FISH Vysis ALK Break Apart FISH Probe Kit (Abbott) 
• 
To investigate detection of ALK mutations/fusions in plasma and circulating tumor 
cells. 
 
SECTION 3.3.1: 
Rationale for Alectinib Dosage 
With no MTD determined in Study AF-001JP, dose escalation progressed in the United 
States North American Study NP28761/AF-002JG using a modified 3 + 3 design, where 
3 patients were assessed for DLT evaluation whereas additional patients were enrolled 
for PK evaluation. 
Alectinib at 600 mg should be administered orally BID with food (within 30 minutes after 
a meal, in the morning and evening. 
SECTION 3.3.6: 
Rationale for Secondary Endpoint of Time to CNS 
Progression 
Preliminary evidence of CNS benefit with alectinib has been observed in patients in the 
two ongoing Phase I/II studies. 
SECTION 3.3.8: 
Rationale for Biomarker Assessments  
ALK rearrangements can be monitored in circulating tumor cells in blood (Ilie et al. 2012; 
Pailler et al. 2013).  Intact tumor cells are released into the circulation; hence, using 
specific surface markers, it is possible to selectively separate them from the remaining 
cells in the blood.  This allows downstream analysis like IHC or FISH, and in rare 
occasions, there is enough material to perform reverse transcription polymerase chain 
reaction or sequencing to detect mutant mRNA.  The presence of ALK rearrangements 
will be investigated in circulating tumor cells before treatment and at the end of study.  
This information will be used to investigate the use of blood as a surrogate of tumor for 


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diagnostic purposes and to monitor the presence of ALK rearrangements in circulating 
tumor cells in the blood before and after treatment. 
Currently, ALK positivity for fusions can only be determined in tissue samples using 
assays such as FISH, IHC or PCR.  As tissue sampling is difficult and tissue biopsy 
sample sizes from lung cancer patients are very small, testing of several important 
biomarkers is challenging.  Many NSCLC patients may not have enough tumor tissue 
available and therefore cannot be tested for some biomarkers such as ALK.  Plasma ALK 
assays analyzing circulating tumor nucleic acids will enable more NSCLC patients to 
be tested for ALK fusions.  Information from plasma ALK assays will be used to 
investigate the use of circulating tumor nucleic acids from plasma as a surrogate for 
tumor tissue for diagnostic purposes. 
SECTION 3.4.4: 
Patient-Reported Outcome Measures 
For patients who discontinue treatment for reasons other than disease progression and 
who progress within the first 6 months of survival follow-up, PRO measures will be 
administered every 4 weeks until disease progression and then decreased to every 
8 weeks until 6 months post treatment. 
For patients who discontinue treatment for reasons other than disease progression and 
have not yet progressed at 6 months post treatment, PRO measures will be 
administered every 4 weeks until disease progression and will no longer be required 
thereafter.  
SECTION 3.4.5: 
Exploratory Outcome Measures  
• 
Total testosterone to calculate free testosterone and free testosterone levels (either 
by direct measurement or by calculation using albumin and SHBG), FSH, and LH, 
in blood to measure the onset of hypogonadism in adult men 
• 
ALK fusion status in circulating tumor nucleic acids from plasma to evaluate and 
compare efficacy and safety in patients with treatment-naïve NSCLC that is 
ALK-positive by plasma ALK tests (PCR and/or sequencing) for diagnostic 
purposes  
• 
ALK fusion status in circulating tumor cells in blood. 
 
SECTION 4.1.2:  
Exclusion Criteria  
• 
Administration of strong/potent cytochrome P450 (CYP)3A inhibitors or inducers 
within 14 days prior to the first dose of study treatment and while on treatment with 
alectinib or crizotinib (see Appendix 3) except for oral corticosteroids up to 20 mg of 
prednisolone equivalent per day. 
• 
History of hypersensitivity to any of the additives in the alectinib drug formulation 
(lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, 
hydroxypropyl cellulose, sodium lauryl sulfate [SLS], magnesium stearate). (see 
Section 4.3.1.1 for further details) 
• 
History of hypersensitivity to any of the additives in the crizotinib drug formulation. 
(silica, colloidal anhydrous cellulose, microcrystalline calcium hydrogen phosphate, 


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anhydrous sodium starch glycolate, magnesium stearate). (see Section 4.3.1.2 for 
further details)  
 
SECTION 4.2: METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
The independent review of scans for the secondary endpoints of PFS on the basis 
of IRC and time to CNS progression on the basis of IRC will be performed in a 
blinded fashion. 
SECTION 4.3.1: 
Formulation, Packaging, and Handling  
SECTION 4.3.1.1: Alectinib 
Alectinib capsules should be administered orally BID with food (within 30 minutes after a 
meal), in the morning and evening. 
SECTION 4.3.2: 
Dosage, Administration, and Compliance 
SECTION 4.3.2.1: Alectinib  
Alectinib 600 mg (four 150-mg capsules) should be administered orally BID with food 
(within 30 minutes after a meal), in the morning and evening. 
SECTION 4.4.1: 
Permitted Therapy  
• 
Systemic corticosteroid should be no more than oral 20 mg prednisone equivalent 
daily.  Inhalation corticosteroid is allowed.  Steroid equivalence converter could be 
found at: http://www.medcalc.com/steroid.html 
• 
For medications that are inhibitors of P gp transporter, the investigator should use 
caution and monitoring when considering concomitant use of alectinib.  The major 
metabolite of alectinib, M4, has been shown to be a substrate of this transporter.  
Strong inhibitors of P gp should be avoided, if possible (see Appendix 3). 
• 
For medications that are metabolized by CYP3A and CYP2C8, the investigator 
should use caution and monitoring when considering concomitant use of alectinib.  
Alectinib has been shown to have potential for inhibition of CYP3A and CYP2C8, 
including potential time dependent inhibition.  Sensitive CYP3A and CYP2C8 
substrates should be avoided.  If co administration cannot be avoided, it is 
recommended that drug levels and/or signs for toxicity are carefully monitored (see 
Appendix 3). 
 
SECTION 4.4.2: 
Prohibited Therapy  
Thus, the investigator should consult the prescribing information for any concomitant 
medication as well as the Internet references provided below when determining whether 
a certain medication is metabolized by or strongly inhibits or induces CYP3A. 
SECTION 4.5.3: 
Corticosteroid Use for CNS Metastase 
As per Section 4.4.1 of the protocol, systemic corticosteroid use cannot exceed oral 20 
mg of prednisone equivalent daily. 
SECTION 4.5.7: 
Tumor and Response Evaluations 
Response will be assessed by the investigator on the basis of physical examinations.  
Clinical lesions will be documented by color photography (with caliper measurement for 


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measurable lesions), computed tomography (CT) scans, and other modalities (e.g., MRI, 
brain scans), using RECIST v1.1 (see Appendix 4). 
SECTION 4.5.8.1: Laboratory Assessments  
• 
Serum chemistry (sodium, potassium, chloride, bicarbonate, fasting glucose, BUN 
or urea, creatinine [including calculated eGFR using the Modification of Diet in 
Renal Disease formula, see Appendix 7]; CPK; gamma-glutamyl transferase (GGT); 
calcium; total and direct bilirubin; total protein; albumin; ALT; AST; alkaline 
phosphatase [ALP]; phosphorus; magnesium; thyroid-stimulating hormone; and total 
testosterone and free testosterone (either by direct measurement or by calculation 
using, albumin and SHBG) to calculate free testosterone, FSH, and LH [for male 
patients only]) 
• 
Urinalysis.  Urine samples will be collected according to the schedule of 
assessments (Appendix 1) (first morning urine sample for baseline and end of 
treatment visit, spot urine for rest of visits).  Urine protein will be measured by 
dipstick test in order to assess micro  and macroproteinuria. 
 
SECTION 4.5.8.3: Pre- and Fresh Post-Treatment Tumor Biopsies 
(Optional 
The remaining mandatory (Section 4.5.8.2) and optional specimens(Section 4.5.8.3) 
will be destroyed within 5 years after the date of final closure of the clinical database.   
SECTION 4.5.8.4: Blood and Plasma Samples 
Mandatory plasma samples will be obtained to determine: 
• 
Mutation status in ALK and other escape genes (e.g., EGFR, KRAS).  It will require 
20 mL of blood (2 tubes of 10 mL each) to be collected at baseline, at the Visit 3 
(Week 16) treatment, and subsequently at every second treatment visit (every 16 
weeks) (see Appendix 1  for detailed information) until disease progression, and 
during post-progression on treatment in case of isolated, asymptomatic CNS 
progression. 
• 
ALK rearrangement in plasma.  This will require 20 mL of blood (2 tubes of 10 mL 
each) to be collected at baseline. 
 
Mandatory blood (plasma) samples will be obtained to determine: 
• 
ALK mutations assessment in circulating tumor cellsnucleic acids.  It will require 20 
mL of blood sample to be collected (2 tubes of 10 mL each) at baseline for plasma 
preparation and at disease progression (at the last treatment or post progression 
visit).  It should match in time to tumor progression (CNS and/or systemic disease 
progression). 
 
Optional blood samples will be collected to obtain: 
• 
Plasma.  Centrally ALK negative tested patients (by Ventana ALK IHC) who agree 
to donate  10 ml plasma will be assessed by plasma ALK assays (PCR and/or 
Sequencing) for the development of a plasma ALK diagnostic test 
 


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For biomarkers, a maximum of 43 mL of blood will be collected at baseline (20 mL of 
blood for plasma purification and determination of mutation status in ALK and other 
escape genes, 20 mL of blood for plasma purification and detection of ALK 
rearrangements, and 3 mL blood for pharmacogenomics research)for ALK fusion 
detection in circulating tumor cells, and 3 mL for pharmacogenomics research), Twenty 
mL of blood (for plasma purification and determination of mutation status in ALK and 
other escape genes) will be collected at Visit 3 (Week 16) and subsequently at every 
second visit (every 16 weeks), and 3220 mL will be collected at disease progression 
(CNS and/or systemic disease progression) (20 mL for plasma purification, for 
determination of mutation status in ALK and other escape genes and 20 mL for ALK 
fusion detection in circulating tumor cells). 
On the basis of continuous analysis of the data in this study and other studies, or on the 
basis of data from literature, collection of plasma and circulating tumor cell samples with 
exploratory purposes may be stopped at any time if they are deemed not informative. 
SECTION 4.5.8.5: Samples for Pharmacokinetic Assessments 
Serial/intensive samples will be collected in a subset of patients (10%–15% [at least 
approximately n = 20] of patients receiving alectinib) on Visit 0 (baseline, after the first 
dose) and Visit 1 (Week 4) at the timepoints specified in Appendix 2. 
SECTION 4.5.9: 
Electrocardiograms 
The following parameters should be captured on the eCRF: heart rate, RR, PQ, QRS 
and QT duration, and QT interval corrected using Fridericia’s formula (QTcF). In the 
event that the ECG machine does not directly provide results for RR and/or QTcF, 
these parameters can be derived using the formulae provided in Appendix 10. 
SECTION 4.5.10: 
Patient-Reported Outcomes 
Patients will use an ePRO device to capture PRO data and maintain a diary of daily 
drug intake (crizotinib arm) / drug intake with food (alectinib arm).  The ePRO device 
and instructions for completing the PRO questionnaires and diaries electronically will be 
provided by the investigator staff. 
SECTION 4.5.11.3: Sample Collection 
For all samples, date of consent should be recorded on the associated RCR page of the 
eCRF. 
SECTION 5.1.1: 
Adverse Events Collection 
All serious SAEs and non-SAEs will be reported on the standard AE/SAE eCRF. 
SECTION 6: 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Hypothesis tests will be two-sided with a significance level of 5% unless otherwise 
indicated. 


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SECTION 6.8: EXPLORATORY ANALYSES 
Total testosterone to calculate free testosterone, and free testosterone levels (either by 
direct measurement or by calculation using albumin, and sex hormone-binding globulin 
(SHBG) calculator: (http://www.issam.ch/freetesto.htm) and FSH and LH levels in blood 
will be measured (see Appendix 1) in male patients enrolled in the study for exploratory 
analysis of an onset of hypogonadism. 
ALK plasma assays (PCR and /or sequencing) will be used as exploratory assays for 
ALK positive and consented ALK negative patients.  Results from these analyses will be 
used to quantify the degree of correlation between ALK plasma tests and Ventana IHC 
and Vysis FISH for the detection of ALK positive NSCLC.  The ALK plasma assay 
population may be used for exploratory efficacy and safety analysis.  This analysis 
population will be used to support diagnostic development.  Assays from this 
population may be used for the registration of a plasma assay as a companion diagnostic. 
This analysis will be dependent on the successful technical development of a plasma 
ALK assay. 
SECTION 9.5: PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
APPENDIX 1:  Schedule of Assessments 
The Schedule of Assessments has been revised to reflect the changes to the protocol. 
APPENDIX 3:  List of Substrates, Inhibitors, and Inducers of Drug-
Metabolizing Enzymes and Transporters  
Appendix 3 has been revised to reflect the changes to the protocol. 
APPENDIX 4:  Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1: Excerpt from Original Publication 
Appendix 4 has been revised to improve clarity. 
APPENDIX 10:  Formulae for the Calculation of QTCF and RR  
Appendix 10 has been added. 
SAMPLE INFORMED CONSENT FORMS 
The sample Informed Consent Forms have been revised to reflect the changes to the 
protocol. 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 18 
PROTOCOL SYNOPSIS .................................................................................... 19 
1. 
BACKGROUND .......................................................................................... 30 
1.1 
Background on Anaplastic Lymphoma 
Kinase−Positive Non−Small Cell Lung Cancer...................... 30 
1.2 
Background on Alectinib........................................................ 32 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 37 
2. 
OBJECTIVES.............................................................................................. 39 
2.1 
Efficacy Objectives ................................................................ 39 
2.2 
Safety Objectives................................................................... 40 
2.3 
Pharmacokinetic Objectives .................................................. 40 
2.4 
Patient-Reported Outcome Objectives .................................. 40 
2.5 
Exploratory Objectives........................................................... 40 
3. 
STUDY DESIGN ......................................................................................... 41 
3.1 
Description of Study .............................................................. 41 
3.2 
End of Study.......................................................................... 43 
3.3 
Rationale for Study Design.................................................... 43 
3.3.1 
Rationale for Alectinib Dosage .............................................. 43 
3.3.2 
Rationale for Patient Population ............................................ 45 
3.3.3 
Rationale for Control Group................................................... 45 
3.3.4 
Rationale for Open-Label Design .......................................... 46 
3.3.5 
Rationale for Primary Endpoint Selection .............................. 47 
3.3.6 
Rationale for Secondary Endpoint of Time to 
CNS Progression................................................................... 48 
3.3.7 
Rationale for PK Sample Collection Schedule....................... 49 
3.3.8 
Rationale for Biomarker Assessments................................... 49 
3.3.9 
Rationale for PRO Assessments ........................................... 50 
3.4 
Outcome Measures ............................................................... 51 
3.4.1 
Efficacy Outcome Measures.................................................. 51 
3.4.2 
Safety Outcome Measures .................................................... 51 
3.4.3 
Pharmacokinetic Outcome Measures.................................... 52 


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3.4.4 
Patient-Reported Outcome Measures ................................... 52 
3.4.5 
Exploratory Outcome Measures ............................................ 53 
4. 
MATERIALS AND METHODS .................................................................... 53 
4.1 
Patients.................................................................................. 53 
4.1.1 
Inclusion Criteria.................................................................... 53 
4.1.2 
Exclusion Criteria................................................................... 55 
4.2 
Method of Treatment Assignment and Blinding..................... 56 
4.3 
Study Treatment.................................................................... 56 
4.3.1 
Formulation, Packaging, and Handling.................................. 56 
4.3.1.1 
Alectinib................................................................................. 56 
4.3.1.2 
Crizotinib................................................................................ 57 
4.3.2 
Dosage, Administration, and Compliance.............................. 57 
4.3.2.1 
Alectinib................................................................................. 57 
4.3.2.2 
Crizotinib................................................................................ 57 
4.3.3 
Investigational Medicinal Product Accountability ................... 58 
4.3.4 
Post-Trial Access to Alectinib ................................................ 58 
4.4 
Concomitant Therapy ............................................................ 59 
4.4.1 
Permitted Therapy ................................................................. 59 
4.4.2 
Prohibited Therapy ................................................................ 60 
4.4.3 
Prohibited Food ..................................................................... 61 
4.5 
Study Assessments ............................................................... 61 
4.5.1 
Informed Consent Forms and Screening Log........................ 61 
4.5.2 
Medical History and Demographic Data ................................ 62 
4.5.3 
Corticosteroid Use for CNS Metastases ................................ 62 
4.5.4 
Physical Examinations........................................................... 62 
4.5.5 
Vital Signs.............................................................................. 62 
4.5.6 
ECOG Performance Status ................................................... 63 
4.5.7 
Tumor and Response Evaluations......................................... 63 
4.5.8 
Laboratory, Biomarker, and Other Biological 
Sample .................................................................................. 64 
4.5.8.1 
Laboratory Assessments ....................................................... 64 
4.5.8.2 
Pre-Treatment Tumor Samples (Mandatory)......................... 64 


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4.5.8.3 
Pre- and Fresh Post-Treatment Tumor Biopsies 
(Optional)............................................................................... 65 
4.5.8.4 
Blood and Plasma Samples................................................... 66 
4.5.8.5 
Samples for Pharmacokinetic Assessments.......................... 67 
4.5.9 
Electrocardiograms................................................................ 68 
4.5.10 
Patient-Reported Outcomes .................................................. 68 
4.5.11 
Samples for Roche Clinical Repository.................................. 69 
4.5.11.1 
Overview of the Roche Clinical Repository............................ 69 
4.5.11.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 69 
4.5.11.3 
Sample Collection.................................................................. 69 
4.5.11.4 
Confidentiality........................................................................ 70 
4.5.11.5 
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 70 
4.5.11.6 
Withdrawal from the Roche Clinical Repository..................... 71 
4.5.11.7 
Monitoring and Oversight....................................................... 71 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 71 
4.6.1 
Patient Discontinuation.......................................................... 71 
4.6.2 
Study Treatment Discontinuation........................................... 72 
4.6.3 
Study and Site Discontinuation.............................................. 72 
5. 
ASSESSMENT OF SAFETY....................................................................... 73 
5.1 
Safety Plan ............................................................................ 73 
5.1.1 
Adverse Events Collection..................................................... 73 
5.1.2 
Adverse Events Relating to ALK Inhibitors and/or 
the Tyrosine Kinase Inhibitor Class and Alectinib 
Data....................................................................................... 73 
5.1.2.1 
Interstitial Lung Disease ........................................................ 73 
5.1.2.2 
Hepatobiliary Laboratory Test Elevations .............................. 73 
5.1.2.3 
Hematologic Abnormalities.................................................... 74 
5.1.2.4 
Gastrointestinal Disorders ..................................................... 74 
5.1.2.5 
Skin Disorders ....................................................................... 74 
5.1.2.6 
Vision Disorders .................................................................... 75 
5.1.2.7 
Edema ................................................................................... 75 


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5.1.2.8 
Cardiovascular Effects........................................................... 75 
5.1.2.9 
Abnormal Renal Function ...................................................... 76 
5.1.2.10 
Muscular Adverse Events and CPK Elevations ..................... 76 
5.1.3 
Management of Specific Adverse Events with 
Alectinib................................................................................. 77 
5.1.4 
Safety of Crizotinib and Management of Adverse 
Events.................................................................................... 81 
5.2 
Safety Parameters and Definitions ........................................ 84 
5.2.1 
Adverse Events ..................................................................... 84 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 85 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 85 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 86 
5.3.1 
Adverse Event Reporting Period ........................................... 86 
5.3.2 
Eliciting Adverse Event Information ....................................... 86 
5.3.3 
Assessment of Severity of Adverse Events ........................... 86 
5.3.4 
Assessment of Causality of Adverse Events ......................... 87 
5.3.5 
Procedures for Recording Adverse Events............................ 88 
5.3.5.1 
Diagnosis Versus Signs and Symptoms................................ 88 
5.3.5.2 
Adverse Events that are Secondary to Other 
Events.................................................................................... 88 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 88 
5.3.5.4 
Abnormal Laboratory Values ................................................. 89 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 90 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 90 
5.3.5.7 
Deaths ................................................................................... 90 
5.3.5.8 
Preexisting Medical Conditions.............................................. 91 
5.3.5.9 
Lack of Efficacy or Worsening of Non-Small Cell 
Lung Cancer.......................................................................... 91 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 91 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 92 
5.3.5.12 
Patient-Reported Outcome Data ........................................... 92 


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5.3.5.13 
Adverse Events in Individuals Not Enrolled in the 
Study ..................................................................................... 92 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 92 
5.4.1 
Emergency Medical Contacts................................................ 93 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 93 
5.4.2.1 
Events That Occur Prior to Study Drug Initiation ................... 93 
5.4.2.2 
Events That Occur After Study Drug Initiation ....................... 93 
5.4.3 
Reporting Requirements for Pregnancies.............................. 94 
5.4.3.1 
Pregnancies in Female Patients............................................ 94 
5.4.3.2 
Pregnancies in Female Partners of Male Patients................. 94 
5.4.3.3 
Abortions ............................................................................... 95 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 95 
5.5 
Follow-Up of Patients after Adverse Events .......................... 95 
5.5.1 
Investigator Follow-Up........................................................... 95 
5.5.2 
Sponsor Follow-Up ................................................................ 95 
5.6 
Post-study Adverse Events.................................................... 96 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 96 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 96 
6.1 
Determination of Sample Size ............................................... 97 
6.2 
Summaries of Conduct of Study............................................ 98 
6.3 
Summaries of Treatment Group Comparability ..................... 99 
6.4 
Efficacy Analyses .................................................................. 99 
6.4.1 
Primary Efficacy Endpoint...................................................... 99 
6.4.2 
Secondary Efficacy Endpoints............................................. 100 
6.4.2.1 
Sensitivity Analyses............................................................. 102 
6.4.2.2 
Subgroup Analyses ............................................................. 102 
6.5 
Safety Analyses................................................................... 102 
6.6 
Pharmacokinetic Analyses................................................... 103 
6.7 
Patient-Reported Outcome Analyses .................................. 104 


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6.7.1 
Time to Deterioration of Patient-Reported Lung 
Cancer Symptoms............................................................... 104 
6.7.2 
Additional Patient-Reported Outcomes ............................... 105 
6.8 
Exploratory Analyses........................................................... 105 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 106 
7.1 
Data Quality Assurance....................................................... 106 
7.2 
Electronic Case Report Forms............................................. 107 
7.3 
Electronic Patient-Reported Outcome Data......................... 107 
7.4 
Source Data Documentation................................................ 107 
7.5 
Use of Computerized Systems ............................................ 108 
7.6 
Retention of Records........................................................... 108 
8. 
ETHICAL CONSIDERATIONS.................................................................. 108 
8.1 
Compliance with Laws and Regulations .............................. 108 
8.2 
Informed Consent ................................................................ 109 
8.3 
Institutional Review Board or Ethics Committee.................. 110 
8.4 
Confidentiality...................................................................... 110 
8.5 
Financial Disclosure ............................................................ 111 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 111 
9.1 
Study Documentation .......................................................... 111 
9.2 
Protocol deviations .............................................................. 111 
9.3 
Site Inspections ................................................................... 111 
9.4 
Administrative Structure....................................................... 111 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 112 
9.6 
Protocol Amendments ......................................................... 113 
10. REFERENCES ......................................................................................... 114 


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LIST OF TABLES 
Table 1 
Overall Response Rates and Time to Response in Patients 
in Part 2 of Study AF-001JP........................................................ 34 
Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib ...................................................................................... 77 
Table 3 
Crizotinib Dose Modification⎯Hematologic Toxicities 
(Except Lymphopenia) ................................................................ 82 
Table 4 
Crizotinib Dose Modification⎯Non-Hematologic Toxicities......... 83 
Table 5 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in the NCI CTCAE ......................................... 87 
 
 
LIST OF FIGURES 
Figure 1 
Change in Size of Target Lesions as Assessed by the 
Independent Review Committee in Part 2 of Study AF-001JP 
Using RECIST v1.1 (Data Cutoff Date: 18 April 2013)................ 33 
Figure 2 
Duration of Dosing by Cohort in Patients in Part 1 of 
Study NP28761/AF-002JG (Data Cutoff Date: 
12 September 2013) ................................................................... 35 
Figure 3 
Best Percent Change in Size of Target Lesions from 
Baseline as Assessed by the Investigator in Patients in 
Part 1 of Study NP28761/AF-002JG (Data Cutoff Date: 
12 September 2013) ................................................................... 36 
Figure 4 
Summary of Study Design .......................................................... 43 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 119 
Appendix 2 
Schedule of Alectinib Pharmacokinetic Assessments............... 127 
Appendix 3 
List of Substrates, Inhibitors, and Inducers of Drug-
Metabolizing Enzymes and Transporters.................................. 128 
Appendix 4 
Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1: Excerpt from Original Publication.......................... 130 
Appendix 5 
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 141 
Appendix 6 
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires .......... 142 
Appendix 7 
Modification of Diet in Renal Disease (MDRD) Formula ........... 150 
Appendix 8 
Anaplastic Lymphoma Kinase (ALK) Immunohistochemistry.... 151 
Appendix 9 
Drug Metabolism Enzymes, Transporters (DMET), and Liver 
Injury Polymorphisms................................................................ 152 
Appendix 10 Formulae for the Calculation of QTcF and RR.......................... 154 


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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
RANDOMIZED, MULTICENTER, PHASE III, 
OPEN-LABEL STUDY OF ALECTINIB VERSUS 
CRIZOTINIB IN TREATMENT-NAIVE ANAPLASTIC 
LYMPHOMA KINASE-POSITIVE ADVANCED 
NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: BO28984 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2013-004133-33 
IND NUMBER: 
111723 
UTN NUMBER: 
 
TEST PRODUCT: 
Alectinib (RO5424802) 
MEDICAL MONITOR: 
 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return a copy of the form to your local study monitor.  Please retain the original 
for your study files. 


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PROTOCOL SYNOPSIS 
TITLE: 
RANDOMIZED, MULTICENTER, PHASE III, OPEN-LABEL STUDY 
OF ALECTINIB VERSUS CRIZOTINIB IN TREATMENT-NAIVE 
ANAPLASTIC LYMPHOMA KINASE-POSITIVE ADVANCED 
NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: 
BO28984 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2013-004133-33 
IND NUMBER: 
111723 
UTN NUMBER: 
 
TEST PRODUCT: 
Alectinib (RO5424802) 
PHASE: 
Phase III 
INDICATION: 
Anaplastic lymphoma kinase−positive (ALK-positive) non−small cell 
lung cancer (NSCLC) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Efficacy Objectives 
The primary efficacy objective for this study is as follows: 
• 
To evaluate and compare the efficacy of alectinib compared to crizotinib in patients with 
treatment-naïve anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung 
cancer (NSCLC), as measured by investigator-assessed progression-free survival (PFS) 
The secondary efficacy objectives for this study are as follows: 
• 
To evaluate and compare the Objective Response Rate (ORR) and Duration of Response 
(DOR) 
• 
To evaluate and compare the time to progression in the CNS on the basis of Independent 
Review Committee (IRC) review of radiographs by Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 and Revised Assessment in Neuro Oncology (RANO) criteria, as 
well as: 
To evaluate CNS objective response rate (C-ORR) in patients with CNS metastases 
who have measurable disease in the CNS at baseline  
To assess CNS duration of response (C-DOR) in patients who have a CNS Objective 
Response  
To assess CNS progression rates (C-PR) at 6, 12, 18, and 24 months on the basis of 
cumulative incidence  
• 
To evaluate and compare the PFS assessment by the IRC 
• 
To evaluate and compare the overall survival (OS) 
 
Safety Objective 
The safety objective for this study is as follows: 
• 
To evaluate the safety and tolerability of alectinib compared to crizotinib 
 


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Pharmacokinetic Objective 
The secondary pharmacokinetic (PK) objective for this study is as follows: 
• 
To characterize the pharmacokinetics of alectinib and metabolite(s) 
 
Patient-Reported Outcome Objectives 
The secondary patient-reported outcome (PRO) objectives for this study are as follows: 
• 
To evaluate and compare time to deterioration (TTD) in patient-reported lung cancer 
symptoms of cough, dyspnea (single item and multi-item subscales), chest pain, 
arm/shoulder pain, and fatigue as measured by the European Organization for the 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire − Core 
(QLQ-C30) and the supplemental lung cancer module (QLQ-LC13) as well as a composite 
of three symptoms (cough, dyspnea, chest pain) 
• 
To evaluate and compare PROs of health-related quality of life (HRQoL), patient functioning, 
and side effects of treatment as measured by the EORTC QLQ-C30 and EORTC 
QLQ-LC13 
 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To evaluate and compare patient's health status as assessed by the EuroQoL 5 Dimension 
(EQ-5D-3L) questionnaire to generate utility scores for use in economic models for 
reimbursement 
• 
To evaluate and compare an onset of hypogonadism in adult men by measuring total 
testosterone and free testosterone (either by direct measurement or by calculation using 
albumin and sex hormone-binding globulin (SHBG)), follicle-stimulating hormone (FSH) and 
luteinizing hormone (LH) levels in blood 
• 
To evaluate and compare efficacy and safety in patients with treatment-naïve ALK-positive 
NSCLC as assessed by the FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott). 
• 
To investigate molecular mechanisms of resistance to ALK inhibitors 
• 
To investigate detection of ALK mutations/fusions in plasma  
 
Study Design 
Description of Study 
This is a randomized, active controlled, multicenter Phase III open-label study in patients with 
treatment-naive ALK-positive advanced NSCLC.  All patients are required to provide 
pretreatment tumor tissue to confirm the presence of ALK rearrangement (using Ventana 
immunohistochemistry [IHC] testing).  Patients will be randomized 1:1 into one of the two 
treatment arms to receive either alectinib or crizotinib. 
This study will comprise approximately 180 centers, in around 30 countries worldwide. 
Central randomization will be performed via an interactive voice or web-based response system 
(IxRS) using the following stratification factors:  Eastern Cooperative Oncology Group 
Performance Status (ECOG PS) (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at 
baseline (yes vs. no).  An IxRS manual containing relevant information will be provided to each 
study site. 
The experimental arm will receive alectinib at 600 mg orally twice daily (BID), taken with food.  
The control arm will receive crizotinib at 250 mg orally BID, taken with or without food.  The first 
dose of the study drug should be administered as soon as possible after randomization, 
preferably within 24 hours, and no later than 48 hours after randomization. 
Patients will be treated until disease progression, unacceptable toxicity, withdrawal of consent, 
or death.  After disease progression (as per RECIST v1.1), patients should discontinue the 
study medication. After disease progression, patients will be treated at the discretion of the 
investigator according to local practice.  Information regarding the nature and the duration of 
subsequent therapies will be collected. 


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In case of isolated asymptomatic CNS progression (e.g., new CNS oligometastases) a local 
therapy can be given (e.g., stereotactic radiotherapy or surgery) followed by continuation of 
either alectinib (in alectinib arm) or crizotinib (in crizotinib arm) until systemic disease 
progression and/or symptomatic CNS progression.  The decision to continue the treatment 
beyond isolated, asymptomatic CNS progression is at the investigator’s discretion for patients 
who can continue to benefit from respective treatment. 
Patients who discontinue treatment prior to disease progression (e.g., due to unacceptable 
toxicity or withdrawal of consent) will continue to be followed until disease progression and for 
OS regardless of whether they subsequently receive non-study anti-cancer therapy.  Data for 
subsequent therapy will be collected for the analysis of OS. 
Number of Patients 
Approximately 286 patients will be randomly assigned in a 1:1 allocation ratio to the two 
treatment arms via a block stratified randomization procedure and over a planned recruitment 
period of 24 months. 
Randomization will guard against systematic selection bias and should ensure the comparability 
of treatment groups.  To assist balance in important prognostic factors, randomization will be 
stratified by ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at baseline 
(yes vs. no). 
Target Population  
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not 
amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive 
as assessed by the Ventana IHC test.  Sufficient tumor tissue to perform ALK IHC and ALK 
FISH is required.  Both tests will be performed at designated central laboratories. 
• 
Age ≥ 18 years old 
• 
Life expectancy of at least 12 weeks 
• 
ECOG PS of 0−2 
• 
Patients with no prior systemic treatment for advanced or recurrent (Stage IIIB not 
amenable for multimodality treatment) or metastatic (Stage IV) NSCLC 
• 
Adequate hematologic function: 
Platelet count ≥ 100 × 109/L 
ANC ≥ 1500 cells/μL 
Hemoglobin ≥ 9.0 g/dL 
• 
Adequate renal function: 
An estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet 
in Renal Disease equation of at least 45 mL/min/1.73 m2 
• 
Patients must have recovered from effects of any major surgery or significant traumatic 
injury at least 28 days before the first dose of study treatment. 
• 
Measurable disease (by RECIST v1.1) prior to the administration of study treatment 
• 
Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed 
incidentally at study baseline).  Asymptomatic CNS lesions might be treated at the 
discretion of the investigator as per local clinical practice.  If patients have neurological 
symptoms or signs due to CNS metastasis, patients need to complete whole brain radiation 
or gamma knife irradiation treatment.  In all cases, radiation treatment must be completed at 
least 14 days before enrollment and patients must be clinically stable. 
• 
For all females of childbearing potential, a negative pregnancy test must be obtained within 
3 days before starting study treatment. 


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• 
For women who are not postmenopausal ( ≥ 12 months of non-therapy-induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus):  agreement to remain abstinent or 
use single or combined contraceptive methods that result in a failure rate of  < 1% per year 
during the treatment period and for at least 3 months after the last dose of study drug.  
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  Examples of 
non-hormonal contraceptive methods with a failure rate of < 1% per year include tubal 
ligation, male sterilization, hormonal implants, established, proper use of combined oral or 
injected hormonal contraceptives, and certain intrauterine devices.  Alternatively, two 
methods (e.g., two barrier methods such as a condom and a cervical cap) may be 
combined to achieve a failure rate < 1% per year.  Barrier methods must always be 
supplemented with the use of a spermicide.  
• 
For men:  agreement to remain abstinent or use a condom plus an additional contraceptive 
method that together result in a failure rate of  < 1% per year during the treatment period 
and for at least 3 months after the last dose of study drug.  Abstinence is only acceptable if 
it is in line with the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.   
• 
Able and willing to provide written informed consent prior to performing any study related 
procedures and to comply with the study protocol, including patients must be willing and 
able to use the electronic patient-reported outcome device. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients with a previous malignancy within the past 3 years are excluded (other than 
curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by 
endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered 
to have no impact in PFS and OS for the current NSCLC). 
• 
Any GI disorder that may affect absorption of oral medications, such as mal-absorption 
syndrome or status post-major bowel resection 
• 
Liver disease characterized by: 
ALT or AST > 3 × ULN (≥ 5 × ULN for patients with concurrent liver metastasis) 
confirmed on two consecutive measurements 
OR 
Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or other 
conditions of decompensated liver disease such as coagulopathy, hepatic 
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices 
OR 
Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis 
• 
National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) 
Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding 
alopecia), which have not shown improvement and are strictly considered to interfere with 
current study medication 
• 
History of organ transplant 
• 
Co-administration of anti-cancer therapies other than those administered in this study 
• 
Patients with baseline QTc > 470 ms or symptomatic bradycardia 
• 
Administration of strong/potent cytochrome P4503A inhibitors or inducers within 14 days 
prior to the first dose of study treatment and while on treatment with alectinib or crizotinib 
• 
Administration of agents with potential QT interval prolonging effects within 14 days prior to 
the first administration of study drug and while on treatment  
• 
History of hypersensitivity to any of the additives in the alectinib drug formulation (see 
Section 4.3.1.1 for details)   


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• 
History of hypersensitivity to any of the additives in the crizotinib drug formulation (see 
Section 4.3.1.2 for details) 
• 
Pregnancy or lactation  
• 
Known HIV positivity or AIDS-related illness 
• 
Any clinically significant concomitant disease or condition that could interfere with, or for 
which the treatment might interfere with, the conduct of the study or the absorption of oral 
medications or that would, in the opinion of the Principal Investigator, pose an unacceptable 
risk to the patient in this study 
• 
Any psychological, familial, sociological, or geographical condition potentially hampering 
compliance with the study protocol requirements and/or follow-up procedures; those 
conditions should be discussed with the patient before trial entry 
 
Length of Study 
The time from first patient screened to end of study, defined below, will be approximately 
43 months. 
End of Study 
This study is event driven, with a recruitment period of approximately 24 months.  The required 
number of events for the final analysis of the primary endpoint is expected approximately 
33 months after the first patient has been enrolled.  Patients are to be treated until disease 
progression, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.  
Follow-up for survival will continue until the survival follow-up analysis or the Sponsor decides to 
end the trial, whichever occurs first.  The study will formally end once the survival follow-up 
analysis is complete. 
A survival follow-up analysis will be performed once approximately 50% of patients 
(i.e., 143 patients) have died, which is estimated to occur approximately 42 months after the first 
patient has been enrolled. 
Outcome Measures 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
• 
PFS, which is defined as the time from randomization to the first documented disease 
progression, as determined by the investigators (primary endpoint) or IRC (secondary 
endpoint) using RECIST v1.1 or death from any cause, whichever occurs first.  Patients 
without an event will be censored at the last tumor assessment either during follow-up or 
during study treatment.  Patients with no post-baseline assessments will be censored at the 
date of randomization. 
• 
ORR, which is defined as the percentage of patients who attain complete response (CR) or 
partial response (PR); response, as determined by the investigators using RECIST v1.1.  
Patients without any assessments will be regarded as non-responders 
• 
Time to CNS progression, which is defined as the time from randomization to the first 
occurrence of disease progression in the CNS as determined by IRC using RECIST 
v1.1 and RANO (separate assessments and analyses), as well as C-ORR in patients with 
CNS metastases who have measurable disease in the CNS at baseline, C-DOR in patients 
who have a CNS Objective Response, and C-PR at 6, 12, 18, and 24 months 
• 
DOR, which is defined as the time from when response (CR or PR) was first documented to 
first documented disease progression or death (whichever occurs first).  This will only be 
calculated for patients who have a best overall response of CR or PR.  Patients who do not 
progress or die after they have had a response are censored at the date of their last tumor 
measurement. 
• 
OS, which is defined as the time from randomization to death from any cause.  Patients 
without an event will be censored at the last date known to be alive.  Patients without any 
follow-up information will be censored at the date of randomization. 
 


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Safety Outcome Measures 
The secondary safety outcome measures for this study are as follows: 
• 
Serious and non-serious adverse events 
• 
Safety laboratory tests values 
• 
Vital signs (blood pressure, heart rate), ECG 
• 
Results from Physical examination 
 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Sparse (pre-dose) PK samples for measurement of alectinib and its major metabolite(s) will 
be collected in all study patients receiving alectinib treatment 
• 
Serial/intensive PK sampling will be collected in a subset of consenting patients enrolled to 
receive alectinib treatment (approximately 10%−15%, at least approximately n = 20) 
• 
PK parameters will be determined as appropriate and where data allow: 
The pharmacokinetics of alectinib (and metabolite[s], if appropriate) will be described, 
and the between-patient variability will be estimated using a population PK approach.  
The potential influence of covariates that contribute significantly to the between-patient 
differences in PK parameters of alectinib will also be explored and quantified. 
Non-compartmental analysis may be conducted in patients undergoing serial/intensive 
PK sample collection, as appropriate and where data allow. 
 
Patient-Reported Outcome Measures 
The PRO measures for this study are as follows: 
• 
EORTC QLQ-C30 and the EORTC QLQ-LC13 to determine the impact of alectinib 
compared with crizotinib as measured by TTD in patient-reported lung cancer symptoms 
(e.g., cough, dyspnea [single item and multi-item scales], pain in chest, pain in 
arm/shoulder, fatigue) 
• 
The EORTC QLQ-C30 and EORTC QLQ-LC13 to measure PROs of HRQoL, patient 
functioning, and side effects of therapy compared between patients treated with alectinib 
and those treated with crizotinib 
 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
EQ-5D-3L to generate utility scores for use in economic models for reimbursement 
• 
Total testosterone and free testosterone levels (either by direct measurement or by 
calculation using albumin and SHBG), FSH, and LH, in blood to measure an onset of 
hypogonadism in adult men 
• 
The FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) to evaluate and compare 
efficacy and safety in patients with treatment-naïve NSCLC that is ALK-positive by FISH 
test 
• 
Post progression tumor mutation status to study molecular mechanisms of resistance to 
ALK inhibitors 
• 
ALK mutation status in plasma DNA to monitor efficacy and disease progression 
• 
ALK fusion status in plasma 
 
Investigational Medicinal Products 
Test Product 
Alectinib comes in a capsule dosage form containing the following active ingredient: 
[Chemical name] 9-Ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-6, 
11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride 


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Each capsule contains 150 mg of alectinib (as free base) along with lactose monohydrate, 
carmellose calcium, hydroxypropyl cellulose, SLS, and magnesium stearate. 
Alectinib capsules should be stored in accordance with the storage instructions on the label. 
Alectinib capsules should be administered orally BID with food in the morning and evening. 
Comparator 
Crizotinib comes in a hard capsule dosage form.  Each capsule contains 250 mg or 200 mg 
crizotinib.  Crizotinib hard capsules should be stored in accordance with the storage instructions 
on the label.  Crizotinib capsules should be administered orally BID. 
For further details, see the local prescribing information for crizotinib (Xalkori®). 
Non-Investigational Medicinal Products 
Standard-of-care therapy administered to all patients in addition to test product or comparator. 
Statistical Methods 
Primary Analysis 
PFS is defined as the time from date of randomization to the date of first documented disease 
progression or death, whichever occurs first.  The primary endpoint of PFS will be determined 
on the basis of investigator assessment of progression using RECIST v1.1.  Patients who have 
not experienced disease progression or death at the time of analysis will be censored at the last 
tumor assessment date either during study treatment or during follow-up.  Patients with no post-
baseline tumor assessment will be censored at the date of randomization. 
Patients who discontinue treatment prior to disease progression (e.g., due to toxicity) will 
continue on study and will be followed until disease progression and for OS regardless of 
whether they subsequently receive anti-cancer therapy. 
The treatment comparison of PFS will be based on a stratified log-rank test at the 5% level of 
significance (two-sided).  The stratification factors are the randomization stratification factors:  
ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at baseline (yes vs. no), 
as recorded on the eCRF.  Results from an unstratified log-rank test will also be presented. 
The Kaplan-Meier method will be used to estimate the median PFS for each treatment arm with 
95% confidence limits, and a Kaplan-Meier curve will be constructed to provide a visual 
description of the difference between the treatment arms.  A stratified Cox proportional 
regression model will be used including treatment in order to provide an estimate of the 
treatment effect expressed as a hazard ratio (HR) (alectinib vs. crizotinib), as well as a 95% CI. 
The difference between the two treatment groups will be assessed and tested for the following 
hypothesis:  the survival distribution function (SDF) of PFS of the alectinib treatment group is 
the same as for the crizotinib treatment group versus the alternative that the two distributions 
are different:  
H0:  SDF (alectinib) = SDF (crizotinib) 
versus 
H1:  SDF (alectinib) ≠ SDF (crizotinib) 
where SDF denotes the survival distribution function of the parameter PFS. 
Determination of Sample Size   
The focus of this clinical trial is hypothesis testing, and the primary endpoint of PFS was used to 
determine the sample size of the study. 
At the time of initially writing the protocol, there were no Phase III data available on crizotinib in 
the first line setting in ALK-positive patients.  The median PFS for crizotinib administered as 
second line therapy from the global randomized Phase III PROFILE 1007 study was 7.7 months 
(95% CI: 6.0%, 8.8%).  From the Phase II single arm study of patients who had received ≥ 1 line 
of chemotherapy (with 85% patients having received ≥ 2 prior chemotherapy regimens), the 
median PFS was 8.5 months (95% CI: 6.2%, 9.9%).  The Phase III PROFILE 1014 study of 
crizotinib versus standard pemetrexed−platinum-based chemotherapy in previously untreated 
patients with ALK-positive non-squamous NSCLC reported a median PFS of 10.9 months for 
crizotinib (Mok et al. 2014). 
Thus, an initial assumption of median PFS of 9.8 months for the crizotinib arm has been 
reassessed based on data from the Phase III study PROFILE 1014 to 10.9 months.  A HR of 


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0.65 for alectinib versus crizotinib (i.e., an increase from 10.9 months median PFS to 16.8 
months) will be targeted.  In this study, 286 patients will be enrolled in a 1:1 randomization 
allocation.  Enrollment will take approximately 24 months on the basis of an assumption of non-
linear recruitment as follows: 
• 
Month 1:  1 patient per month 
• 
Month 2:  2 patients per month 
• 
Month 3:  4 patients per month 
• 
Month 4:  6 patients per month 
• 
Month 5:  8 patients per month 
• 
Month 6:  10 patients per month 
• 
Month 7:  12 patients per month 
• 
Months 8−12:  13 patients per month 
• 
Months 13−14:  14 patients per month 
• 
Month 15 onwards:  15 patients per month 
 
A total of 170 PFS events are required to achieve 80% power at a two-sided alpha level of 5%.  
This number of PFS events is estimated to occur approximately 33 months after the first patient 
has been enrolled. 
Interim Analyses 
No interim analysis for efficacy or futility is planned. 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
AUC 
area under the concentration−time curve 
BID 
twice daily 
Cmax 
maximum concentration 
C-DOR 
CNS duration of response 
C-ORR 
CNS objective response rate 
C-PR 
CNS progression rate 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DOT 
duration of treatment 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EGFR 
epidermal growth factor receptor 
EML4 
echinoderm microtubule-associated protein-like 4 
EORTC  
European Organization for the Research and Treatment of Cancer  
ePRO 
electronic patient-reported outcome 
EQ-5D-3L 
EuroQoL 5 Dimension 
FDA 
U.S. Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FPP 
FISH Positive Population 
FSH 
follicle-stimulating hormone 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
HRQoL 
health-related quality of life 


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Abbreviation 
Definition 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITT 
intent-to-treat 
IxRS 
interactive voice or web-based response system 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
LH 
luteinizing hormone 
MET 
mesenchymal-epithelial transition factor 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCA 
non-compartmental analysis 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
not evaluable 
NSCLC 
non−small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
P-gp 
P-glycoprotein 
PBPK 
physiologically based pharmacokinetic 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PRO 
patient-reported outcome 
QLQ-C30 
Quality of Life Questionnaire−Core 
QLQ-LC13 
Quality of Life Questionnaire lung cancer module 
QTcF 
QT interval corrected according using Fridericia’s formula 
RANO 
Revised Assessment in Neuro Oncology 
RCR 
Roche Clinical Repository 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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Abbreviation 
Definition 
ROS1 
c-ros oncogene 1 
SAE 
serious adverse event 
SAP 
Safety Analysis Population 
SD 
stable disease 
SDF 
survival distribution function 
SLS 
sodium lauryl sulfate 
TKI 
tyrosine kinase inhibitor 
TTD 
time to deterioration 
UGT 
uridine 5'-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 


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1. 
BACKGROUND 
1.1 
BACKGROUND ON ANAPLASTIC LYMPHOMA 
KINASE−POSITIVE NON−SMALL CELL LUNG CANCER 
Non−small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality 
worldwide.  Lung cancer was estimated to cause 160,340 deaths in the United States 
in 2012, accounting for 28% of all cancer-related deaths according to the report from the 
American Lung Association (Lung Cancer Fact Sheet).  There is an annual incidence of 
310,000 cases of NSCLC in men in the Europe with a mortality of 276,000 deaths 
(GLOBOCAN 2008).  Among women in the Europe, there is an annual incidence of 
107,000 cases and a mortality of 91,000 deaths.  In total, there are 417,000 cases of 
NSCLC and 367,000 deaths in Europe each year, which represents a major health 
problem.  Survival rates for lung cancer tend to be much lower than other common 
cancers because of its late diagnosis and limited effective therapy in the advanced stage.  
The expected 5-year survival rate for all patients in whom lung cancer is diagnosed is 
16.3% compared with 65.2% for colon cancer, 90.0% for breast cancer, and 99.9% for 
prostate cancer (Siegel et al. 2012).  Conventional anti-cancer therapies are far from 
satisfactory, and there is an unmet medical need for the development of new therapies 
for NSCLC. 
Recent progress in the identification of genetic mutations or chromosomal 
rearrangements in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral 
oncogene homolog (KRAS), mesenchymal-epithelial transition factor (MET), and other 
genes has provided new opportunities to use targeted therapeutic agents for the 
treatment of NSCLC, when the tumor is identified as having these mutations 
(Katayama et al. 2011; Doebele et al. 2012). 
Approximately 5% of NSCLC cases have been shown to harbor the echinoderm 
microtubule-associated protein-like 4 (EML4)−anaplastic lymphoma kinase (ALK) fusion 
gene as a result of a chromosomal inversion at 2p21 and 2p23 (Choi et al. 2010; 
Ou et al. 2012).  The formation of the resulting ALK fusion protein results in activation 
and dysregulation of the gene’s expression and signaling, which can contribute to 
increased cell proliferation and survival in tumors expressing these genes.  This is 
further supported by reports that the TFG and KIF5B genes can also serve as ALK 
fusion partners in some NSCLC patients.  Expression of these ALK fusion genes in 
mouse 3T3 fibroblasts causes their transformation and enhanced proliferation.  ALK 
gene alterations are generally in a mutually exclusive relationship with mutations in 
EGFR or KRAS (Soda et al. 2007; Inamura et al. 2008; Inamura et al. 2009; 
Wong et al. 2009), although EGFR mutations may develop as a resistance mechanism 
after treatment with crizotinib (Doebele et al. 2012).  Inhibition of ALK activity in Ba/F3 
cells transfected with the EML4-ALK fusion protein resulted in inhibition of cell growth 
(Ou et al. 2012), whereas a small molecule inhibitor of ALK demonstrated anti-tumor 
efficacy in two xenograft models in athymic mice, namely, the H3122 NSCLC and 
Karpas299 anaplastic large cell lymphoma models harboring the EML4-ALK and 


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nucleophosmin-ALK fusion proteins, respectively.  Hence, ALK appears to be a suitable 
therapeutic target for NSCLC with ALK gene rearrangements. 
Wild-type ALK is expressed at very low levels in most normal human tissues, but is 
expressed at higher levels in a few limited types of tissue such as developing and 
mature nervous system tissue (glial cells, neurons, endothelial cells, and pericytes) 
(Pulford et al. 1997).  By contrast, an aberrant ALK with constitutively active kinase 
results from the formation of the EML4-ALK fusion gene by chromosomal translocation. 
Currently, the only approved medicine for treatment-naïve ALK-positive NSCLC is 
crizotinib (Xalkori®, Pfizer, Inc.), an inhibitor of receptor tyrosine kinases including ALK, 
hepatocyte growth factor receptor (HGFR, c-Met), recepteur d’origine nantais (RON), 
and c-ros oncogene 1 (ROS1) (Sahu et al. 2013).  
Crizotinib was first granted accelerated approval by the U.S. Food and Drug 
Administration (FDA) for the treatment of patients with locally advanced or metastatic 
NSCLC that is positive for ALK as detected by an FDA-approved test in August 2011. 
The approval was based on two single-arm trials.  The primary endpoint of both trials 
was ORR as assessed by the investigator.  In one study, the ORR was 50% 
(95% CI: 42%, 59%) with a median response duration of 42 weeks, and, in the other 
study, the ORR was 61% (95% CI: 52%, 70%) with a median response duration of 48 
weeks (Camidge et al. 2012; Kim et al. 2012).  In November 2013, the FDA granted 
regular approval for crizotinib on the basis of demonstrating superior PFS and ORR for 
crizotinib compared with chemotherapy in patients with ALK-positive NSCLC whose 
disease progressed after platinum-based doublet chemotherapy (PROFILE 1007 study).  
An open-label active-controlled multinational randomized trial enrolled 347 patients with 
ALK-positive metastatic NSCLC.  Patients were required to have disease progression 
following platinum-based chemotherapy.  The trial demonstrated significantly prolonged 
PFS with crizotinib treatment compared with chemotherapy (HR = 0.49 [95% CI: 0.37, 
0.64], p < 0.0001).  Median PFS was 7.7 months for patients treated with crizotinib and 
3.0 months for patients treated with chemotherapy.  The ORR was significantly higher 
for patients treated with crizotinib (65% vs. 20%), with median response durations of 
7.4 months for patients treated with crizotinib and 5.6 months for patients treated with 
chemotherapy.  No difference in overall survival (OS) was noted between the two groups 
(HR = 1.02 [95% CI: 0.68%, 1.54%]) in a planned interim analysis (Shaw et al. 2013).  
Common adverse reactions in clinical trials with crizotinib, occurring at an incidence of 
25% or higher, included visual disorders, nausea, diarrhea, vomiting, constipation, 
edema, elevated transaminases, and fatigue (National Cancer Institute 2013).  These 
results showed that an ALK inhibitor is effective in patients with NSCLC harboring ALK 
fusion genes.  Crizotinib has subsequently been approved in other countries, such as 
Japan, Korea, Canada, and Switzerland.  In the European Union, crizotinib was 
conditionally approved in October 2012 for the treatment of adults with previously treated 
ALK positive NSCLC. 


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Although substantial benefit has been observed with crizotinib therapy, relapse remains 
the norm.  Studies with patients who had progression with crizotinib treatment revealed 
two main reasons for treatment failure: the development of resistance because of 
secondary (e.g., gatekeeper) mutations (predominantly in ALK or occasionally in other 
genes, such as EGFR, cKIT, or KRAS) (Katayama et al. 2011; Doebele et al. 2012; 
Kim et al. 2013) and CNS relapse (crizotinib has impaired control of brain metastases in 
comparison to other sites of systemic disease).  The CNS is the primary site of initial 
treatment failure in 46% of patients with ALK-positive NSCLC treated with crizotinib 
(Costa et al. 2011; Chun et al. 2012; Weickhardt et al. 2012).  Significant morbidity is 
associated with brain metastases as a function of brain involvement, and because of 
treatment (corticosteroids, surgery, and radiation) required for disease control. 
A new generation of ALK inhibitors will have the potential to overcome these two major 
limitations of crizotinib treatment and may offer patients a better chance of prolonged 
remission and minimize the development of CNS metastases and the attendant 
comorbidity. 
1.2 
BACKGROUND ON ALECTINIB 
Alectinib (also RO5424802 or CH5424802) is a newly developed small molecule, highly 
selective, and potent oral next-generation ALK inhibitor with a benzo[b]carbazole 
scaffold.  In enzyme inhibition assays performed in vitro, this compound has been shown 
to selectively inhibit ALK.  The compound also shows high antitumor activity both in vitro 
and in vivo against tumor cell lines with some types of ALK gene alteration, including 
NSCLC and anaplastic large cell lymphoma lines harboring an ALK translocation and a 
neuroblastoma line harboring amplified ALK gene. 
Nonclinical pharmacology studies showed that alectinib is efficacious in a model of 
tumors expressing an ALK fusion bearing the L1196M mutation, which is associated with 
resistance to crizotinib, and alectinib is effective in mouse NCI H2228 NSCLC xenografts 
that are already maximally suppressed by crizotinib.  Alectinib also prolongs survival in 
an intracerebral NCI H2228 implantation model, and it reduces tumor growth in an 
intracranial model monitored using bioluminescence. 
The clinical development program for alectinib, to date, comprises three ongoing 
Phase I/II studies in patients with ALK-positive NSCLC.  The ongoing Phase I/II studies 
are as follows:  Study AF-001JP, which is being conducted in Japan; Study 
NP28761/AF-002JG, which is being conducted in US and Canada; and Study NP28673, 
which is being conducted globally. 
The first-in-human study AF-001JP is an open-label Phase I/II study being conducted in 
Japan.  This study is assessing the pharmacokinetics, safety, and efficacy of alectinib in 
patients with ALK-positive NSCLC who are crizotinib-naïve and have disease 
progression after at least one line of chemotherapy.  This study has completed 
enrollment, but it is still ongoing.  A total of 70 patients were included (24 patients in the 


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Phase I portion and 46 patients in the Phase II portion of the study).  In the Phase I 
portion of the study, at the data cutoff date of 31 July 2012, 24 patients were treated at 
doses of 20−300 mg twice daily (BID).  No dose-limiting toxicities (DLTs) or adverse 
events of Grade 4 were noted up to the highest dose; thus, 300 mg BID was evaluated 
in the Phase II portion of the study without further escalating the dose.  In the Phase II 
portion of the study, 46 patients were treated with the highest evaluated dose of 300 mg 
BID, of whom 43 achieved an objective response (93.5%; 95% CI: 82.1%, 98.6%) and 
7 patients had a complete response (CR) on the basis of an independent radiological 
review in the 12-month follow-up analysis (data cutoff for response data: 18 April 2013).  
The median duration of treatment (DOT) in the study has not been achieved at that date 
because 86% of patients were still on treatment in the study, but the projected median 
DOT is more than 14 months as data mature. 
Figure 1 shows the waterfall plot of the best change from baseline in the size of target 
lesions by an independent radiological review.  Table 1 shows the objective response 
rate (ORR) by time interval.  The majority (86%) of patients had a time to response of 
within 6 weeks after administration of the first dose. 
Figure 1 Change in Size of Target Lesions as Assessed by the 
Independent Review Committee in Part 2 of Study AF-001JP 
Using RECIST v1.1 (Data Cutoff Date: 18 April 2013) 
 


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Two of 7 patients who were assessed as having a CR had lymph nodes as the target 
lesions.  Per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), 
the percent change from baseline for patients with CR can be less than 100% when 
lymph nodes are identified as the target lesions.  Therefore, they were assessed as 
having CR, although their tumor change from baseline was less than 100%. 
Table 1 
Overall Response Rates and Time to Response in Patients 
in Part 2 of Study AF-001JP 
Response (Data Cutoff Date: 18 April 2013) 
IRC Assessment (N = 46) 
Complete response 
7 
Partial response 
36 
Stable disease 
1 
Progressive disease 
0 
Not evaluable 
2 
Total response 
43 
Overall response rate (95% CI) 
93.5% (82.1%, 98.6%) 
Time to Response 
IRC Assessment (N = 43) 
0 to ≤ 3 weeks 
22 (51%) 
> 3 to ≤ 6 weeks 
15 (35%) 
> 6 to ≤ 9 weeks 
3 (7%) 
> 9 weeks 
3 (7%) 
IRC = Independent Review Committee. 
 
In Study NP28761/AF-002JG (crizotinib-failed ALK-positive NSCLC patients), the 
Phase I portion has completed enrollment.  Two ‘bridging’ cohorts of patients receiving 
alectinib using the 150-mg capsule at 600 and 900 mg BID were included in 
Study NP28761/AF-002JG to transition/facilitate the planned formulation for the Phase II 
trials.  A total of 47 patients were enrolled in Phase I (Part 1).  There does not appear to 
be any substantial difference in pharmacokinetics between the two formulations 
(20/40-mg capsule and the 150-mg capsule) at the 600-mg dose on the basis of 
available data. 
The radiological imaging analysis performed in 44 evaluable patients who had a baseline 
scan and at least one follow-up scan (data cutoff date: 12 September 2013) has shown 
that 2 of 7 patients in the 300-mg BID dosage cohort, 5 of 7 patients in the 460-mg BID 
dosage cohort, 4 of 10 patients in the 600-mg BID dosage cohort, and 4 of 13 patients 
(including 1 patient with CR) in the 900-mg BID dosage cohort have achieved a 
confirmed partial response (PR), as assessed by the investigator.  Three of 10 patients 
in the 600-mg BID dosage cohort, 2 of 7 patients in the 760-mg BID dosage cohort, and 
4 of 13 patients in the 900-mg BID dosage cohort have achieved a PR, as assessed by 
the investigator, which is still to be confirmed.  Three patients (all in the 600-mg BID 






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both systemic disease and CNS progression).  No patient discontinued because of CNS 
progression alone. 
In addition, 2 patients with leptomeningeal carcinomatosis received benefit from alectinib 
treatment.  One patient with leptomeningeal spread in Study NP28761/AF-002JG 
achieved PR after 6 weeks of treatment.  Another patient with leptomeningeal 
carcinomatosis but without systemic lesions was treated under a single-patient 
Investigational New Drug (IND) application because of ineligibility to enter either of the 
two Phase II alectinib studies (because of the high intake of dexamethasone for 
symptom control).  After 6 weeks of treatment, this patient achieved CR as 
demonstrated by complete disappearance of gadolinium enhancement on magnetic 
resonance imaging (MRI) and disappearance of positive CSF cytology.  This patient has 
been able to reduce corticosteroids to physiological replacement dose only. 
See the Alectinib Investigator's Brochure for additional details on nonclinical and clinical 
studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Over the past 10 years, the treatment of NSCLC has become increasingly focused on 
guiding treatment based on the presence or absence of an actionable mutation.  
Numerous oncogenes have now been identified in NSCLC, including mutations in the 
genes coding for EGFR, KRAS, phosphoinositide-3-kinase (specifically, the catalytic α 
polypeptide), and EGFR 2 (Pao and Girard 2011).  As described in previous sections, a 
translocation in the gene encoding the receptor tyrosine kinase ALK, leading to the 
expression of ALK fusion proteins, was identified as an oncogenic driver in a subset of 
patients with NSCLC (Soda et al. 2007).  ALK rearrangements are found in 
approximately 4.6% of unselected patients with NSCLC (Koivunen et al. 2008; 
Takeuchi et al. 2008; Boland et al. 2009; Wong et al. 2009; Bang 2011; Kim et al. 2011; 
Paik et al. 2011; Cardarella et al. 2012; Dai et al. 2012; Fukui et al. 2012;). 
Crizotinib is the first ALK inhibitor that has been approved and registered in multiple 
countries worldwide for the treatment of ALK-positive NSCLC.  Crizotinib is an oral 
small-molecule multitargeted tyrosine kinase inhibitor (TKI) targeting ALK, MET, RON, 
and ROS1 tyrosine kinases (Sahu et al. 2013, Shaw et al. 2013).  The previous clinical 
studies reported that the median PFS with crizotinib ranged from 7.7−9.7 months 
(Camidge et al. 2012, Kim et al. 2013, Shaw et al. 2013).  The PROFILE 1014 study, a 
Phase III study of crizotinib compared to standard pemetrexed-platinum-based 
chemotherapy, was presented at the ASCO 2014 congress (Mok et al. 2014).  The study 
met its primary objective of prolonging progression-free survival in previously untreated 
patients with ALK-positive non-squamous NSCLC with median PFS of 10.9 and 
7.0 months (HR: 0.454; 95% CI: 0.346, 0.596; p < 0.0001) for crizotinib and 
pemetrexed-platinum-based chemotherapy, respectively. 


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Although substantial benefit has been observed with crizotinib therapy, relapse 
eventually occurs.  Two major reasons for this are the development of resistance 
because of secondary (e.g., gatekeeper) mutations, or CNS relapse 
(Katayama et al. 2011; Doebele et al. 2012; Kim et al. 2013).  This could be due to the 
fact that crizotinib is a P-gp substrate and has a low penetration in the CNS.  Thus, 
ALK-positive NSCLC treated with crizotinib has impaired control of brain metastases 
relative to other sites of systemic disease, with 46% of progressions in patients treated 
with crizotinib involving the CNS (Costa et al. 2011; Weickhardt et al. 2012).  The CNS 
becomes a sanctuary site for ALK-positive NSCLC treated with crizotinib⎯a physiologic 
and anatomic mechanism of drug resistance. 
Alectinib is a highly selective and potent oral next generation ALK inhibitor.  Clinical data 
collection from the Phase II portion is still ongoing.  Study AF-001JP, assessing alectinib 
in patients with ALK-positive NSCLC who are crizotinib-naïve and have disease 
progression after at least one line of chemotherapy, reported that the median treatment 
duration in the study had not been achieved as 86% of patients were still active on the 
study, but the projected median DOT is estimated to be at least 14 months at the final 
point of data collection (Inoue et al. 2013). 
Moreover, alectinib is a lipophilic drug and is not a P-glycoprotein (P-gp) substrate.  
Thus, it is able to penetrate the blood-brain barrier and has the potential to reach higher 
concentrations in the brain as compared to substrates of P-gp such as crizotinib.  This 
has been shown in the nonclinical setting on the basis of the prolongation of survival in a 
mouse model with implanted CNS lesions and in a tissue distribution study with a single 
oral dose of [14C]-alectinib at 1 mg/kg in albino rats (Ou et al. 2013).  Preliminary clinical 
data from the Phase I/II studies show consistent therapeutic efficacy of alectinib in brain 
metastases. 
The clinical efficacy data is compelling given the demonstrated activity for a longer 
progression-free interval with alectinib treatment and improved activity in the CNS.  This 
progression-free interval delays the impact of CNS metastases on neurologic function 
along with the morbidities associated with treatment like brain radiation, surgery and 
corticosteroid use required for disease control.  The currently available clinical safety 
data is supportive of an acceptable safety and tolerability profile with alectinib.  
Altogether, it would be important to compare alectinib to crizotinib as a therapeutic 
option for treatment-naïve ALK-positive advanced NSCLC patients. 
Alectinib was granted approval in Japan on 04 July 2014 for treatment of ALK fusion 
gene-positive, unresectable, recurrent or advanced NSCLC. 
In this proposed Phase III study, treatment-naïve patients with ALK-positive advanced 
NSCLC will be enrolled and will be randomized to receive either crizotinib or alectinib 
treatment.  The results of this study will determine whether alectinib treatment has 
superior efficacy compared to crizotinib. 


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The first Phase I dose-escalation study of alectinib (Study AF001-JP, conducted only in 
Japan) with a dose schedule of 20, 40, 80, 160, 240, and 300 mg BID orally, showed 
that alectinib was generally well tolerated without major toxicities.  Of the 58 patients 
who received treatment with 300 mg BID alectinib in Study AF-001JP, 27 experienced 
Grade 3 adverse events and 9 experienced serious adverse events.  No deaths were 
reported during this study and up to 28 days after treatment discontinuation.  There were 
5 adverse events leading to treatment discontinuation in Part 2 (brain edema, sclerosing 
cholangitis, interstitial lung disease [ILD], ALT increased, and tumor hemorrhage).  
Alectinib was well tolerated at all doses investigated in this study.  Its adverse event 
profile was consistent with the one known to be associated with TKIs.  In the Phase II 
Study NP28761/AF-002JG, alectinib was well tolerated with no DLTs or 
treatment-related dose modifications up to 600 mg BID.  Two DLTs were reported at 
900 mg BID.  The recommended alectinib Phase II dosage of 600 mg BID was chosen 
as having the best balance between clinical safety, efficacy, and pharmacokinetic (PK) 
data as observed in the Phase I/II studies (see Section 3.3.1). 
On the basis of available preliminary data, the estimated benefits of alectinib treatment 
outweigh the risks.  Specifically: 
• 
Available nonclinical and clinical data demonstrate that alectinib is active in NSCLC 
in crizotinib-naïve patients as well as after progression on prior crizotinib therapy. 
• 
Clinical safety data in humans up to 900 mg BID demonstrate that its safety profile 
is consistent to the one known to be associated with TKIs. 
 
Identified and potential risks associated with alectinib treatment will continue to be 
closely monitored throughout the clinical program.  Patient safety during the alectinib 
program is ensured by targeting the most appropriate patient population, stringent safety 
monitoring by the Sponsor and Independent Data Monitoring Committee (IDMC), and by 
protocol-specified study drug interruption criteria. 
2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The primary efficacy objective for this study is: 
• 
To evaluate and compare the efficacy of alectinib compared to crizotinib in patients 
with treatment-naïve ALK-positive advanced NSCLC, as measured by 
investigator-assessed PFS 
 
The secondary efficacy objectives for this study are: 
• 
To evaluate and compare the Objective Response Rate (ORR) and Duration of 
Response (DOR) 
• 
To evaluate and compare the time to progression in the CNS on the basis of IRC 
review of radiographs by RECIST v1.1 and Revised Assessment in Neuro Oncology 
(RANO) criteria, as well as: 


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to evaluate CNS objective response rate (C-ORR) in patients with CNS 
metastases who have measurable disease in the CNS at baseline  
to assess CNS duration of response (C-DOR) in patients who have a CNS 
Objective Response  
to assess CNS progression rates (C-PR) at 6, 12, 18, and 24 months on the 
basis of cumulative incidence  
• 
To evaluate and compare the PFS assessment by the IRC 
• 
To evaluate and compare the OS 
 
2.2 
SAFETY OBJECTIVES 
The secondary safety objective for this study is: 
• 
To evaluate the safety and tolerability of alectinib compared to crizotinib 
 
2.3 
PHARMACOKINETIC OBJECTIVES 
The secondary PK objective for this study is: 
• 
To characterize the pharmacokinetics of alectinib and metabolite(s) 
 
2.4 
PATIENT-REPORTED OUTCOME OBJECTIVES 
The secondary patient-reported outcome (PRO) objectives for this study are: 
• 
To evaluate and compare time to deterioration (TTD) in patient-reported lung cancer 
symptoms of cough, dyspnea (single item and multi-item subscales), chest pain, 
arm and shoulder pain, and fatigue as measured by the European Organization for 
the Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire−Core (QLQ-C30) and the supplemental lung cancer module 
(QLQ-LC13) as well as a composite of three symptoms (cough, dyspnea, chest pain) 
• 
To evaluate and compare PROs of (HRQoL), patient functioning, and side effects of 
treatment as measured by the EORTC QLQ-C30 and EORTC QLQ-LC13 
 
2.5 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are: 
• 
To evaluate and compare patient’s health status as assessed by the EuroQoL 5 
Dimension (EQ-5D-3L) questionnaire to generate utility scores for use in economic 
models for reimbursement 
• 
To evaluate and compare the onset of hypogonadism in adult men by measuring 
total testosterone and free testosterone (either by direct measurement or by 
calculation using albumin and sex hormone-binding globulin (SHBG, follicle-
stimulating hormone (FSH) and luteinizing hormone (LH) levels in blood 
• 
To evaluate and compare efficacy and safety in patients with treatment-naive 
ALK-positive NSCLC as assessed by the FISH Vysis® ALK Break Apart FISH Probe 
Kit (Abbott) 


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• 
To evaluate and compare efficacy and safety in patients having treatment-naïve 
ALK positive NSCLC as assessed by plasma ALK assays (PCR and/or sequencing)  
• 
To determine the correlation between ALK status as assessed by plasma ALK PCR 
and/or plasma ALK sequencing tests, with ALK status obtained using the Ventana 
ALK IHC and FISH Vysis ALK Break Apart FISH Probe Kit (Abbott) 
• 
To investigate molecular mechanisms of resistance to ALK inhibitors. 
• 
To investigate detection of ALK mutations/fusions in plasma 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a randomized, active-controlled, multicenter Phase III open-label study in patients 
with treatment-naïve ALK-positive advanced NSCLC.  All patients are required to 
provide pretreatment tumor tissue to confirm the presence of ALK rearrangement (by 
Ventana immunohistochemistry [IHC] test).  Patients will be randomized 1:1 into one of 
the two treatment arms to receive either alectinib or crizotinib. 
This study will comprise approximately 180 centers, in around 30 countries worldwide. 
The primary endpoint of the study is investigator-assessed PFS. 
Central randomization will be performed via an interactive voice or web-based response 
system (IxRS) using the following stratification factors:  Eastern Cooperative Oncology 
Group Performance Status (ECOG PS) (0/1 vs. 2), race (Asian vs. non-Asian), and CNS 
metastases at baseline (yes vs. no).  An IxRS manual containing relevant information 
will be provided to each study site. 
The experimental arm will receive alectinib at 600 mg orally BID, taken with food.  The 
control arm will receive crizotinib at 250 mg orally BID, taken with or without food.  The 
first dose of the study drug should be administered as soon as possible after 
randomization, preferably within 24 hours, and no later than 48 hours after 
randomization. 
Patients will be treated until disease progression, unacceptable toxicity, withdrawal of 
consent, or death.  After disease progression (as per RECIST v1.1), patients should 
discontinue the study medication.  After disease progression, patients will be treated at 
the discretion of the investigator according to local practice.  Information regarding the 
nature and the duration of subsequent therapies will be collected. 
In case of isolated asymptomatic CNS progression (e.g., new CNS oligometastases), 
local therapy can be given (e.g., stereotactic radiotherapy or surgery) followed by 
continuation of either alectinib (in alectinib arm) or crizotinib (in crizotinib arm) until 
systemic disease progression and/or symptomatic CNS progression.  The decision to 
continue the treatment beyond isolated, asymptomatic CNS progression is at the 


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investigator’s discretion for patients who can continue to benefit from their respective 
treatment. 
Patients who discontinue treatment prior to disease progression (e.g., due to 
unacceptable toxicity or withdrawal of consent) will continue to be followed until disease 
progression and for OS regardless of whether they subsequently receive non-study 
anti-cancer therapy.  Data for subsequent therapy will be collected for the analysis of OS. 
Approximately 286 patients (143 per treatment arm) will be enrolled into the study over a 
planned competitive recruitment period of 24 months.  Patients inappropriately 
randomized into the study will not be replaced.  The final analysis evaluating the primary 
endpoint of investigator-assessed PFS will occur when approximately 170 patients have 
progressed or died which is expected to occur approximately 33 months after the first 
patient has been enrolled.  Data collection will continue for each patient until death or 
study closure, whichever occurs first. 
An IDMC will be established to monitor the progress of the study and ensure that the 
safety of patients enrolled in the study is not compromised as outlined in Section 9.4. 
A summary of the study design is shown in Figure 4. 
A schedule of assessments is provided in Appendix 1. 




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The first-in-human study, AF-001JP evaluated escalating doses of alectinib in an 
accelerated titration scheme to rapidly identify the maximum tolerated dose (MTD).  All 
doses, including the highest evaluated dose in the study, 300 mg BID, were well 
tolerated with no DLTs observed at any dose.  The highest tested dose, 300 mg BID, 
was further evaluated in the Phase II portion of the study and demonstrated robust 
efficacy and good safety with an ORR by IRC of 93.5% (43/46 patients; 95% CI: 82.1%, 
98.6%). 
With no MTD determined in Study AF-001JP, dose escalation progressed in the North 
American Study NP28761/AF-002JG using a modified 3 + 3 design, where 3 patients 
were assessed for DLT evaluation whereas additional patients were enrolled for PK 
evaluation.  The starting dose in Study NP28761/AF-002JG was the highest dosage 
evaluated in Study AF-001JP, 300 mg BID.  Following multiple dosages of alectinib at 
300 mg BID in Study NP28761/AF-002JG, median alectinib exposure (area under the 
concentration time curve [AUC] from 0 to 10 hours) appeared to be approximately 
two-fold lower compared with that in patients from Study AF-001JP, which demonstrated 
robust efficacy and safety.  Dose escalation progressed with evaluation of higher doses 
of alectinib up to 900 mg BID. 
In Study NP28761/AF-002JG, no DLTs were observed in the dose escalation cohorts up 
to dose-level of 900 mg BID.  However, 2 patients in the subsequent 900 mg BID 
bridging cohort experienced a DLT; 1 patient had Grade 3 headache and 1 patient had 
Grade 3 neutropenia, and both patients continued study treatment at a reduced dosage 
of 600 mg BID.  Overall, alectinib was well tolerated in the study population.   
Importantly, administration of 600 mg BID provides systemic exposures that meet or 
exceed exposures achieved in patients receiving 300 mg BID in Study AF-001JP, 
demonstrating its robust efficacy and safety in crizotinib-naïve patients.  Furthermore, in 
Study NP28761/AF-002JG, the 600 mg BID regimen has demonstrated promising 
activity in crizotinib-resistant patients, including activity in patients with CNS metastases 
while being tolerated by patients.  On the basis of available preclinical data, 
administration of alectinib 600 mg BID provides systemic exposures within the expected 
range (on the basis of regression of available data) for tumor regression observed in 
mouse xenograft models. 
Thus, on the basis of nonclinical and clinical data, a dosing regimen of 600 mg BID of 
alectinib has been chosen as the optimal therapeutic dose level with the best balance 
between efficacy and safety. 
Alectinib at 600 mg should be administered orally BID with food in the morning and 
evening. 


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3.3.2 
Rationale for Patient Population 
The study population will comprise patients with non-resectable, locally advanced and 
metastatic NSCLC who have been shown to be ALK-positive by the Ventana IHC test 
performed at central laboratories specially designated for the study.  Patients should not 
have received any prior treatment for advanced NSCLC (treatment-naive). 
Both experimental (alectinib) and control (crizotinib) treatments are ALK-targeted 
therapies.  The clinical practice guidelines recommend targeted treatment for patients 
with metastatic, oncogene-driven disease as first-line systemic therapy (i.e., 
EGFR-inhibitors for EGFR-positive NSCLC and ALK-inhibitors for ALK-positive NSCLC) 
(NCCN 2014).  
To be eligible for the study, determination of ALK positivity will be performed centrally 
using the IHC assay (see Appendix 8) that is being developed by Ventana Medical 
Systems as a companion diagnostic to alectinib.  IHC may replace fluorescence in situ 
hybridization (FISH)-based identification of ALK rearrangement as the standard 
companion diagnostic in the future.  IHC is faster, easier to perform in local laboratories, 
and requires less equipment compared with the FISH assay.  In addition, IHC has high 
concordance with FISH and a lower false-negative rate (Kim et al. 2011). 
3.3.3 
Rationale for Control Group 
Targeted therapy (including ALK-targeted therapy) is likely to have a greater anti-tumor 
effect than standard chemotherapy, offering patients a higher response rate and longer 
durability of response with less toxicity compared with any potential chemotherapy 
options (Mok et al. 2009; Rosell et al. 2012; Sequist et al. 2013; Shaw et al. 2013). 
Crizotinib (Xalkori) is an oral small-molecule multi-targeted TKI targeting ALK, MET, 
RON, and ROS1 tyrosine kinases (Sahu et al. 2013, Shaw et al. 2013).  It is the only 
first-generation ALK inhibitor that has been approved in multiple countries worldwide for 
the treatment of ALK-positive NSCLC. 
In the United States, in November 2013, crizotinib was granted a regular approval for the 
ALK-positive NSCLC setting regardless of treatment line (XALKORI® U.S. Package 
Insert), whereas in Europe, crizotinib is currently only approved conditionally for patients 
with previously treated ALK-positive NSCLC (Crizotinib SmPC). 
The NCCN guidelines recommend crizotinib as a first-line therapy for patients with 
advanced ALK-positive NSCLC (NCCN 2014). 
The randomized Phase III PROFILE 1014 study was conducted to assess the efficacy of 
crizotinib versus standard platinum-based chemotherapy (pemetrexed plus cisplatin or 
carboplatin) as first-line treatment for patients with ALK-positive, non-squamous NSCLC.  
The study met its primary objective of prolonging progression-free survival in previously 
untreated patients with ALK-positive non-squamous NSCLC with median PFS of 


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10.9 and 7.0 months (HR: 0.454; 95% CI: 0.346, 0.596; p < 0.0001) for crizotinib and 
pemetrexed platinum-based chemotherapy, respectively (Mok et al. 2014).  The authors 
concluded that these findings support crizotinib as the standard of care for patients with 
previously untreated advanced ALK-positive non-squamous NSCLC (Mok et al. 2014). 
Crizotinib will be dosed as per standard dose recommendations from prescribing 
information; patients in the crizotinib arm will receive crizotinib at 250 mg orally BID with 
or without food until disease progression, unacceptable toxicity, withdrawal of consent, 
or death.  See Section 5.1.4 for criteria for dosing interruption and/or dose reduction for 
treatment with crizotinib.  
3.3.4 
Rationale for Open-Label Design 
An open-label study design is more appropriate for patients enrolled in this particular trial 
for a number of reasons described below, and with the ultimate goal to ensure patient 
compliance as much as possible. 
For a blinded study design, all enrolled patients would be required to take five large 
capsules twice per day.  This high pill count results from the difference in capsule size 
between crizotinib (size 0) and alectinib (size 1).  Each dose would comprise one 
250-mg capsule of crizotinib or matching placebo and four 150-mg capsules of alectinib 
or matching placebo.  In order to blind, crizotinib capsules must be over-encapsulated. 
That further increases the size of a capsule from size 0 to size 00.  Size 00 is usually the 
largest capsule size used orally for humans.  For some patients, size 00 capsules are 
too large to swallow.  This high pill count of large capsules is considered to be a 
significant burden to patients and increases the risk of non-compliance. 
Additionally, a blinded study would increase the complexity of standard dose reductions.  
Dose interruption or dose reduction may be required on the basis of individual safety and 
tolerability.  The standard dose reductions for crizotinib would be 200 mg BID (different 
capsule, size 1), followed by 250 mg QD.  Dose reductions for alectinib would occur in 
150-mg steps.  In a double blind study, these multiple step dose reductions introduce a 
high level of complexity and potential for error. 
In order to avoid a significant burden to patients with high pill count, increased risk of 
non-compliance, and complexity of standard dose reductions, adequate steps have been 
taken to ensure the validity of the data in an open-label study design.  These include 
performing a supportive analysis of efficacy on the basis of determining progression by 
an IRC, performing sensitivity analyses to demonstrate the robustness of the primary 
endpoint, defining progression using established response evaluation criteria 
(RECIST v1.1), performing tumor assessment at the same frequency in both arms and 
adhering to protocol-defined schedules, and finalizing the strategy for the final analysis 
of the primary endpoint before trial start, including developing predefined methods for 
handling missing data and censoring rules.  Efficacy analyses will only be performed at 


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the pre-specified analysis timepoints in the protocol (final analysis once 170 PFS events 
have occurred and survival follow-up analysis at 143 events). 
3.3.5 
Rationale for Primary Endpoint Selection 
The investigator-assessed PFS (which will be supported by IRC-assessed PFS analysis, 
one of the secondary endpoints of the study) is the primary endpoint for this trial. 
PFS, as an endpoint, can reflect tumor growth and can be assessed before the 
determination of a survival benefit, and its determination is not generally confounded by 
subsequent therapies.  Whether an improvement in PFS represents a direct clinical 
benefit or a surrogate for clinical benefit depends on the magnitude of the effect and the 
risk-benefit of the new treatment compared to available therapies (Guidance for 
Industry 2007; European Medicines Agency 2012).  A PFS HR of 0.65 will be targeted, 
which constitutes a clinically meaningful benefit in this patient population as it will delay 
the use of platinum-based chemotherapy and will potentially reduce the frequency of 
CNS relapse and the morbidity associated with treating CNS metastases. 
The assumed median PFS of patients in the alectinib treatment arm is 16.8 months, and 
an OS of more than 30 months is expected, which equates to a post-progression 
survival of at least 13 months.  Patients with ALK-positive NSCLC treated with crizotinib 
in the second-line setting had a median PFS of 7.7 months and an interim median OS of 
20.3 months (Shaw et al. 2013), which equated to a post-progression survival of 
12.6 months.  This lengthy post-progression survival provides an opportunity for 
subsequent treatment with other ALK inhibitors, several additional lines of chemotherapy, 
or participation in additional clinical trials. 
Patients in both study arms who experience disease progression on study treatment will 
likely be treated with other subsequent treatment options, including ALK inhibitors.  
The availability of crizotinib on the market, as well as the likely availability of other 
next-generation ALK TKIs, and the availability of other investigational agents in clinical 
trials offer potential treatment options to patients in the study who will eventually have 
disease progression.  Subsequent therapies frequently confound the detection of an OS 
benefit, particularly in a setting with a long post-progression survival, such as 
ALK-positive NSCLC.  This has been observed in trials for EGFR TKIs, in which strong 
PFS benefits were observed without evidence of OS benefit (Rosell et al. 2009; 
Fukuoka et al. 2011). 
The long post-progression survival and the confounding effects of subsequent lines of 
therapy indicate that it would be difficult to detect an OS benefit in this setting.  
Nevertheless, OS is one of the study’s secondary endpoints.  The crossover from the 
crizotinib arm to alectinib will not be allowed in this study, with the aim of preserving the 
trial’s ability to potentially demonstrate some degree of treatment benefit of alectinib in 
OS.  However, the study will not be powered to demonstrate any statistically significant 
difference in the secondary endpoint of OS. 


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To ensure the validity of the PFS as the primary endpoint, a number of measures have 
been implemented: full IRC assessment to support the analysis of the primary endpoint, 
a substantial target magnitude of benefit (target HR = 0.65) and study assessments that 
will allow a robust evaluation of risk-benefit (standard RECIST criteria to define 
progression with fixed assessment intervals that are identical in both treatment arms and 
a robust definition of PFS and prospectively defined methods to assess, quantify, and 
analyze PFS, including censoring methods and sensitivity analyses). 
3.3.6 
Rationale for Secondary Endpoint of Time to CNS Progression 
Lung cancer is the most common type of cancer to spread to the brain, with at least 40% 
of people with lung cancer developing brain metastases at some point during their 
disease.  ALK-positive NSCLC has a propensity to metastasize to the brain, and 
crizotinib has impaired control of brain metastases in comparison to other sites of 
systemic disease (Chun et al. 2012). 
Delaying or preventing the development of CNS metastases would provide patients with 
clinically meaningful benefit by avoiding consequences of neurological deficits from brain 
metastasis or by delaying/preventing long-term side effects associated with steroid use 
and brain irradiation. 
Preliminary evidence of CNS benefit with alectinib has been observed in patients in the 
two ongoing Phase I/II studies.  See Section 1.2 and Alectinib Investigator's Brochure 
for additional details. 
Time to CNS progression is defined as the time from randomization until radiographic 
evidence of CNS progression is documented.  The aim of the pre-specified analysis will 
be to evaluate whether alectinib significantly delays or prevents the development of CNS 
metastases. 
Randomization of the Phase III study will be stratified by the presence or absence of 
CNS metastasis at baseline. 
Imaging analysis by consistently used uniform image acquisition technique (MRI scans) 
will be performed routinely at baseline and at subsequent follow-up assessments along 
with every systemic imaging tumor assessment or whenever clinically indicated (i.e., 
clinical suspicion of CNS metastasis) in order to achieve an accurate determination of 
time to CNS progression.  This ensures that early brain metastatic lesions are detected 
and that assessment bias between the two arms is avoided by having regularly 
scheduled scans. 
An independent central radiological review will be performed for all patients and the 
analysis of time to CNS progression, or response will be based on the data from the 
independent review.  The review will be based on the standard RECIST v1.1 criteria to 
assess the CNS lesions, and a second independent review on the basis of the RANO 


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criteria, which are typically used to assess brain tumors (Wen et al. 2010), will be 
performed.  The assessment will be performed independently from the overall disease 
progression assessment. 
3.3.7 
Rationale for PK Sample Collection Schedule 
To date, the pharmacokinetics of alectinib have been characterized in 
chemotherapy-failed, crizotinib-naive patients with NSCLC in Study AF-001JP and in 
patients who have failed chemotherapy and crizotinib treatment in 
Study NP28761/AF-002JG and Study NP28673.  In order to better understand the 
pharmacokinetics of alectinib and to further support the development of a robust 
population PK model for alectinib in order to better understand, identify, and characterize 
variables which lead to changes in exposure, characterization of alectinib 
pharmacokinetics will be done in this study.  This study will include PK assessment of 
alectinib in ALK inhibitor treatment-naive patients with ALK-positive advanced NSCLC by 
collecting trough samples from all patients receiving alectinib.  Serial/intensive PK 
samples will be collected from a subset of patients (10%−15% [at least n = 20] of patients 
receiving alectinib) to facilitate the PK assessment.  The data that will be collected from 
this study will enable more robust understanding of alectinib pharmacokinetics in the 
global crizotinib-naive population including investigation and potential identification of 
sources of variability influencing alectinib pharmacokinetics and/or response to alectinib 
therapy.  Results from PK data collection in this study and analyses of PK data could 
help support optimal use of alectinib therapy. 
3.3.8 
Rationale for Biomarker Assessments 
Several molecular mechanisms of resistance to crizotinib have been reported in the 
literature: increased copy number of ALK gene, increased expression of ALK mRNA, 
secondary mutations in ALK (e.g., gatekeeper mutation), and changes (e.g., increased 
copy number, increased phosphorylation, or point mutations) in escape genes such as 
EGFR, cKIT, or KRAS (Katayama et al. 2011; Doebele et al. 2012; Kim et al. 2013).  In 
order to investigate molecular mechanisms of resistance to ALK inhibitors and ALK 
mutation status, tumor samples will be collected before treatment and at the time of 
disease progression with the goal of sequencing nucleic acids.  Two types of 
approaches will be used: 1) targeted sequencing of a panel of genes known to be 
involved in cancer and 2) unbiased genomic sequencing.  
Mutations in cancer genes appearing from drug resistance can be monitored in 
circulating nucleic acids in plasma (Forshew et al. 2012).  Tumor nucleic acids are shed 
into circulation in amounts that allow direct amplification by polymerase chain reaction 
and sequencing.  Plasma samples will be collected before treatment and at certain 
timepoints during treatment, to monitor mutations in ALK and other genes involved in 
resistance to ALK inhibitors.  Information from mutated genes in the tumor will be 
correlated with mutations in plasma DNA. 


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Determination of ALK positivity will be initially performed by Ventana IHC (see 
Appendix 8).  In addition, the Abbott Vysis FISH test will be used as an exploratory 
assay, after patients have been enrolled in this study.  Results from these analyses will 
be used to quantify the degree of correlation between FISH and IHC for the detection of 
ALK-positive NSCLC.  For exploratory purposes, other methods to determine ALK 
positivity (e.g., reverse transcription-polymerase chain reaction) may also be used. 
Currently, ALK positivity for fusions can only be determined in tissue samples using 
assays such as FISH, IHC or PCR.  As tissue sampling is difficult and tissue biopsy 
sample sizes from lung cancer patients are very small, testing of several important 
biomarkers is challenging.  Many NSCLC patients may not have enough tumor tissue 
available and therefore cannot be tested for some biomarkers such as ALK.  Plasma ALK 
assays analyzing circulating tumor nucleic acids will enable more NSCLC patients to 
be tested for ALK fusions.  Information from plasma ALK assays will be used to 
investigate the use of circulating tumor nucleic acids from plasma as a surrogate for 
tumor tissue for diagnostic purposes. 
3.3.9 
 Rationale for PRO Assessments 
In the treatment of lung cancer, it is important to both increase survival and palliate 
symptoms because disease symptoms have negative impacts on HRQoL 
(Hyde and Hyde 1974; Hopwood and Stephens 1995; Sarna et al. 2008).  This is 
especially true for trials that use PFS as a primary endpoint, where it is important to 
translate the delay in disease progression into an endpoint that is meaningful to patients. 
Pain (chest; arm and shoulder), dyspnea, cough, and fatigue have been regarded as the 
most frequent and clinically relevant disease-related symptoms experienced by patients 
with NSCLC.  The BR.21 study (erlotinib vs. chemotherapy in second- or third-line 
NSCLC) demonstrated that longer TTD in the pain, dyspnea, and cough scales of the 
EORTC QLQ-C30 and QLQ-LC13 was consistent with superior PFS, OS, and 
quality-of-life benefits in the erlotinib arm as compared with the placebo arm 
(Aaronson et al. 1993; Bergman et al. 1994; Bezjak et al. 2006).  Additionally, patients in 
the crizotinib PROFILE 1005 trial reported clinically significant improvements (by 
10 points) in the pain, cough, dyspnea, and fatigue symptom scales seen as early as 
2 weeks on treatment (Crinò et al. 2011). 
The EORTC QLQ-C30 and QLQ-LC13 were used in the Phase III PROFILE 1007 study 
(second-line crizotinib vs. chemotherapy).  The study reported significantly greater 
overall reduction from baseline in the symptoms of alopecia, cough, dyspnea, fatigue, 
chest pain, arm or shoulder pain, and pain in other parts of the body with crizotinib than 
with chemotherapy (p < 0.001 for all comparisons, without adjustment for multiple testing).  
Patients treated with crizotinib also had a significantly greater delay in the worsening of 
symptoms.  There was also a significantly greater overall improvement from baseline in 
the global quality of life among patients who received crizotinib treatment than among 
those who received chemotherapy (p < 0.001).  In all domains measuring function, 


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except for the domain measuring cognitive function, there was a significantly greater 
overall improvement from baseline among patients in the crizotinib group than among 
patients in the chemotherapy group (Shaw et al. 2013). 
Therefore, to assess the quality of life of patients in this trial, PRO data will be collected 
from patients enrolled in this study using the validated questionnaires EORTC 
QLQ-C30 and QLQ-LC13. 
3.4 
OUTCOME MEASURES 
3.4.1 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
• 
PFS, which is defined as the time from randomization to the first documented 
disease progression, as determined by the investigators (primary endpoint) or IRC 
(secondary endpoint) using RECIST v1.1 or death from any cause, whichever 
occurs first.  Patients without an event will be censored at the last tumor 
assessment either during follow-up or during study treatment.  Patients with no 
post-baseline assessments will be censored at the date of randomization. 
• 
ORR, which is defined as the percentage of patients who attain CR or PR; response, 
as determined by the investigators using RECIST v1.1.  Patients without any 
assessments will be regarded as non-responders. 
• 
Time to CNS progression, which is defined as the time from randomization to the 
first occurrence of disease progression in the CNS as determined by IRC using 
RECIST v1.1 and RANO (separate assessments and analyses), as well as C-ORR 
in patients with CNS metastases who have measurable disease in the CNS at 
baseline, C-DOR in patients who have a CNS Objective Response, and C-PR at 
6, 12, 18, and 24 months. 
• 
DOR, which is defined as the time from when response (CR or PR) was first 
documented to first documented disease progression or death (whichever occurs 
first).  This will only be calculated for patients who have a best overall response of 
CR or PR.  Patients who do not progress or die after they have had a response are 
censored at the date of their last tumor measurement. 
• 
OS, which is defined as the time from randomization to death from any cause.  
Patients without an event will be censored at the last date known to be alive.  
Patients without any follow-up information will be censored at the date of 
randomization. 
 
3.4.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Serious and non-serious adverse events 
• 
Safety laboratory tests values 
• 
Vital signs (blood pressure, heart rate), ECG 
• 
Physical examination 


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3.4.3 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Sparse (pre-dose) PK samples for measurement of alectinib and its major 
metabolite(s) will be collected in all study patients receiving alectinib treatment.  See 
Appendix 1 and Appendix 2 for PK sampling times. 
• 
Serial/intensive PK sampling will be collected in a subset of consenting patients 
enrolled to receive alectinib treatment (approximately 10%−15%, at least 
approximately n = 20).  See Appendix 1 and Appendix 2 for PK sampling times. 
• 
PK parameters will be determined as appropriate and where data allow: 
The pharmacokinetics of alectinib (and metabolite[s], if appropriate) will be 
described, and the between-patient variability will be estimated using a 
population PK approach.  The potential influence of covariates that contribute 
significantly to the between-patient differences in PK parameters of alectinib will 
also be explored and quantified. 
Non-compartmental analysis (NCA) may be conducted in patients undergoing 
serial/intensive PK sample collection, as appropriate and where data allow. 
 
3.4.4 
Patient-Reported Outcome Measures 
The PRO measures included for this study are as follows and will be administered to 
patients every 4 weeks until disease progression and during post-progression on 
treatment in case of isolated, asymptomatic CNS progression; at the post-treatment visit 
(4 weeks after permanent treatment discontinuation); and every follow-up visit (every 
8 weeks) after post-treatment visit for 6 months: 
• 
The EORTC QLQ-C30 and EORTC QLQ-LC13 to determine the impact of alectinib 
compared with crizotinib as measured by TTD in patient-reported lung cancer 
symptoms (e.g., cough, dyspnea [single item and multi-item scales], pain in chest, 
pain in arm/shoulder, fatigue). 
• 
The EORTC QLQ-C30 and EORTC QLQ-LC13 to measure PROs of HRQoL, 
patient functioning, and side effects of therapy compared between patients treated 
with alectinib and those treated with crizotinib. 
 
For patients who discontinue treatment for reasons other than disease progression and 
who progress within the first 6 months of survival follow-up, PRO measures will be 
administered every 4 weeks until disease progression and then decreased to every 
8 weeks until 6 months post treatment. 
For patients who discontinue treatment for reasons other than disease progression and 
have not yet progressed at 6 months post treatment, PRO measures will be 
administered every 4 weeks until disease progression and will no longer be required 
thereafter.  


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3.4.5 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
EQ-5D-3L to generate utility scores for use in economic models for the purpose of 
reimbursement 
• 
Total testosterone and free testosterone levels (either by direct measurement or by 
calculation using albumin and SHBG, FSH, and LH, in blood to measure the onset 
of hypogonadism in adult men 
• 
Results from the FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) to evaluate 
and compare efficacy and safety in patients with treatment-naive NSCLC that is 
ALK-positive by FISH test  
• 
ALK fusion status in circulating tumor nucleic acids from plasma to evaluate and 
compare efficacy and safety in patients with treatment-naive NSCLC that is 
ALK-positive by plasma ALK tests (PCR and/or sequencing) for diagnostic 
purposes  
• 
Post-progression tumor mutation status to study molecular mechanisms of 
resistance to ALK inhibitors 
• 
ALK mutation status in plasma DNA to monitor efficacy and disease progression 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
The target population is patients with treatment-naive, ALK-positive, non-resectable, 
locally advanced and metastatic NSCLC. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage 
IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that 
is ALK-positive as assessed by the Ventana IHC test.  Sufficient tumor tissue to 
perform ALK IHC and ALK FISH is required.  Both tests will be performed at 
designated central laboratories. 
• 
Age ≥ 18 years old 
• 
Life expectancy of at least 12 weeks 
• 
ECOG PS of 0−2 
• 
No prior systemic treatment for advanced or recurrent NSCLC (Stage IIIB not 
amenable to multimodality treatment) or metastatic (Stage IV) NSCLC 
• 
Adequate hematologic function: 
Platelet count ≥ 100 × 109/L 
ANC ≥ 1500 cells/μL 
Hemoglobin ≥ 9.0 g/dL 


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• 
Adequate renal function: 
An estimated glomerular filtration rate (eGFR) calculated using the Modification 
of Diet in Renal Disease equation of at least 45 mL/min/1.73 m2 
• 
Patients must have recovered from effects of any major surgery or significant 
traumatic injury at least 28 days before the first dose of study treatment. 
• 
Measurable disease (by RECIST v1.1) prior to the administration of study treatment 
• 
Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed 
incidentally at study baseline).  Asymptomatic CNS lesions might be treated at the 
discretion of the investigator as per local clinical practice.  If patients have 
neurological symptoms or signs due to CNS metastasis, patients need to complete 
whole brain radiation or gamma knife irradiation treatment.  In all cases, radiation 
treatment must be completed at least 14 days before enrollment and patients must 
be clinically stable. 
• 
For all females of childbearing potential, a negative pregnancy test must be 
obtained within 3 days before starting study treatment. 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus), agreement to 
remain abstinent or use single or combined contraceptive methods that result in a 
failure rate of < 1% per year during the treatment period and for at least 3 months 
after the last dose of study drug.  Abstinence is only acceptable if it is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.  Examples of non-hormonal contraceptive 
methods with a failure rate of < 1% per year include tubal ligation, male sterilization, 
hormonal implants, established and proper use of combined oral or injected 
hormonal contraceptives, and certain intrauterine devices.  Alternatively, two 
methods (e.g., two barrier methods such as condom and cervical cap use) may be 
combined to achieve a failure rate of < 1% per year.  Barrier methods must always 
be supplemented with the use of a spermicide.  
• 
For men, agreement to remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of < 1% per year during the 
treatment period and for at least 3 months after the last dose of study drug.  
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception. 
• 
Able and willing to provide written informed consent prior to performing any 
study-related procedures and to comply with the study protocol, including patients 
must be willing and able to use the electronic patient-reported outcome (ePRO) 
device. 
 


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4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients with a previous malignancy within the past 3 years are excluded (other than 
curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer 
by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is 
considered to have no impact in PFS and OS for the current NSCLC). 
• 
Any GI disorder that may affect absorption of oral medications, such as 
mal-absorption syndrome or status post-major bowel resection 
• 
Liver disease characterized by: 
ALT or AST > 3 × ULN (≥ 5 × ULN for patients with concurrent liver metastasis) 
confirmed on two consecutive measurements 
OR 
Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or 
other conditions of decompensated liver disease such as coagulopathy, hepatic 
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal 
varices 
OR 
Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis 
• 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy 
such as radiotherapy (excluding alopecia), which have not shown improvement and 
are strictly considered to interfere with current study medication 
• 
History of organ transplant 
• 
Co-administration of anti-cancer therapies other than those administered in this 
study 
• 
Patients with baseline QTc > 470 ms or symptomatic 
• 
Administration of strong/potent cytochrome P450 (CYP)3A inhibitors or inducers 
within 14 days prior to the first dose of study treatment and while on treatment with 
alectinib or crizotinib (see Appendix 3)  
• 
Administration of agents with potential QT interval prolonging effects within 14 days 
prior to the first administration of study drug and while on treatment.  See 
Section 4.4.2 for further details 
• 
History of hypersensitivity to any of the additives in the alectinib drug formulation 
(seeSection 4.3.1.1 for further details) 
• 
History of hypersensitivity to any of the additives in the crizotinib drug formulation 
(see Section 4.3.1.2 for further details) 
• 
Pregnant or lactating 
• 
Known HIV positivity or AIDS-related illness 


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• 
Any clinically significant concomitant disease or condition that could interfere with, 
or for which the treatment might interfere with, the conduct of the study or the 
absorption of oral medications or that would, in the opinion of the Principal 
Investigator, pose an unacceptable risk to the patient in this study 
• 
Any psychological, familial, sociological, or geographical condition potentially 
hampering compliance with the study protocol requirements and/or follow-up 
procedures; those conditions should be discussed with the patient before trial entry 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label trial, for which the rationale is described in Section 3.3.4. 
Approximately 286 patients will be randomly assigned in a 1:1 allocation ratio to the two 
treatment arms via a block-stratified randomization procedure and over a planned 
recruitment period of 24 months. 
Randomization will guard against systematic selection bias and should ensure the 
comparability of treatment groups.  To assist balance in important prognostic factors, 
randomization will be stratified by ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and 
CNS metastases at baseline (yes vs. no). 
Central randomization and drug pack number allocations will be performed and 
managed by an IxRS.  Further details will be provided in an IxRS manual. 
The independent review of scans for the secondary endpoints of PFS and time to CNS 
progression on the basis of IRC will be performed in a blinded fashion. 
4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Alectinib 
Alectinib comes in a hard capsule dosage form containing the following active ingredient: 
[Chemical name] 9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-6,11-
dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride 
Each capsule contains 150 mg of alectinib (as free base) along with lactose 
monohydrate, carmellose calcium, hydroxypropyl cellulose, sodium lauryl sulfate (SLS), 
and magnesium stearate as excipients. 
Alectinib capsules should be stored in accordance with the storage instructions on the 
label. 
Alectinib capsules should be administered orally BID with food in the morning and 
evening. 


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The formulation contains SLS as an excipient.  This excipient is known to be potentially 
associated with GI adverse events such as nausea, vomiting, diarrhea, and abdominal 
pain. 
For further details, see the alectinib Investigator's Brochure. 
4.3.1.2 
Crizotinib 
Crizotinib comes in a hard capsule dosage form.  Each capsule contains 250 mg or 
200 mg crizotinib.  Crizotinib hard capsules should be stored in accordance with the 
storage instructions on the label.  Crizotinib capsules should be administered orally BID. 
For further details, see the local prescribing information for crizotinib (XALKORI® U.S. 
Package Insert). 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Alectinib 
Alectinib 600 mg (four 150-mg capsules) should be administered orally BID with food in 
the morning and evening. 
If a patient misses a dose, it can be taken within 4 hours of the scheduled time.  If the 
time is greater than 4 hours, or if the patient vomits the dose, the patient should wait until 
the next scheduled time and take the next scheduled dose.  Patients should not take 
two doses at the same time to make up for a missed dose. 
Guidelines for dosage modifications and treatment interruptions or discontinuation due to 
specified adverse events are provided in Section 5.1.3. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF. 
4.3.2.2 
Crizotinib 
Crizotinib at 250 mg (one 250-mg capsule) should be administered orally BID with or 
without food (in the morning and evening). 
If a dose is missed, then it should be taken as soon as the patient remembers unless it is 
less than 6 hours until the next dose, in which case the patient should not take the 
missed dose.  Patients should not take 2 doses at the same time to make up for a 
missed dose.  If vomiting occurs after taking a dose of crizotinib, the next dose should be 
taken as scheduled.  
If dose reduction is necessary, then the dose of crizotinib should be reduced to 200 mg 
taken BID.  If further dose reduction is necessary, then the dose should be modified to 


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250 mg taken once daily.  Guidelines for dosage modification and treatment interruption 
or discontinuation are provided in Section 5.1.4. 
Any overdose or incorrect administration of crizotinib should be noted on the crizotinib 
Administration eCRF.  Adverse events associated with an overdose or incorrect 
administration of crizotinib should be recorded on the Adverse Event eCRF. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(alectinib and crizotinib) will be provided by the Sponsor where required by local health 
authority regulations.  The study site will acknowledge receipt of IMPs and confirm the 
shipment condition and content.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Post-Trial Access to Alectinib 
The Sponsor will offer post-trial access to the study drug alectinib free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive study drug after the end of the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or would not 
otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for ALK-positive NSCLC 


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• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for ALK-positive NSCLC 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy 
Concomitant medication includes any medication (e.g., prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used 
by a patient from screening to the study completion/discontinuation visit.  All concomitant 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
All therapy and/or medication administered to manage adverse events should be 
recorded on the Adverse Event eCRF. 
The medications and/or treatments below are permitted: 
• 
Anticoagulants and antithrombotic agents (i.e., coumadin-derived anticoagulants, 
unfractionated heparin or low-molecular heparins, aspirin (≤ 325 mg/day), and 
clopidogrel. 
• 
Acetaminophen up to 2 g/day 
• 
Gastric pH elevating medications (such as proton pump inhibitors, H2 blockers, or 
antacids) 
• 
Local therapy (e.g., stereotactic radiotherapy or surgery) may be given to patients 
with isolated asymptomatic CNS progression (e.g., new CNS oligometastases). 
 
Caution should be exercised when the following are co-administered with alectinib: 
• 
For medications that are substrates of P-gp transporter or breast cancer resistance 
protein transporter, the investigator should use caution and monitoring when 
considering concomitant use of alectinib.  Alectinib has been shown to have 
potential for inhibition of these transporters.  Substrates with a narrow therapeutic 
index (e.g., methotrexate, digoxin) should be avoided.  If co-administration cannot 
be avoided, it is recommended that drug levels and/or signs for toxicity are carefully 
monitored (see Appendix 3). 
 
Caution should be exercised when the following are co-administered with crizotinib. 
• 
Crizotinib has been shown to be a moderate inhibitor of CYP3A.  Dose reduction 
may be needed for co-administered drugs that are predominantly metabolized by 


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CYP3A in patients receiving crizotinib.  Concurrent use of CYP3A substrates with 
narrow therapeutic indices should be avoided (see Appendix 3). 
• 
On the basis of an in vitro study, crizotinib is predicted to inhibit intestinal P-gp.  
Therefore, administration of crizotinib with medicinal products that are substrates of 
P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin) may increase their 
therapeutic effect and adverse reactions (see Appendix 3).  Close clinical 
surveillance is recommended when crizotinib is administered with these medicinal 
products. 
• 
Bradycardia has been reported during clinical studies; therefore, avoid using 
crizotinib in combination with other agents known to cause bradycardia (e.g., beta-
blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin) to 
the extent possible 
• 
In vitro studies in human hepatocytes indicated that crizotinib may induce 
pregnane X receptor and constitutive androstane receptor-regulated enzymes 
(e.g., CYP3A4, CYP2B6, CYP2C8, CYP2C9, UGT1A1).  However, there was no 
observed induction in vivo when crizotinib was coadministered with the CYP3A 
probe substrate midazolam.  Caution should be exercised in administering crizotinib 
in combination with medicinal products that are predominantly metabolized by these 
enzymes.  Of note, the effectiveness of concomitant administration of oral 
contraceptives may be altered. 
• 
In vitro studies indicated that crizotinib is an inhibitor of CYP2B6.  Therefore, 
crizotinib may have the potential to increase plasma concentrations of 
coadministered drugs that are metabolized by CYP2B6 (e.g., bupropion, efavirenz). 
 
4.4.2 
Prohibited Therapy 
Use of the following therapies (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) is prohibited during the study and for at 
least 14 days prior to initiation of study treatment (either alectinib or crizotinib), unless 
otherwise specified below.  Exceptions to restrictions of the concomitant therapies listed 
below (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) may be made if the rationale is discussed and documented 
between the investigator and the Sponsor’s Clinical Pharmacologist. 
• 
Potent inducers of CYP3A (e.g., rifampin, rifabutin, phenobarbital, phenytoin, 
carbamazepine, and St. John’s wort [Hypericum perforatum]) within 2 weeks or 
5 half-lives (whichever is longer) before the first dose of study drug treatment and 
while on treatment with study drugs (see Appendix 3). 
• 
Potent inhibitors of CYP3A (e.g., ketoconazole) within 2 weeks or 5 half-lives 
(whichever is longer) before the first dose of study drug treatment and while on 
treatment with study drug (see Appendix 3). 
• 
Any concomitant medications known to affect QT interval duration, including but not 
limited to the following drugs: amiodarone, cisapride, clarithromycin, methadone, 
and quinidine, within 2 weeks before the first dose of study drug treatment and while 
on treatment with study drugs and through the end of the study. 


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• 
Systemic immunosuppressive drugs, cytotoxic or chemotherapeutic agents 
(other than study drug treatment), ergot derivatives, probenecid, and bile 
acid-binding resins while on study treatment. 
• 
Systemic chemotherapy. 
• 
Radiotherapy/radionuclide therapy except for palliative radiotherapy to bone lesions 
or for pain control.  If palliative radiation is indicated for bone metastases, palliative 
radiation may start within 24 hours of the last dose of alectinib, unless, in the 
judgment of the investigator, patient safety will require a longer washout period prior 
to palliative therapy.  Dosing of alectinib may resume with the resolution of any 
radiation toxicity to  ≤ Grade 1. 
• 
Additional investigational drug (except for during the follow-up period). 
 
The list of medications provided above is not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication 
as well as the Internet references provided below when determining whether a certain 
medication strongly inhibits or induces CYP3A.  In addition, the investigator should 
contact the Medical Monitor if questions arise regarding medications not listed above. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM292362.pdf 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx (for P450 drug interactions) 
 
4.4.3 
Prohibited Food 
Use of grapefruit or grapefruit juice should be avoided during the study and for at least 
14 days prior to the initiation of study treatment (either alectinib or crizotinib) because it 
is a potent CYP3A inhibitor and may increase plasma concentration of either alectinib or 
crizotinib. 
4.5 
STUDY ASSESSMENTS 
See Appendix 1 for the schedule of assessments performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 


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4.5.2 
Medical History and Demographic Data 
Medical history includes a record of clinically significant diseases, surgeries, cancer 
history (including prior cancer therapies and procedures), reproductive status, smoking 
history, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 28 days prior 
to the screening visit. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Corticosteroid Use for CNS Metastases 
For patients with CNS metastases requiring corticosteroid use, the corticosteroid intake 
should be captured at all tumor assessment visits and compared to the corticosteroid 
intake at the time of the last disease assessment.  The changes will be recorded as 
Increased, Unchanged, or Decreased.  Increases and decreases in corticosteroid intake 
should be clinically justified.  Increases in corticosteroid dose for reasons other than for 
CNS metastases control do not need to be taken into consideration when making this 
comparison. 
4.5.4 
Physical Examinations 
A complete physical examination at screening and baseline should include an evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, GI, genitourinary, and neurological systems as well as 
height and weight.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
Note:  for patients with known CNS metastases, a neurological examination must be 
performed at each tumor assessment visit and compared to the neurological 
examination performed at the time of the last disease assessment.  Definition of clear 
neurological worsening is difficult to describe because progression in the CNS can 
present in numerous ways.  Accordingly, evaluation of neurological function at each 
disease assessment will be based purely on the investigator’s assessment of the 
patient’s neurological state compared to the neurological function at the time of the last 
disease assessment.  Neurological status will be recorded as Improved, Stable, or 
Worsened. 
4.5.5 
Vital Signs 
Vital signs will include measurements of respiratory rate, oxygen saturation, pulse rate, 
and systolic and diastolic blood pressure while the patient is in a seated position, and 
temperature. 


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4.5.6 
ECOG Performance Status 
PS will be measured using the ECOG Performance Status Scale (see Appendix 5).  It is 
recommended, where possible, that a patient’s PS be assessed by the same person 
throughout the study. 
4.5.7 
Tumor and Response Evaluations 
Disease burden must be documented at screening and re-assessed at each subsequent 
tumor evaluation.  Response will be assessed by the investigator on the basis of physical 
examinations.  Clinical lesions will be documented by color photography (with caliper 
measurement for measurable lesions), computed tomography (CT) scans, and other 
modalities (e.g., MRI, brain scans), using RECIST v1.1 (see Appendix 4).  For assessing 
response in patients with measurable disease, the preferred radiologic tumor response 
assessment is CT scan with intravenous contrast.  If intravenous contrast is 
contraindicated, a non-contrast-enhanced chest CT scan will be acceptable for chest 
lesions, and MRI can be used for non-chest lesions.  If contrast-enhanced MRI is 
contraindicated, then non-contrast-enhanced MRI will suffice.  Positron emission 
tomography (PET) scan, bone scan, and ultrasound cannot be used to measure lesion as 
per RECIST v1.1 (see Appendix 4).   
The same radiographic procedure used to define measurable disease sites at screening 
must be used throughout the study (e.g., the same contrast protocol for CT scans).  
Assessments should be performed by the same evaluator to ensure internal consistency 
across visits. 
CT/MRI scans of chest and abdomen, and MRI scans of the brain should be performed 
for all patients as described in Schedule of Assessments (see Appendix 1) at screening, 
then every 8 weeks subsequently until disease progression and during post-progression 
on treatment in case of isolated, asymptomatic CNS progression and at the 
post-treatment visit (4 weeks after permanent treatment discontinuation).  CT/MRI scans 
of the neck bone and pelvis should be included if clinically indicated.  At the investigator’s 
discretion, CT/MRI scans may be repeated at any time if PD is suspected. 
Note: Brain imaging should be performed using MRI with the following image acquisition 
requirements. 
• 
Minimum sequences required: 
Pre-contrast T1, T2/FLAIR 
Post-contrast T1, with two orthogonal planes (or a volume acquisition) 
recommended 
• 
Recommended slice thickness ≤ 5 mm with no gap 
 
Patients with known or suspected bone metastases should undergo radionuclide bone 
scan at screening.  Bone scan, PET scan, or plain films are not considered adequate 
imaging techniques to measure bone lesions and do not need to be repeated routinely 


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but can be used to confirm the presence or disappearance of bone lesions.  Lytic bone 
lesions or mixed lytic-blastic lesions, with identifiable soft tissue components that can be 
evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
measurable lesions of the soft tissue component and meet the definition of measurability 
and should be followed by cross-sectional imaging. 
4.5.8 
Laboratory, Biomarker, and Other Biological Sample 
4.5.8.1 
Laboratory Assessments 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis of the following: 
• 
Hematology (hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
absolute differential count [neutrophils, eosinophils, lymphocytes, monocytes, 
basophils, other cells]) 
• 
Coagulation (PT [or INR], and aPTT) 
• 
Serum chemistry (sodium, potassium, chloride, bicarbonate, fasting glucose, BUN 
or urea, creatinine [including calculated eGFR using the Modification of Diet in 
Renal Disease formula, see Appendix 7]; CPK; gamma-glutamyl transferase (GGT); 
calcium; total and direct bilirubin; total protein; albumin; ALT; AST; alkaline 
phosphatase [ALP]; phosphorus; magnesium; thyroid-stimulating hormone; and total 
testosterone and free testosterone (either by direct measurement or by calculation 
using, albumin and SHBG), FSH, and LH [for male patients only]) 
• 
Urinalysis.  Urine samples will be collected according to the schedule of 
assessments (Appendix 1)(first morning urine sample for baseline and end of 
treatment visit, spot urine for rest of visits).  Urine protein will be measured by 
dipstick test. 
• 
Pregnancy test.  All women who are not postmenopausal (≥ 12 months of 
non-therapy-induced amenorrhea) or surgically sterile will have a serum pregnancy 
test at screening, within 3 days of dosing.  Urine pregnancy tests will be performed 
anytime during the course of the study, as per investigator’s discretion.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
 
4.5.8.2 
Pre-Treatment Tumor Samples (Mandatory) 
Mandatory pre-treatment tumor samples will be collected to centrally examine ALK 
status by Ventana IHC (eligibility criteria) and Vysis FISH.  Tumor blocks (formalin-fixed, 
preferred 10% neutral-buffered formalin) are the preferred source, but if blocks are not 
available, unstained slides (ten to fifteen 5-µm slides cut less than 3 months before 
screening) are also accepted.  Remaining tumor blocks will be returned to the sites; 
slides will not be returned. 
For fresh tumor biopsies (guided by ultrasound or CT scan), acceptable methods include 
core biopsies for lung and liver lesions and bronchoscopic biopsies for lung lesions.  The 
minimum size for the biopsy needle recommended is 20G. 


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Central ALK testing to determine or confirm patient ALK status will be performed at a 
Sponsor designated central laboratory.  After completion of ALK testing for enrollment 
with a pre-specified ALK test by Ventana IHC (Appendix 8), patient samples will also be 
centrally tested by FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) for possible 
companion diagnostic development.  Additionally, other ALK assays may be used for 
testing patient samples to establish performance characteristics of these assays for 
diagnostic development.  Testing may be performed on all screened patients (screen-
failed and enrolled).  These additional testing data will have no impact on eligibility, and 
testing will be performed only after eligibility is established for each patient.  In addition, 
local ALK test information, baseline demographic, and disease-related characteristic 
data for all screened patients may be collected in order to support potential registration 
of a companion diagnostic assay for alectinib. 
The tumor sample may also be tested for the presence of EGFR mutations, if requested 
by the investigator. 
Pre-treatment tumor samples may be used, after proper informed consent is obtained, 
for genomic sequencing. 
For sample handling procedures, storage conditions and shipment instructions, see the 
laboratory manual. 
4.5.8.3 
Pre- and Fresh Post-Treatment Tumor Biopsies (Optional) 
Pre-treatment tumor samples (preferably formalin-fixed blocks but if not available a 
minimum of 10-15 unstained 5 µm slides) for ALK testing is a mandatory requirement for 
this study.  Optional additional pre-treatment tumor samples and fresh post-treatment 
tumor biopsy at disease progression or permanent treatment discontinuation (at the last 
treatment or post-progression visit) may be collected, with proper informed consent.  
These samples will be used to help to understand molecular mechanisms of resistance 
to ALK inhibitors by genomic sequencing.  Remaining tumor blocks will be returned to 
the sites, slides will not be returned. 
The remaining mandatory (Section 4.5.8.2) and optional specimens(Section 4.5.8.3) 
will be destroyed within 5 years after the date of final closure of the clinical database.  
Other residual tissue material (slides, extracts, etc.) will be destroyed within 5 years after 
the date of final closure of the clinical database. 
On the basis of continuous analysis of the data in this study and other studies, or on the 
basis of data from literature, collection of optional tumor biopsies with exploratory 
purposes may be stopped at any time if the data from the samples collected do not 
produce useful information. 


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4.5.8.4 
Blood and Plasma Samples 
Mandatory plasma samples will be obtained to determine: 
• 
Mutation status in ALK and other escape genes (e.g., EGFR, KRAS).  It will require 
20 mL of blood (2 tubes of 10 mL each) to be collected at baseline, at the Visit 
3 (Week 16) treatment, and subsequently at every second treatment visit (every 
16 weeks) (see Appendix 1 for detailed information) until disease progression, and 
during post-progression on treatment in case of isolated, asymptomatic CNS 
progression.  For sample handling procedures, storage conditions and shipment 
instructions, see the laboratory manual.  These samples will not be taken in 
countries where regulatory agency or Institutional Review Board (IRB) does not 
allow genetic testing. 
• 
ALK rearrangement in plasma.  This will require 20 mL of blood (2 tubes of 10 mL 
each) to be collected at baseline. 
 
Mandatory blood samples will be obtained to determine: 
• 
All patients who are randomized in alectinib arm will also participate in retrospective 
pharmacogenomic research to understand inter-individual variability of safety and 
pharmacokinetics of alectinib.  For this purpose, a 3-mL blood sample will be drawn 
at baseline (see Section 4.5.8.4.1). 
 
Optional blood samples will be collected to obtain: 
• 
Plasma.  Centrally ALK negative tested patients (by Ventana ALK IHC) who agree 
to donate  10 ml plasma will be assessed by plasma ALK assays (PCR and/or 
Sequencing) for the development of a plasma ALK diagnostic test 
• 
A source of healthy tissue for patients who agreed to participate in the optional 
genomic sequencing assessment.  For patients in the crizotinib arm, a 3-mL blood 
sample will be drawn at baseline.  For patients in the alectinib arm, a source of 
healthy tissue will be used as a portion of the sample for the pharmacogenomics 
research (see Section 4.5.8.4.1) 
• 
A portion of this blood sample will also be used as a source of healthy tissue for the 
patients on alectinib treatment who agree to participate in the optional genomic 
sequencing research. 
 
For biomarkers, a maximum of 43 mL of blood will be collected at baseline (20 mL of 
blood for plasma purification and determination of mutation status in ALK and other 
escape genes, 20 mL of blood for plasma purification and detection of ALK 
rearrangements, and 3 mL blood for pharmacogenomics research.  Twenty mL of blood 
(for plasma purification and determination of mutation status in ALK and other escape 
genes) will be collected at Visit 3 (Week 16) and subsequently at every second visit 
(every 16 weeks), and 20 mL will be collected at disease progression (CNS and/or 
systemic disease progression) for plasma purification, for determination of mutation 
status in ALK and other escape genes. 


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Details of sample handling procedures, sample storage and shipment will be described 
in a separate laboratory manual. 
On the basis of continuous analysis of the data in this study and other studies, or on the 
basis of data from literature, collection of plasma with exploratory purposes may be 
stopped at any time if they are deemed not informative. 
4.5.8.4.1 
Samples for Pharmacogenomic Assessments 
One sample (approximately 3 mL of whole blood) will be collected from all patients on 
alectinib treatment.  Samples will be used for the evaluation of genetic polymorphisms of 
drug metabolic enzymes including, but not limited to, CYP2C9, CYP3A4/5, and UGT1A1, 
and transporters (e.g., organic anion transporter polypeptide 1B1) and for genetic 
variants that could contribute to potentially drug-related liver safety assessments 
(including but not limited to human leukocyte antigen, see Appendix 9 for more details). 
For sample handling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Only in circumstances where there is concern for collection of this 
genetic material for above evaluations can this assessment be considered not 
mandatory as part of study assessments in this study.  Results of any analyses from 
these samples will be reported outside the clinical study report. 
4.5.8.5 
Samples for Pharmacokinetic Assessments 
PK samples will be collected in all patients on alectinib treatment, as indicated in 
Appendix 1 and Appendix 2 for the analysis of alectinib and its major metabolite(s) 
(RO5468924, RO5507197, and/or others, if applicable and if appropriate, and if assays 
are available).  Residual samples following PK analysis may be used to evaluate 
profiling for alectinib metabolite(s). 
All trough/pre-dose PK samples should be collected within 2 hours BEFORE the 
morning doses of study medications.  
Serial/intensive samples will be collected in a subset of patients (10%–15% [at least 
approximately n = 20] of patients receiving alectinib) on Visit 0 (baseline, after the first 
dose) and Visit 1 (Week 4) at the timepoints specified in Appendix 2. 
Plasma concentrations for alectinib and its metabolite(s), if applicable, will be measured 
by specific and validated liquid chromatography tandem mass spectrometry methods. 
For each sample, approximately 2 mL of venous blood will be collected for alectinib PK 
analysis at the timepoints specified in the PK schedule in Appendix 1 and Appendix 2. 
Patients who permanently discontinue from study drugs will also discontinue from all PK 
assessments.  The procedures for the collection, handling, storage, and shipping of 
plasma samples for the PK analysis are specified in the Laboratory Manual.  


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These samples will be destroyed when the final Clinical Study Report is complete. 
On the basis of continuous analysis of the data in this study and other studies, any 
sample type collection may be stopped at any time if the data from the samples collected 
do not produce useful information or at the discretion of the Sponsor. 
4.5.9 
Electrocardiograms 
An ECG will be recorded at specified timepoints as outlined in the schedule of 
assessments (Appendix 1) at screening, Visit 0 (baseline), Visit 1 (Week 4), Visit 
4 (Week 24), Visit 8 (Week 56), and at the last treatment visit and as clinically indicated 
throughout the study.  All ECG recordings must be performed using a standard high-
quality, high-fidelity digital electrocardiograph machine equipped with computer-based 
interval measurements.  All ECGs are to be obtained prior to other procedures 
scheduled at that same time (e.g., vital sign measurements, blood draws, study drug 
administration) as well as prior to meals.  Circumstances that may induce changes in 
heart rate, including environmental distractions (e.g., television, radio, conversation), 
should be avoided during the pre-ECG resting period and during ECG recording. 
Patients must have been in a supine or semi-supine position for at least 5 minutes prior 
to the recording being taken.  The same recording position (supine or semi-supine) and 
the same equipment should be used for each patient throughout the study.  The ECG 
printout must be (1) reviewed by a medically qualified member of the study team at the 
site, (2) annotated to indicate any clinical finding, and (3) dated and signed by this 
person and filed in the patient notes.  ECG parameters will be entered on the ECG 
eCRF.  The following parameters should be captured on the eCRF: heart rate, RR, PQ, 
QRS and QT duration, and QT interval corrected using Fridericia’s formula (QTcF). In 
the event that the ECG machine does not directly provide results for RR and/or QTcF, 
these parameters can be derived using the formulae provided in Appendix 10. 
If any ECG abnormality is associated with an adverse event, it must be recorded and 
managed as described in Section 5.  Management of QT interval prolongation should be 
done according to guidance provided in Section 5.1.3.  
If considered appropriate by the Sponsor, ECGs may be analyzed retrospectively at a 
central laboratory.  Guidance for abnormal ECG results (QT prolongation) is provided in 
Table 2. 
4.5.10 
Patient-Reported Outcomes 
PROs (EORTC QLQ-C30, QLQ-L13, and EQ-5D) will be collected to more fully 
characterize the clinical profile of alectinib.  The instruments will be translated as 
required in the local language.  To ensure instrument validity and that data standards 
meet health authority requirements, the PROs scheduled for administration during a 
clinic visit (EORTC QLQ-C30, QLQ-L13, and EQ-5D) should be completed prior to the 
performance of non-PRO assessments and the administration of study treatment. 


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Patients will use an ePRO device to capture PRO data and maintain a diary of daily 
drug intake (crizotinib arm) / drug intake with food (alectinib arm).  The ePRO device 
and instructions for completing the PRO questionnaires and diaries electronically will be 
provided by the investigator staff.  The data will be transmitted via pre-specified 
transmission method (e.g., web or wireless) automatically after entry to a centralized 
database at the ePRO vendor.  The data can be accessed by appropriate study 
personnel securely via the Internet. 
4.5.11 
Samples for Roche Clinical Repository 
4.5.11.1 
Overview of the Roche Clinical Repository 
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future. 
Specimens for the RCR will be collected from patients who give specific consent to 
participate in optional research.  RCR specimens will be used to achieve the following 
objectives: 
• 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.11.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's IRB or Ethics Committee (EC) and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval for RCR sampling, 
this section of the protocol (Section 4.5.11) will not be applicable at that site. 
4.5.11.3 
Sample Collection 
For RCR purposes, 10 mL of blood will be collected.  Any remaining tissue samples from 
study-related or non-study related procedures that are performed during the study may 
also be collected for RCR purposes.  For all samples, date of consent should be 
recorded on the associated RCR page of the eCRF.  For sampling procedures, storage 
conditions, and shipment instructions, see the laboratory manual. 


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RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below. 
4.5.11.4 
Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
4.5.11.5 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 


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objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether the patient has given consent to participate 
by completing the RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research. 
4.5.11.6 
Withdrawal from the Roche Clinical Repository 
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study BO28984 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study BO28984. 
4.5.11.7 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 


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• 
Investigator or Sponsor determines it is in the best interest of the patient 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients who withdraw consent for treatment should continue to be 
followed for tumor assessments until progression and for OS, provided they have not 
withdrawn consent for the study.  However, patients will not be followed for any reason 
after consent for the study has been withdrawn.  Patients who withdraw from the study 
will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Pregnancy 
• 
Inability to tolerate study medication on the basis of the investigator judgment 
See guidelines for managing adverse events and for comprehensive guidance on study 
drug discontinuation in Section 5.1.3. 
Patients who discontinue study drug prematurely will be asked to return to the clinic for 
tumor assessments until progression as per study schedule (see Appendix 1). 
The primary reason for premature study drug discontinuation should be documented on 
the appropriate eCRF.  Patients who discontinue study drug prematurely will not be 
replaced. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
 


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5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
5.1.1 
Adverse Events Collection 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events (SAEs) caused by a protocol-mandated intervention should be 
reported (e.g., SAEs related to invasive procedures such as biopsies).  After the first 
dose of study treatment and up to the 4-week follow-up after the last dose of study 
treatment, all adverse events (AEs) regardless of seriousness, causality assessment, or 
actions taken reported by the investigator or designated medically qualified study site 
personnel will be collected as described below.  At each visit, the investigator or 
designated medically qualified study personnel will ask the patient if any untoward 
medical event occurred since the last visit.  It is the investigator’s responsibility to record 
all AEs in the source patient’s medical records. 
All SAEs and non-SAEs will be reported on the standard AE/SAE eCRF. 
5.1.2 
Adverse Events Relating to ALK Inhibitors and/or the Tyrosine 
Kinase Inhibitor Class and Alectinib Data 
Events described in Section 5.1.2.1 through Section 5.1.2.10 will be closely monitored 
and represent selected AEs for this study. 
A more detailed safety profile of alectinib is provided in the alectinib Investigator's 
Brochure. 
5.1.2.1 
Interstitial Lung Disease 
TKIs, including ALK inhibitor crizotinib, have been associated with the occurrence of 
treatment-related ILD (including fatalities). 
See Section 5.1.3 for management and follow-up. 
5.1.2.2 
Hepatobiliary Laboratory Test Elevations 
Hepatobiliary findings were observed in both the rat and monkey 4- and 13-week toxicity 
studies with alectinib, and findings in the 13-week studies were similar to those of the 
4-week studies.  The findings were at or close to clinically relevant exposures.  
Hepatobiliary effects included increased hepatic ALP, direct bilirubin, GGT and liver 
weight, vacuolation/degeneration/necrosis of bile duct epithelium, inflammatory cell 
infiltration in Glisson’s sheath, enlargement/focal necrosis of hepatocytes, and 
enlargement of Kupffer cells. 
Abnormal hepatobiliary laboratory test values, such as increased ALT, AST, or bilirubin 
levels, have been observed after alectinib administration.  AST, ALT, and total bilirubin 
levels temporarily increased in the initial stages of treatment and then improved.  


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In patients treated with other tyrosine kinase ALK inhibitor drugs, abnormal liver function 
tests and fatal cases of hepatic failure have been reported. 
See Section 5.1.3 for management and follow-up. 
5.1.2.3 
Hematologic Abnormalities 
Hematologic findings were observed in both the rat and monkey 4- and 13-week toxicity 
studies with alectinib, and findings in the 13-week studies were similar to those of the 
4-week studies.  Findings were at or close to clinically relevant exposures.  Hematologic 
adverse effects such as anemia, thrombocytopenia, bleeding, and neutropenia have 
been observed with most TKIs, including ALK inhibitor crizotinib. 
Hematologic abnormalities of neutropenia, leukopenia, thrombocytopenia, and anemia 
have been reported with alectinib administration.  Neutrophil counts generally decreased 
early and remained stable thereafter. 
See Section 5.1.3 for management and follow-up. 
5.1.2.4 
Gastrointestinal Disorders 
GI disorders such as nausea, vomiting, constipation, and diarrhea have been reported 
with alectinib.  Similar GI disorders have been observed with other TKIs, including ALK 
inhibitor crizotinib. 
SLS (sodium lauryl sulfate, syn. sodium dodecyl sulfate) is a surfactant excipient in the 
clinical formulation at a concentration of 50% (w/w SLS to active pharmaceutical 
ingredient).  This excipient is a known GI irritant and may be associated with GI AEs 
including nausea, vomiting, diarrhea, and abdominal pain.  Of note, GI tract toxicity as 
the safety determinant of SLS is not because of systemic toxicity, but a consequence of 
local irritation to the GI tract.  In general, when mixed with diet, higher levels of SLS⎯a 
known GI tract mucosal irritant⎯are tolerated versus gavage administrations. 
See Section 5.1.3 for management and follow-up. 
5.1.2.5 
Skin Disorders 
Results of an in vitro phototoxicity study indicated that alectinib may have phototoxic 
potential. 
Skin rash has been reported with majority of TKIs including those targeting the ALK 
receptor (Hartmann et al. 2009). 
Cases of skin rash and photosensitivity have been reported with alectinib and were 
generally Grade 1 or 2. 
See Section 5.1.3 for management and follow-up. 


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5.1.2.6 
Vision Disorders 
In the rat quantitative whole body autoradiography study, tissue radioactivity 
disappeared over time, following a time course comparable to that of plasma 
radioactivity, except for melanin-containing tissues such as uveal tract of eyes, which 
had much higher and more sustained exposure in pigmented rats.  This is consistent 
with what is commonly observed for lipophilic basic drugs. 
Vision disorders, including diplopia, photopsia, blurred vision, visual impairment, and 
vitreous floaters, have been reported with several TKIs, including ALK inhibitors 
(crizotinib) (Shaw et al. 2013). 
Vision disorders, such as dry eye, blepharitis, conjunctivitis, blurred vision, and vision 
impaired, have been reported with alectinib and were generally Grades 1 and 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.7 
Edema 
Most TKIs, including ALK inhibitor crizotinib, have been associated with edema.  Events 
of edema have been reported with alectinib, mostly Grade 1 or 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.8 
Cardiovascular Effects 
QT interval prolongation appears to be an off-target class effect of some TKIs, including 
ALK inhibitor crizotinib (Shah et al. 2013; XALKORI® U.S. Package Insert).  Many TKIs 
have been associated with bradycardia and hypertension. 
In the in vitro study of the cardiovascular system, alectinib inhibited the hERG current 
(IC20: 58 ng/mL; IC50: 217 ng/mL).  Because plasma protein binding by alectinib is ≥ 99%, 
the plasma concentration of alectinib required to induce the same inhibition in vivo would 
be 100 or more times greater than the concentration required in vitro.  In the monkey 
telemetry study, there were no effects on the ECG, any of the other cardiovascular 
parameters or body temperature at doses up to 15 mg/kg (mean maximum 
concentration [Cmax]: 279 ng/mL). 
In a preliminary non- Good Laboratory Practice telemetry study in conscious cynomolgus 
monkeys, a slight hypotensive effect (approximately 10 mmHg) was seen when alectinib 
was administered at 20 and 60 mg/kg orally with no effects on ECG or heart rate.  The 
hypotensive effect of alectinib observed in monkeys was considered to likely be caused 
by vasodilatation induced by L-type Ca2+ channel inhibition. 
Events of bradycardia have been reported with alectinib.  Preliminary heart rate data 
(based on ECG and pulse measurements) from the ongoing alectinib clinical trials show 
a decrease in heart rate during alectinib treatment, which is mainly asymptomatic.  In 
patients treated with other ALK inhibitors (crizotinib and ceritinib), bradycardia adverse 


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events, as well as decreases in heart rate based on ECG and pulse measurements, 
have also been reported.  
In case of bradycardia, concomitant medications must be evaluated to identify those that 
are known to cause bradycardia, as well as anti-hypertensive medications; and 
discontinuation or dose reduction of these concomitant medications must be considered. 
See Section 5.1.3 for management and follow-up. 
5.1.2.9 
Abnormal Renal Function 
In the 2-week non-human primate study at 60 mg/kg, an increase in creatinine was 
observed but no changes were observed in histopathology.  In all other non-human 
primate studies, no changes in creatinine were observed. 
Serum creatinine increases have been reported with alectinib treatment and were 
generally Grades 1 and 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.10 
Muscular Adverse Events and CPK Elevations 
Postmarketing experience with some TKIs includes reports of myopathy and 
rhabdomyolysis (Hohenegger 2012). 
Blood CPK increases, generally Grades 1 and 2, and muscular AEs have been reported 
with alectinib treatment. 
See Section 5.1.3 for management and follow-up and Table 2 for guidelines for 
managing AEs. 


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5.1.3 
Management of Specific Adverse Events with Alectinib 
Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib 
Event 
Action to Be Taken 
Interstitial lung disease 
• 
Patients should be monitored for pulmonary symptoms 
indicative of pneumonitis.  
• 
Study drug should be permanently discontinued in patients 
diagnosed with interstitial lung disease. 
Hepatobiliary AE and 
laboratory test elevations 
 
Liver test laboratory abnormalities are to be reported as AEs only if 
fulfilling the criteria listed in Section 5.3.5.4 and Section 5.3.5.6. 
• 
If ALT or AST  > 3 × baseline, repeat testing of ALT, AST, 
ALP, and total bilirubin within 48–72 hours, with inquiry 
about symptoms.  If upon repeat testing the transaminases 
remain  > 3 × baseline, but are not  > 5 × baseline or not 
accompanied with bilirubin increases or do not match any 
other rule for permanent discontinuation, then monitoring 
can continue as per investigator judgment, and dose 
modification is not necessary. 
• 
At any time during the study treatment, if symptoms compatible 
with liver injury are observed, liver enzymes should be 
measured as soon as possible.  
• 
Study drug treatment has to be permanently discontinued if 
any of the following occurs: 
First observation of ALT or AST  > 8 × ULN 
ALT or AST > 5 × ULN for more than 2 weeks 
First observation of ALT or AST > 3 × ULN and total 
bilirubin > 2 × ULN  
First observation of ALT or AST > 3 × ULN and the 
appearance of jaundice or signs of hepatic dysfunction or 
other symptoms (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or 
eosinophilia [> 5%]). 
• 
Following study drug discontinuation, weekly monitoring of 
laboratory values should continue until the abnormal values 
have normalized to pre-treatment levels and/or an adequate 
explanation of the abnormal value is found. 
• 
Resumption of study drug is not allowed in patients 
discontinuing because of any of the above criteria. 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
Hematologic abnormalities Hematologic laboratory abnormalities are to be reported as AEs 
only if fulfilling the criteria listed in Section 5.3.5.4. 
• 
In case of hematologic toxicity:  Grade 4 (neutropenia, 
thrombocytopenia):  
Give supportive treatment per treating physician. 
First episode:  Temporarily interrupt alectinib until ANC is 
above 1200/µL and platelets are above 75 K/µL.  Upon 
resumption, reduce alectinib dose by 150 mg (1 capsule) 
BID (450 mg BID). 
Second episode:  Reduce dose by another 150 mg 
(1 capsule) BID (300 mg BID).  
Third episode:  Permanently discontinue alectinib. 
• 
In case of hematologic toxicity:  Grade 3 (neutropenia, 
thrombocytopenia):  
Temporarily interrupt alectinib until ANC is above 1200/µL 
and platelets are above 75 K/µL. 
Give supportive treatment per treating physician. 
If improvement to Grade ≤ 2 does not occur within 
3 weeks, permanently discontinue alectinib. 
• 
In case of hematologic toxicity:  Grade 1 or 2 (neutropenia, 
thrombocytopenia) no action is required. 
Gastrointestinal tract AEs 
(e.g., nausea, vomiting, 
diarrhea) 
The events are expected to be minimized by taking the study drug 
with meal.  In case GI events occur, appropriate measures should 
be taken in accordance with local clinical practice guidelines.  If GI 
toxicities are observed and not tolerable, treatment with study drug 
should be temporarily interrupted until recovery to Grade 1 or lower.
Skin disorder AEs 
(e.g., phototoxicity, rash) 
Patients should be advised to avoid prolonged sun exposure while 
taking alectinib and for at least 5 days after study drug 
discontinuation.  Patients should also be advised to use a 
broad-spectrum sun screen and lip balm of at least SPF > 30 to help 
protect against potential sunburn 
Vision disorders 
Investigators should consider referring the patients for an 
ophthalmological evaluation according to local clinical practice 
guidelines, if vision disorders persist or worsen in severity, and to 
advise patients to exercise caution when driving or operating 
machinery due to the risk of developing a vision disorder. 
Edema 
Physical examinations will be performed routinely in clinical trials.  
In case edema events occur, appropriate measures should be taken 
in accordance with local clinical practice guidelines 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
QT prolongation 
• 
Grade 1 (450−480 ms):  no action required 
• 
Grade 2 (481−500 ms): 
First and second episodes:  Continue study medication 
and monitoring 
Third episode:  Decrease the current dose of alectinib by 
150 mg (1 capsule) BID (450 mg BID) 
• 
Grade 3 ( ≥ 501 ms on at least two separate ECGs): 
Temporarily interrupt alectinib and refer patient to a 
cardiologist 
First episode:  If improvement to Grade ≤ 1 or baseline, 
restart with a dose of alectinib decreased by 150 mg 
(1 capsule) BID (450 mg BID) 
Second episode:  If improvement to Grade ≤ 1 or baseline, 
restart with a dose of alectinib decreased by 150 mg 
(1 capsule) BID (300 mg BID) 
Third episode:  Permanently discontinue alectinib 
• 
Grade 4 (≥ 501 ms or > 60 ms change from baseline and 
Torsade de pointes or polymorphic ventricular tachycardia or 
signs/symptoms of serious arrhythmia): 
Discontinue alectinib permanently and admit patient into 
the hospital for monitoring 
Abnormal kidney function 
AEs 
Kidney function laboratory abnormalities are to be reported as AEs 
only if fulfilling the criteria listed in Section 5.3.5.4. 
• 
If, at any time during the study treatment, eGFR decreases 
by  > 50% of the baseline visit value, the patient has to be 
carefully monitored.  All of the underlying factors that may 
have acutely impacted serum creatinine levels need to be 
evaluated and corrected (e.g., dehydration, recent exposure 
to contrast media, increased amount of cooked meat in diet, 
concomitant medications affecting renal function as 
appropriate, etc.). 
• 
Any eGFR decrease by > 50% of the baseline visit value 
requires repeat testing. 
If, at the repeat test, the eGFR decrease is still > 50% of 
the baseline visit value, the treatment with alectinib should 
be interrupted. 
• 
Alectinib treatment may be resumed with caution if the 
eGFR value has increased to approximately the baseline 
visit value. 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
Muscular AEs and/or CPK 
elevations 
CPK laboratory abnormalities are to be reported as AEs only if 
fulfilling the criteria listed in Section 5.3.5.4. 
• 
Myopathy should be considered in any patient with diffuse 
myalgia, muscle tenderness or weakness, and/or marked 
elevations of CPK levels.  Patients should promptly report 
unexplained muscle pain, tenderness, or weakness, 
particularly if accompanied by malaise or fever.  CPK levels 
should be assessed in patients reporting these symptoms. 
• 
At the first occurrence of any of asymptomatic CPK values 
(> 10 × ULN, symptomatic CPK  > 5 × ULN, or in the presence of 
severe muscular symptoms with CPK > ULN but  ≤ 5 × ULN) at 
any time during the study treatment, the patient requires 
monitoring of the CPK values until they are normalized to 
pre-treatment levels or a reasonable explanation for the CPK 
elevation and the symptoms is established. 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
Other AEs (including 
bradycardia) or laboratory 
abnormalities: 
• 
Grade 3 or 4: 
Temporarily interrupt alectinib for a maximum of 3 weeks. 
If improvement to Grade ≤ 1 or baseline does not occur 
within 3 weeks, permanently discontinue alectinib. 
First episode:  If improvement to Grade ≤ 1 or baseline 
within 21 days, decrease the current dose of alectinib by 
150 mg (1 capsule) BID (450 mg BID).  
Second episode:  If improvement to Grade ≤ 1 or baseline 
within 21 days, decrease the current dose of alectinib by 
another 150 mg (1 capsule) BID (300 mg BID). 
Third episode:  Permanently discontinue alectinib. 
• 
Grade 2 (except any symptoms and signs that can be 
corrected with supportive care): 
Temporarily interrupt alectinib and resume if recovering to 
Grade ≤ 1 or baseline if clinically indicated. 
First episode:  If improvement to Grade ≤ 1 or baseline 
within 10 days, continue same dose of alectinib.  If 
improvement occurs after 10 days, decrease the current 
dose of alectinib by 150 mg (1 capsule) BID when 
resuming treatment (450 mg BID). 
Second episode:  If improvement to Grade ≤ 1 or baseline 
within 10 days, decrease the current dose of alectinib by 
150 mg (1 capsule) BID (450 mg BID or 300 mg BID if 
after first episode dose was reduced to 450 mg BID).  If 
improvement occurs after 10 days, decrease the current 
dose of alectinib by 300 mg (2 capsules) when resuming 
treatment (300 mg BID or 150 mg BID if after first episode 
dose was reduced to 450 mg BID). 
Third episode:  Permanently discontinue alectinib. 
• 
Grade 1:  no action required 
ANC = absolute neutrophil count; eGFR = estimated glomerular filtration rate.  
Note:  Diarrhea, nausea, and vomiting should be handled with best supportive care first before 
considering dose modification.  Preexisting pleural effusion will not be considered as an adverse 
event. 
 
 
5.1.4 
Safety of Crizotinib and Management of Adverse Events  
Dosing interruption and/or dose reduction may be required on the basis of individual 
safety and tolerability.  If dose reduction is necessary, then the dose of crizotinib should 
be reduced to 200 mg taken BID.  If further dose reduction is necessary, then the dose 
should be modified to 250 mg taken once daily on the basis of individual safety and 
tolerability (XALKORI® U.S. Package Insert; Crizotinib SmPC).  Dose reduction 
guidelines for hematologic and non-hematologic toxicities are provided in Table 3 and 
Table 4. 


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Table 3 
Crizotinib Dose Modification⎯Hematologic Toxicities (Except 
Lymphopenia) 
CTCAEa Grade 
Crizotinib Dosing 
Grade 3 
Withhold until recovery to Grade ≤ 2, then resume at 
the same dose schedule 
Grade 4 
Withhold until recovery to Grade ≤ 2, then resume at 
200 mg twice dailyb 
a National Cancer Institute Common Terminology Criteria for Adverse Events 
b In case of second episode, dosing should be withheld until recovery to Grade ≤ 2, then dosing 
should be resumed at 250 mg once daily.  Crizotinib must be permanently discontinued in case 
of a third episode of Grade 4 hematologic toxicity. 
 


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Table 4 
Crizotinib Dose Modification⎯Non-Hematologic Toxicities 
Criteria 
Crizotinib Dosing 
ALT or AST elevation  > 5 × ULN with total 
bilirubin  ≤ 1.5 × ULN 
Withhold until recovery to baseline or 
≤ 3 × ULN, then resume at reduced dose.  
Crizotinib must be permanently discontinued in 
case of recurrence. 
ALT or AST elevation > 3 × ULN with 
concurrent total bilirubin elevation  > 1.5 × ULN 
(in the absence of cholestasis or hemolysis) 
Permanently discontinue 
Any grade drug-related ILD/pneumonitis 
Permanently discontinue 
QTc 5> 500 ms on at least 2 separate ECGs 
Withhold until recovery to baseline or  < 481 
ms, then resume at reduced dose.  Crizotinib 
must be permanently discontinued in case of 
recurrence (i.e., QTc > 5.5 
500 ms on at least 2 separate ECGs). 
QTc > 500 ms or ≥ 60 ms change from baseline 
with torsade de pointes or polymorphic 
ventricular tachycardia or signs/symptoms of 
serious arrhythmia 
Permanently discontinue 
Bradycardia (heart rate < 60 bpm, symptomatic, 
may be severe and medically significant, 
medical intervention indicated) 
Withhold until recovery to asymptomatic 
bradycardia or to a heart rate ≥ 60 bpm.  
Evaluate concomitant medications known to 
cause bradycardia, as well as anti-hypertensive 
medications.  If a contributing concomitant 
medication is identified and discontinued, or its 
dose is adjusted, resume crizotinib at previous 
dose upon recovery to asymptomatic 
bradycardia or to a heart rate ≥ 60 bpm. 
If no contributing concomitant medication is 
identified, or if contributing concomitant 
medication is identified but not discontinued or 
its dose was not modified, resume crizotinib at 
reduced dose upon recovery to asymptomatic 
bradycardia or to a heart rate of ≥ 60 bpm. 
Bradycardia (heart rate < 60 bpm, 
life-threatening consequences, urgent 
intervention indicated) 
Permanently discontinue if no contributing 
concomitant medication is identified. 
If contributing concomitant medication is 
identified and discontinued, or its dose is 
adjusted, resume at 250 mg once daily upon 
recovery to asymptomatic bradycardia or to a 
heart rate of ≥ 60 bpm, with frequent 
monitoring.  
Crizotinib must be permanently discontinued in 
case of recurrence. 
a 
 


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Gastrointestinal events were commonly reported with crizotinib in clinical trials.  Nausea, 
diarrhea, vomiting, and constipation were the most commonly reported gastrointestinal 
events and were primarily Grade 1 in severity.  Supportive care for gastrointestinal 
events may include standard antiemetic and/or antidiarrheal or laxative medicinal 
products.  In clinical studies with crizotinib, events of gastrointestinal perforations were 
reported (XALKORI® U.S. Package Insert; Crizotinib SmPC). 
Blood counts and liver function tests including ALT, AST, and total bilirubin should be 
monitored as per local prescribing information for crizotinib. 
See local prescribing information for further crizotinib safety information. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
non-SAEs of special interest, performing protocol-specified safety laboratory 
assessments, measuring protocol-specified vital signs,and conducting other protocol-
specified tests that are deemed critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical occurrence in a clinical investigation where a patient is administered a 
pharmaceutical product, regardless of causal attribution.  An AE can therefore be any of 
the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition). 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as 
biopsies) 
 


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5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
An SAE is any AE that meets any of the following criteria: 
• 
Is fatal (i.e., the AE actually causes or leads to death) 
• 
Is life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death) 
This does not include any AE that had it occurred in a more severe form or was 
allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.9) 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an AE (e.g., rated as mild, moderate, or severe, or according to National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] criteria; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF. 
SAEs are required to be reported by the investigator to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2 for reporting 
instructions). 
5.2.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-SAEs of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  AEs of special interest for this study are the 
following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.6) 


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• 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs (see Section 5.2.1 for definition) 
are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Sections 5.4−5.6.  For each AE recorded 
on the Adverse Event eCRF, the investigator will make an assessment of seriousness 
(see Section 5.2.2 for seriousness criteria), severity (see Section 5.3.3), and causality 
(see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on AEs at each patient contact.  All AEs, whether 
reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
SAEs caused by a protocol-mandated intervention (e.g., invasive procedures such as 
biopsies, discontinuation of medications) should be reported (see Section 5.4.2 for 
instructions for reporting SAEs). 
After initiation of study drug, all AEs will be reported until 4 weeks after the last dose 
of study drug.  After this period, the investigator should report any SAEs that are 
believed to be related to study drug treatment (see Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient evaluation timepoints.  Examples of non-directive questions 
include the following: 
• 
"How have you felt since your last clinic visit?" 
• 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The AE severity grading scale for the NCI CTCAE (v4.0) will be used for assessing AE 
severity.  Table 5 will be used for assessing severity for AEs that are not specifically 
listed in the NCI CTCAE. 


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Table 5 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in the NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  On the basis of the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
AE is considered to be related to the study drug, indicating "yes" or "no" accordingly.  
The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
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5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology and concepts when recording AEs 
on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 
5.3.5.1 
Diagnosis Versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported AEs based on 
signs and symptoms should be nullified and replaced by one AE report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events that are Secondary to Other Events 
In general, AEs that are secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events.  A medically significant secondary AE that is separated in 
time from the initiating event should be recorded as an independent event on the 
Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation timepoints.  Such events should only be recorded once on the Adverse Event 
eCRF.  The initial severity (intensity or grade) of the event will be recorded at the time 
the event is first reported.  If a persistent AE becomes more severe, the most extreme 
severity should also be recorded on the Adverse Event eCRF.  If the event becomes 


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serious, it should be reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 
to "serious," providing the date that the event became serious, and completing all data 
fields related to SAEs. 
A recurrent AE is one that resolves between patient evaluation timepoints and 
subsequently recurs.  Each recurrence of an AE should be recorded as a separate event 
on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE.  A laboratory test result must be 
reported as an AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
Note: For oncology trials, certain abnormal values may not qualify as AEs. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5 times the ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the AE.  For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent AEs).  


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5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported 
as an AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment 
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded one on the Adverse Event eCRF (see Section 5.3.5.3 for details 
on recording persistent adverse events). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an AE the occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as an SAE or a non-SAE of special interest (see Section 5.4.2). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified AE reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of NSCLC should be recorded only on the Study 
Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and 


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immediately reported to the Sponsor (see Section 5.4.2).  An independent monitoring 
committee will monitor the frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. 
During survival follow-up, deaths attributed to progression of NSCLC should be recorded 
only on the Survival eCRF. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such 
events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., "more 
frequent headaches"). 
5.3.5.9 
Lack of Efficacy or Worsening of Non-Small Cell Lung Cancer 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs.  These data will be captured as 
efficacy assessment data only.  In most cases, the expected pattern of progression will 
be based on RECIST criteria v1.1 (Appendix 4).  In rare cases, the determination of 
clinical progression will be based on symptomatic deterioration.  However, every effort 
should be made to document progression using objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an AE. 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization (i.e., in-patient admission to a hospital) or 
prolonged hospitalization should be documented and reported as an SAE (per the 
definition of SAE in Section 5.2.2), except as outlined below. 


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The following hospitalization scenarios are not considered to be AEs: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
The patient has not experienced an AE. 
• 
Hospitalization due solely to progression of the underlying cancer 
 
5.3.5.11 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an AE, but it may result in an AE.  All AEs associated with an overdose or incorrect 
administration of study drug should be recorded on the Adverse Event eCRF.  If the 
associated AE fulfills seriousness criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.3.5.12 
Patient-Reported Outcome Data 
AE reports will not be derived from PRO data by the Sponsor, and safety analyses will 
not be performed using PRO data.  However, if any PRO responses suggestive of a 
possible AE are identified during site review of the PRO data, the investigator will 
determine whether the criteria for an AE have been met and, if so, will report the event 
on the Adverse Event eCRF. 
5.3.5.13 
Adverse Events in Individuals Not Enrolled in the Study 
If an AE inadvertently occurs in an individual not enrolled in the study, the Adverse Event 
Form provided to investigators should be completed and submitted to Roche or its 
designee, either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
SAEs 


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• 
Non-SAEs of special interest 
• 
Pregnancies 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting SAEs to the local 
health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor (Roche Medical Responsible) Contact Information 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk as 
well as Medical Monitor contact information will be distributed to all investigators. 
This list can be generated using contact numbers found at the following link: 
http://gcpcenter.roche.com/synergy/portal/view/pdq-spi/gcpcenter/34-64711453. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
5.4.2.1 
Events That Occur Prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported.  The Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to Roche or its designee immediately (i.e., no more than 
24 hours after learning of the event), either by faxing or by scanning and emailing the 
form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur After Study Drug Initiation 
After initiation of study drug, SAEs and non-SAEs of special interest will be reported until 
4 weeks after the last dose of study drug.  Investigators should record all case details 
that can be gathered immediately (i.e., within 24 hours after learning of the event) on the 
Adverse Event eCRF and submit the report via the electronic data capture (EDC) system.  


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A report will be generated and sent to Roche Safety Risk Management by the EDC 
system. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to Roche or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system. 
Instructions for reporting post-study AEs are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 3 months after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Roche Safety Risk Management.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any SAEs associated 
with the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF. 
In the event that the EDC system is unavailable, the Clinical Trial Pregnancy Reporting 
Form provided to investigators should be completed and submitted to Roche or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Once the EDC system is available, all information will 
need to be entered and submitted via the EDC system. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
3 months after the last dose of study drug.  A Pregnancy Report eCRF should be 
completed by the investigator immediately (i.e., no more than 24 hours after learning of 
the pregnancy) and submitted via the EDC system.  Attempts should be made to collect 
and report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  The pregnant partner will need to sign an Authorization 
for Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy.  Once the authorization has been signed, the investigator will update the 


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Pregnancy Report eCRF with additional information on the course and outcome of the 
pregnancy.  An investigator who is contacted by the male patient or his pregnant partner 
may provide information on the risks of the pregnancy and the possible effects on the 
fetus, to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 
5.4.3.3 
Abortions 
Any abortion should be classified as an SAE (as the Sponsor considers abortions to be 
medically significant), recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as an SAE, recorded on the Adverse Event eCRF, and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or 
the patient withdraws consent.  Every effort should be made to follow all SAEs considered 
to be related to study drug or trial-related procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.5.2 
Sponsor Follow-Up 
For SAEs, non-SAEs of special interest, and pregnancies, the Sponsor or a designee 
may follow up by telephone, fax, electronic mail, and/or a monitoring visit to obtain 
additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 


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5.6 
POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the investigator becomes aware of any SAE that 
occurs after the end of the AE reporting period (defined as 4 weeks after the last dose of 
study drug), if the event is believed to be related to study drug treatment.  
The investigator should report these events directly to Roche or its designee, either by 
faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all SAEs and non-SAEs of special interest against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators, IRBs, ECs, and applicable health authorities based on 
applicable legislation. 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference documents: 
• 
Alectinib Investigator's Brochure 
• 
Local prescribing information for crizotinib 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The primary analysis population for efficacy is the intent-to-treat (ITT) population defined 
as all randomized patients.  Patients will be assigned to the treatment group to which 
they were randomized. 
The primary analysis population for safety is the Safety Analysis Population (SAP) 
defined as all patients who received at least one dose of study medication.  Patients will 
be assigned to treatment groups as treated, and all patients who received any dose of 
alectinib will be included in the alectinib treatment arm. 
A secondary analysis population for efficacy and safety is the FISH Positive Population 
(FPP).  For efficacy, this is defined as all patients in the ITT population who were 
ALK-positive using the Vysis FISH assay.  Patients will be assigned to the treatment 
group to which they were randomized.  For safety, this is defined as all patients in the 


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SAP who were ALK-positive using the Vysis FISH assay.  Patients will be assigned to 
treatment groups as treated.  This analysis population will be used to perform a 
supportive analysis of the study data based on the Vysis FISH assay rather than the 
Ventana IHC.  This population may be used for registration purposes in the unlikely 
event of registrational failure of the Ventana IHC companion diagnostic, in which case all 
analyses will be based on this population and the same prespecified testing strategy of 
secondary endpoints defined in Section 6.4.2 will be applied. 
The final analysis of the primary endpoint of PFS will occur when 170 PFS events have 
occurred, on the basis of the investigators’ assessments.  On the basis of the 
assumptions outlined in Section 6.1, this is estimated to occur approximately 33 months 
after the first patient has been enrolled.  A survival follow-up analysis will be performed 
once approximately 50% of patients (i.e., 143 patients) have died, which is estimated to 
occur approximately 42 months after the first patient has been enrolled. 
Hypothesis tests will be two-sided with a significance level of 5% unless otherwise 
indicated. 
The baseline value of any variable will be defined as the last available value recorded 
prior to the first administration of alectinib or crizotinib. 
Further details of all analyses will be provided in the Statistical Analysis Plan. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The focus of this clinical trial is hypothesis testing (Section 6.4.1), and the primary 
endpoint of PFS was used to determine the sample size of the study. 
At the time of initially writing the protocol, there were no Phase III data available on 
crizotinib in the first-line setting in ALK-positive patients.  The median PFS for crizotinib 
administered as second-line therapy from the global randomized Phase III PROFILE 
1007 study was 7.7 months (95% CI: 6.0%, 8.8%).  From the Phase II single arm study 
of patients who had received ≥ 1 line of chemotherapy (with 85% patients having 
received ≥ 2 prior chemotherapy regimens), the median PFS was 8.5 months (95% CI: 
6.2%, 9.9%).  The Phase III PROFILE 1014 study of crizotinib versus standard 
pemetrexed-platinum-based chemotherapy in previously untreated patients with ALK-
positive non-squamous NSCLC reported a median PFS of 10.9 months for crizotinib 
(Mok et al. 2014). 
Thus, an initial assumption of median PFS of 9.8 months for the crizotinib arm has been 
reassessed based on data from the Phase III study PROFILE 1014 to 10.9 months.  A 
HR of 0.65 for alectinib versus crizotinib (i.e., an increase from 10.9 months median PFS 
to 16.8 months) will be targeted. 


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In this study, 286 patients will be enrolled in a 1:1 randomization allocation.  Enrollment 
will take approximately 24 months on the basis of an assumption of non-linear 
recruitment as follows: 
• 
Month 1:  1 patient per month 
• 
Month 2:  2 patients per month 
• 
Month 3:  4 patients per month 
• 
Month 4:  6 patients per month 
• 
Month 5:  8 patients per month 
• 
Month 6:  10 patients per month 
• 
Month 7:  12 patients per month 
• 
Months 8−12:  13 patients per month 
• 
Months 13−14:  14 patients per month 
• 
Month 15 onwards:  15 patients per month 
 
A total of 170 PFS events are required to achieve 80% power at a two-sided alpha level 
of 5%.  This number of PFS events is estimated to occur approximately 33 months after 
the first patient has been enrolled. 
No interim analysis for efficacy or futility is planned. 
A survival follow-up analysis will be performed once approximately 50% of patients 
(i.e., 143 patients) have died.  The median OS in the crizotinib arm is assumed to be 
24 months, and the expected median OS in the alectinib treatment arm is 30 months, 
equating to an HR of 0.83.  On the basis of the sample size (N = 286), the trial will not be 
powered to demonstrate any statistically significant difference in OS of this magnitude.  
At the time of the final analysis of the primary endpoint of PFS, on the basis of the above 
assumptions, 106 OS events are expected to have occurred.  The survival follow-up 
analysis is expected to occur approximately 42 months after the first patient has been 
enrolled. 
A follow-up analysis will be performed based on the FPP.  This will occur once 170 PFS 
events have occurred in the FPP to ensure 80% power of the log-rank test assuming a 
hazard ratio of 0.65 in this sub-population.  Based on a potential discrepancy/technical 
failure rate of 10% between the Ventana IHC assay and the Vysis FISH assay, 
257 patients would be eligible for the FPP analysis, which is estimated to occur 
approximately 35 months after the first patient has been enrolled (i.e., 2 months after the 
primary IHC analysis) based on the above assumptions. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Study enrollment, study treatment administration, reasons for discontinuation from study 
treatment, and reasons for study termination will be summarized by treatment arm for all 


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randomized patients.  Violations of inclusion and exclusion criteria, on the basis of 
information captured on the eCRF, will be reported and summarized by treatment arm. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Summaries of treatment group comparability will be based on the ITT population. 
Demographic, baseline disease characteristics and lung cancer history will be 
summarized by treatment arm for all randomized patients, including the randomization 
stratification factors.  Descriptive baseline summaries of continuous data will present the 
group mean, standard deviation, median, minimum, and maximum.  Descriptive 
summaries of discrete data will present the category counts as frequency and 
percentages. 
Previous and concomitant cancer therapy will also be summarized, as well as 
anti-cancer subsequent therapy.  Previous and concurrent diseases and medications will 
also be summarized. 
6.4 
EFFICACY ANALYSES 
The primary population for all primary and secondary efficacy analyses will be the ITT 
population. 
6.4.1 
Primary Efficacy Endpoint 
PFS is defined as the time from date of randomization to the date of first documented 
disease progression or death, whichever occurs first.  The primary endpoint of PFS will 
be determined on the basis of investigator assessment of progression using 
RECIST v1.1.  Patients who have not experienced disease progression or death at the 
time of analysis will be censored at the last tumor assessment date either during study 
treatment or during follow-up.  Patients with no post-baseline tumor assessment will be 
censored at the date of randomization. 
Patients who discontinue treatment prior to disease progression (e.g., due to toxicity) will 
continue on study and will be followed until disease progression and for OS regardless 
of whether they subsequently receive anti-cancer therapy. 
The treatment comparison of PFS will be based on a stratified log-rank test at the 5% 
level of significance (two-sided).  The stratification factors are the randomization 
stratification factors:  ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS 
metastases at baseline (yes vs. no), as recorded on the eCRF.  Results from an 
unstratified log-rank test will also be presented. 
The Kaplan-Meier method will be used to estimate the median PFS for each treatment 
arm with 95% confidence limits, and a Kaplan-Meier curve will be constructed to provide 
a visual description of the difference between the treatment arms.  A stratified Cox 
proportional regression model will be used including treatment in order to provide an 


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estimate of the treatment effect expressed as a HR (alectinib vs. crizotinib), as well as a 
95% CI. 
The difference between the two treatment groups will be assessed and tested for the 
following hypothesis:  the survival distribution function (SDF) of the alectinib treatment 
group is the same as for the crizotinib treatment group versus the alternative that the two 
distributions are different:  
H0:  SDF (alectinib) = SDF (crizotinib) 
versus 
H1:  SDF (alectinib) ≠ SDF (crizotinib) 
where SDF denotes the survival distribution function of the parameter PFS. 
6.4.2 
Secondary Efficacy Endpoints 
If the primary endpoint of PFS is statistically significant at a two-sided 5% significance 
level, the following secondary endpoints will be tested in the following sequential order, 
each at a two-sided 5% significance level: 
• 
PFS by IRC 
• 
Time to CNS progression 
• 
ORR 
• 
OS 
 
PFS by IRC 
An analysis of PFS on the basis of the IRC assessments will be performed using the 
same methodology as specified for PFS on the basis of investigator assessment. 
Time to CNS Progression 
Time to CNS progression is defined as the time from randomization until radiographic 
evidence of CNS progression.  An independent central radiological review will be 
performed for all patients, and the analysis of CNS progression or response will be on 
the basis of the data from the independent review.  All patients will be included in the 
analysis regardless of their baseline status of CNS metastases.  CNS progression is 
defined as progression due to newly developed CNS lesions and/or progression of 
preexisting baseline CNS lesions.  On the basis of RECIST v1.1, this is defined as a new 
post-baseline CNS/brain lesion(s) and/or an increase of ≥ 20% in the sum of longest 
diameters of the measurable baseline CNS lesions compared to nadir and/or 
unequivocal progression of non-measurable baseline CNS lesions. 
In order to account for the competing risks inherent in such an analysis, HRs, including 
statistical inference on the basis of a two-sided log-rank test, to compare the risk of CNS 
progression between the alectinib and crizotinib treatment groups, will be computed on 
the basis of cause-specific hazard functions. 


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The probability of CNS progression, non-CNS progression, and death will each be 
estimated using cumulative incidence functions. 
For descriptive purposes, estimates of the CNS progression rates over time with 
95% CIs on the basis of cumulative incidence functions will be presented.  A Gray’s test 
to compare the risk of CNS progression between alectinib and crizotinib will also be 
performed as a supportive analysis. 
An exploratory analysis of CNS Time to Progression on the basis of RANO criteria will 
also be performed on the basis of the IRC assessments. 
In the subgroup of patients with measurable CNS lesions at baseline, an exploratory 
analysis of C-ORR defined as the percentage of patients who achieve a best overall 
response of CR or PR (defined by RECIST v1.1 as a 30% decrease in the sum of 
longest diameters of measurable CNS lesions referencing baseline) will also be 
performed.  Duration of CNS response will be listed and may be analyzed if there are a 
sufficient number of CNS responses.  An exploratory analysis of these endpoints will 
also be performed on the basis of RANO criteria assessed by the IRC. 
Objective Response Rate 
ORR, on the basis of investigator assessment, is defined as the percentage of patients 
who attain a CR or PR.  Per RECIST v1.1, confirmation of objective response is not 
required for this secondary endpoint.  Patients without a post-baseline tumor 
assessment will be considered non-responders, as will patients with a best overall 
response of stable disease (SD), PD, or NE (not evaluable). 
An estimate of ORR and its two-sided 95% CI will be calculated using the 
Clopper-Pearson method for each treatment arm.  Response rates in the treatment 
groups will be compared using a stratified Mantel-Haenszel test on the basis of the 
randomization stratification factors.  The difference in ORR between the two treatment 
arms will be presented together with a two-sided 95% CI on the basis of a normal 
approximation to the binomial distribution. 
DOR 
For patients who have experienced an objective response (CR or PR) during the study 
as assessed by the investigator, DOR is defined as the duration from the first tumor 
assessment that supports the patient’s objective response (CR or PR, whichever is first 
recorded) to first documented disease progression or death due to any causes, 
whichever occurred first.  Patients who have not progressed or died at the time of 
analysis will be censored at the last tumor assessment date.  Because the determination 
of DOR is based on a non-randomized subset of patients, formal hypothesis testing will 
not be performed.  DOR will be estimated using Kaplan-Meier methodology and a HR on 
the basis of a Cox proportional regression model will be calculated. 


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Overall Survival 
OS is defined as the time from the date of randomization to the date of death due to any 
cause.  Patients who are not reported as having died at the time of analysis will be 
censored at the date when they were last known to be alive.  Patients who do not have 
post-baseline information will be censored at the date of randomization.  OS will be 
analyzed using the same methodology as specified for the primary endpoint.  A survival 
follow-up will be performed based on more mature data. 
6.4.2.1 
Sensitivity Analyses 
The following sensitivity analyses will be performed on the primary endpoint of PFS: 
• 
The effect of non−protocol-specified anti-cancer therapy prior to progression will be 
assessed by censoring patients at the last adequate tumor assessment prior to the 
start of non−protocol-specified anti-cancer therapy. 
• 
The effect of missing tumor assessments will be assessed if the number of missing 
assessments in either arm is > 5%.  For patients with progression determined 
following one or more missing tumor assessments, the progression will be 
backdated to the first missing tumor assessment. 
• 
The effect of loss to follow-up will be assessed depending on the number of patients 
who are lost to follow-up.  If > 5% of patients are lost to follow-up for PFS in either 
treatment arm, a “worst-case” analysis will be performed in which patients who are 
lost to follow-up will be considered to have progressed at the last date they were 
known to be progression-free. 
 
6.4.2.2 
Subgroup Analyses 
Subgroup analyses of PFS will be performed for patients with baseline CNS metastases 
and for patients without baseline CNS metastases.  In addition, a subgroup analysis of 
Time to CNS Progression will be performed, excluding patients who had pre-treatment 
radiation therapy for CNS lesions. 
All other subgroup analyses will be specified in the SAP. 
6.5 
SAFETY ANALYSES 
The primary population for all safety analyses will be the SAP as defined in Section 6. 
All safety parameters will be summarized in tables to evaluate and compare the safety 
profile of patients treated with alectinib versus crizotinib in terms of: 
• 
Adverse events including adverse events leading to dose modifications or 
interruptions, study drug withdrawal, and death  
• 
Severe, serious, and selected adverse events 
• 
Deaths 
• 
Laboratory parameters and abnormalities 
• 
Vital signs 


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• 
ECGs 
• 
ECOG PS 
 
Adverse events will be coded using MedDRA and summarized by mapped term and 
appropriate thesaurus level.  All adverse events and routine laboratory parameters will 
be assessed according to the NCI CTCAE v4.0 grading system.  For adverse events, the 
most extreme severity will be used for reporting.  Adverse events will be described by 
individual listings and by body system, as well as by severity.  In tables showing the 
overall incidence of adverse events, patients who experienced the same event on more 
than one occasion are counted only once in the calculation of the event frequency. 
Laboratory values will be summarized by treatment arm including summary tables for the 
shifts in grades from baseline to the worst grade observed during treatment.  In order to 
evaluate and compare hypogonadism in the two treatment arms, testosterone levels in 
the blood will be summarized for males by treatment arm over time (for details, see 
Section 6.8). 
Descriptive summary tables of change from baseline over time will be provided for vital 
signs and descriptive statistics will be tabulated for ECOG PS.  ECG findings over time 
will be summarized. 
Study drug administration will be summarized by duration and cumulative dose.  In 
addition, treatment exposure will be summarized including the number of doses received, 
dose intensity, and the percentage of planned dose. 
Subgroup analyses will be performed to evaluate the safety profile within the subgroups 
of patients including by sex, age (< 65 vs. ≥ 65 years), and race (non-Asian vs. Asian). 
An IDMC will review the safety data collected during the conduct of the study.  Safety 
monitoring will be performed periodically.  Further details will be outlined in the IDMC 
Charter. 
6.6 
PHARMACOKINETIC ANALYSES 
Standard NCA may be conducted for PK data collected from patients participating in 
serial/intensive PK collections for relevant analytes, as data allow, as appropriate, and if 
needed.  PK parameters, including but not limited to AUC, maximum concentration 
(Cmax), and time to maximum concentration (Tmax), will be calculated on the basis of the 
available data as appropriate and where data allow.  Additional PK parameters may be 
calculated as deemed appropriate. 
Individual and mean plasma concentrations at each sampling timepoint and/or PK 
parameters for alectinib and metabolite(s) will be listed, as appropriate. 


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Summary statistics (e.g., means, standard deviation, coefficient of variation %, 
geometric means, medians and ranges) for plasma concentrations and/or PK 
parameters for alectinib and metabolite(s) will be presented by treatment and nominal 
collection times (plasma concentrations only), as appropriate.  Additional plots or 
summary statistics may be constructed or calculated, as appropriate. 
Results of PK and/or any PK/pharmacodynamic analyses may be reported outside the 
clinical study report. 
Nonlinear mixed-effects modeling (with software NONMEM) (Beal et al. 1999) will be 
used to analyze the sparse and/or serial/intensive plasma concentration-time data for 
alectinib.  The PK data from this study may be pooled with data from other studies.  
Population and individual PK parameters will be estimated and the influence of various 
covariates (such as age, gender, and body weight) on these parameters will be 
investigated. 
Exploratory analyses will be conducted to investigate the relationship between alectinib 
PK exposure and efficacy/safety parameters. 
Details of the mixed-effects modeling and exploratory analyses will be reported in a 
document separate from the clinical study report. 
6.7 
PATIENT-REPORTED OUTCOME ANALYSES 
The following PRO endpoints will be analyzed and PRO data will be presented 
separately from adverse event data. 
6.7.1 
Time to Deterioration of Patient-Reported Lung Cancer 
Symptoms 
TTD from baseline will be assessed at every study visit (Week 4, Week 8, and then after 
every 4 weeks) until disease progression and during post-progression on treatment in 
case of isolated, asymptomatic CNS progression; at post-treatment Visit (4 weeks after 
permanent treatment discontinuation); and at subsequent 8-weekly survival follow-up 
visits for 6 months, for the following lung cancer symptoms: cough (Question 31 on the 
QLQ-LC13), dyspnea single item (Question 8 on the QLQ-C30), dyspnea multi-item 
subscale (Questions 33-35 on the QLQ-LC13), chest pain (Question 40 on the 
QLQ-LC13), arm/shoulder pain (Question 41 on the QLQ-LC13) and fatigue multi-item 
subscale (Questions 10, 12, and 18 on the QLQ-C30) for patients in each arm.  
Completion and compliance rates will be summarized at each timepoint by treatment 
arm with reasons for missing data.  TTD will be analyzed for the ITT population.  If a 
baseline or post-baseline PRO evaluation is not available, TTD will be censored at the 
date of randomization. If they have not deteriorated, patients will be censored at the last 
time when they completed an assessment for cough, dyspnea (single item), dyspnea 
(subscale items), chest pain, arm/shoulder pain, and fatigue. 


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6.7.2 
Additional Patient-Reported Outcomes 
PROs of HRQoL, lung cancer−related symptoms, and health status will be measured 
using the EORTC QLQ-C30 and EORTC QLQ-LC13. 
Summary statistics (mean, standard deviation, median, and range) of linear transformed 
scores will be reported for all the items and subscales of the EORTC 
QLQ-C30  questionnaire, and the QLQ-LC13 according to the EORTC scoring manual 
guidelines.  Completion and compliance rates will be summarized at each timepoint by 
treatment arm with reasons for missing data.  Only patients with a baseline assessment 
and at least one post-treatment assessment will be included in the analyses. 
6.8 
EXPLORATORY ANALYSES 
The EQ-5D-3L is a generic PRO instrument that is used for across diseases and 
indications cost-effectiveness analyses.  This instrument quantifies the QoL of various 
health outcomes and is applicable to a wide range of health states.  Analyses of this 
outcome will be exploratory and will generate utility scores for use in economic models 
for reimbursement purposes only.  The PRO will be administered every 4 weeks until 
disease progression and during post-progression on treatment in case of isolated, 
asymptomatic CNS progression; at the post-treatment visit (4 weeks after permanent 
treatment discontinuation); and every follow-up visit (every 8 weeks) after post-treatment 
visit for 6 months (see Appendix 1).  
It has been reported that crizotinib therapy triggers rapid suppression of testosterone 
levels in men causing rapid-onset hypogonadism.  It is unknown if reductions in 
testosterone reflect an effect of crizotinib on ALK or on some combination of the drug’s 
targets (i.e., c-MET) (Weickhardt et al. 2012; Weickhardt et al. 2013).  Total testosterone 
and free testosterone levels (either by direct measurement or by calculation using 
albumin, and sex hormone-binding globulin (SHBG) calculator: 
(http://www.issam.ch/freetesto.htm) and FSH and LH levels in blood will be measured 
(see Appendix 1) in male patients enrolled in the study for exploratory analysis of an 
onset of hypogonadism.  The recommended time of day to have a blood sample taken 
for this test is between 7 a.m. and 10 a.m. 
The Abbott Vysis FISH test will be used as an exploratory assay after patients have 
been enrolled in this study.  Results from these analyses will be used to quantify the 
degree of correlation between Vysis FISH and Ventana IHC for the detection of 
ALK-positive NSCLC.  The FPP will be a secondary analysis population for efficacy and 
safety.  This analysis population will be used to perform a supportive analysis of the 
study data based on the Vysis FISH assay rather than the Ventana IHC.  This population 
may be used for registration purposes in the unlikely event of registrational failure of the 
Ventana IHC companion diagnostic, in which case all analyses will be based on this 
population. 


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ALK plasma assays (PCR and /or sequencing) will be used as exploratory assays for 
ALK positive and consented ALK negative patients.  Results from these analyses will be 
used to quantify the degree of correlation between ALK plasma tests and Ventana IHC 
and Vysis FISH for the detection of ALK positive NSCLC.  The ALK plasma assay 
population may be used for exploratory efficacy and safety analysis.  This analysis 
population will be used to support diagnostic development.  Assays from this 
population may be used for the registration of a plasma assay as a companion diagnostic. 
This analysis will be dependent on the successful technical development of a plasma 
ALK assay.  Results of exploratory analyses on post-progression tumor samples to 
measure molecular mechanisms of resistance to ALK inhibitors and plasma samples to 
measure ALK rearrangements in circulating tumor cells will be communicated outside 
the main study report. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC using eCRFs.  
Sites will be responsible for data entry into the EDC system.  In the event of discrepant 
data, the Sponsor will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data. Central laboratory data or other electronic 
data will be sent directly to the Sponsor, using the Sponsor’s standard procedures to 
handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
ePRO data will be collected through use of an electronic device provided by an ePRO 
vendor.  The device is designed for entry of data in a way that is attributable, secure, 
and accurate, in compliance with the FDA regulations for electronic records (21 CFR 
Part 11).  The ePRO device data are available for view access only via secure access to 
a web server.  Only identified and trained users may view the data, and their actions 
become part of the audit trail.  The Sponsor will have view access only.  System 
backups for data stored by the Sponsor and records retention for the study data will be 
consistent with the Sponsor’s standard procedures. 


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7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
Patients will use an ePRO device to capture PRO data.  The data will be transmitted via 
pre-specified transmission method (e.g., web or wireless) automatically after entry to a 
centralized database at the ePRO vendor.  The data can be reviewed by site staff via 
secure access to a web server. 
Once the study is complete, the ePRO data, audit trail, and trial and system 
documentation will be archived.  The investigator will receive patient data for the site in 
both human- and machine-readable formats on an archival-quality compact disc that 
must be kept with the study records as source data.  Acknowledgement of receipt of the 
compact disc is required. In addition, the Sponsor will receive all patient data in a 
machine-readable format on a compact disc. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 


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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a United States 
IND application will comply with FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the European Union or European Economic Area will comply 
with the EU Clinical Trial Directive (2001/20/EC). 


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8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/EC−approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient before his or her 
participation in the study.  The case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC−approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 


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separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  In 
addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 


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8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, which includes an audit trail containing a complete record of all changes 
to data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
Steering Committee is established to provide the study Sponsor with recommendations 
related to any aspect of the trial, specifically study design, data interpretation, 
exploratory analyses, or alternate changes to the trial that may assist in patient accrual, 
data collection, analysis, and interpretation of the study results.  The Sponsor is 
ultimately responsible for all decisions regarding the study. 
The test for the study inclusion criteria of ALK-positive NSCLC will be performed at 
Sponsor’s designated central laboratories and assessed by Ventana IHC test. 
An IDMC will be established to monitor the progress of the study and ensure that the 
safety of patients enrolled in the study is not compromised.  Details of the composition, 
roles, and responsibilities, and processes of the IDMC are documented in a separate 
IDMC charter.  The IDMC will review safety data and can make recommendations to the 


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Sponsor to stop or amend the study on the basis of safety findings.  The frequency of 
these reviews as well as the data to be reviewed will be agreed with the IDMC and 
outlined in the separate IDMC charter.  No stopping for early proof of efficacy will result 
from any of these regular safety reviews.  IDMC review meetings will be held in a blinded 
manner to the Sponsor. 
An IRC will review the tumor assessments to determine the secondary endpoints of the 
overall disease PFS and time to CNS progression, both on the basis of RECIST v1.1.  In 
addition to the secondary endpoint of time to CNS progression together with C-ORR, 
C-DOR, and CNS progression rate at 6, 12, 18, and 24 months, an IRC will review the 
tumor assessments on the basis of RANO criteria. 
The independent review of MRI and CT scans will NOT determine either eligibility OR 
patient treatment.  All treatment decisions will be made by the investigator using local 
assessments. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 


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Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


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Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for 
high-grade gliomas: response assessment in Neuro-Oncology Working Group. J 
Clin Oncol 2010;28:1963−72. 
Wong DWS, Leung ELH, So KKT, et al. The EML4-ALK fusion gene is involved in 
various histologic types of lung cancers from nonsmokers with wild-type EGFR and 
KRAS. Cancer 2009;115:1723−33. 
XALKORI® U.S. Package Insert, Pfizer Inc. 2012 [cited 2014 Jan 20]. Available from: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202570s002lbl.pdf. 
 


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Appendix 1  
Schedule of Assessments 
Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) Until 
PD, Death, or 
Withdrawal 
from Study 
prior to PD 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation) 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D)  
Informed consent 
x 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
Pregnancy testa 
 
x 
To be repeated as necessary 
 
 
 
Physical 
examinationb 
x 
 
x 
x 
x 
x 
x 
 
 
Vital signs 
x 
 
x 
x 
x 
x 
x 
 
 
ECOG PS 
x 
 
x 
x 
x 
x 
x 
 
 
ECGc 
x 
 
xd 
x 
 
x 
 
 
 
Hematology, 
Coagulation 
x 
 
xd 
x 
x 
x 
x 
 
 
Biochemistry 
x 
 
xd 
x 
x 
x 
x 
 
 
Urinalysis 
x 
 
xd 
x 
x 
x 
x 
 
 


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Protocol BO28984, Version 3 
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Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) Until 
PD, Death, or 
Withdrawal 
from Study 
prior to PD 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation) 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D)  
Concomitant 
medications 
x 
 
x 
x 
x 
x 
x 
 
 


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Schedule of Assessments (cont.) 
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Protocol BO28984, Version 3 
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Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) Until 
PD, Death, or 
Withdrawal 
from Study 
prior to PD 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation) 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D)  
Mandatory tumor 
sample for ALK 
testinge 
x 
 
 
 
 
 
 
 
 
Optional plasma 
sample from 
centrally confirmed 
ALK negative 
patients 
(20 ml of blood) 
x 
 
 
 
 
 
 
 
 
Optional tumor 
sample 
 
 
xf 
 
 
xg 
xg 
 
 
Plasma sample for 
ALK fusion 
detection in nucleic 
acids (20 mL of 
blood) 
 
 
xh 
 
 
 
 
 
 


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Protocol BO28984, Version 3 
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Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) Until 
PD, Death, or 
Withdrawal 
from Study 
prior to PD 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation) 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D)  
Plasma for 
detection of ALK 
mutation status 
(20 mL of blood) 
 
 
x 
 
 
xi 
xi 
 
 


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Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) Until 
PD, Death, or 
Withdrawal 
from Study 
prior to PD 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation) 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D)  
Blood sample for 
pharmacogenomics 
research at pre-
dose (3 mL of 
blood) j 
 
 
x 
 
 
 
 
 
 
Tumor 
assessmentk 
xl 
 
xl 
 
x 
xm 
x 
xn 
 
MRI scan of the 
brain 
xl 
 
xl 
 
x 
xm 
x 
xn 
 
PK samples (2 mL 
blood)o 
 
 
x 
x 
x 
x 
 
 
 
PRO (EORTC 
QLQ-C30/LC13); 
EQ-5Dp 
 
 
x 
x 
x 
x 
x 
x 
xq 


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Protocol BO28984, Version 3 
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Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) Until 
PD, Death, or 
Withdrawal 
from Study 
prior to PD 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation) 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D)  
Total testosterone, 
(either by direct 
measurement or by 
calculation using 
albumin, and 
SHBG), FSH, and 
LHr 
 
 
x 
x 
x 
x 
 
 
 
Adverse eventss 
x 
x 
x 
x 
x 
x 
x 
x 
 
Subsequent 
therapy for NSCLC 
 
 
 
 
 
 
x 
x 
xq 
Drug dispensing 
and accountabilityt 
 
 
x 
x 
x 
x 
x 
x (accountability 
only) 
 
Blood Sample for 
Roche Clinical 
Repository (10 mL) 
 
 
x 
 
 
 
 
 
 
ALK = anaplastic lymphoma kinase; ALP = alkaline phosphatase;  CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse 
Events; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30 = European Organization for the Research and 


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Schedule of Assessments (cont.) 
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Protocol BO28984, Version 3 
125 
Treatment of Cancer Quality of Life Questionnaire−Core; EQ-5D = EuroQoL 5 Dimension; FSH = follicle-stimulating hormone; LH = luteinizing 
hormone; MRI = magnetic resonance imaging; NCI = National Cancer Institute; NSCLC = non−small cell lung cancer; PD = progressive disease; 
PK = pharmacokinetic; PRO = patient-reported outcome; ULN = upper limit of normal. 
Notes: First dose of study drug to be taken as soon as patient has been randomized and appropriate drug has been provided–within ≤ 24 hours.  
Post-baseline assessments are to be performed within ± 1 week for the first two 4 weekly and subsequent 8 weekly assessments. 
a Urine or serum, to be repeated as necessary. 
b Including an ophthalmologic examination if clinically indicated. 
c At screening, Visit 0 (baseline), Visit 1 (Week 4), Visit 4 (Week 24), Visit 8 (Week 56), last treatment visit, and as clinically indicated throughout 
the study. 
d Screening laboratory assessment done within 3 days can be counted as the baseline assessment. 
e Preferably blocks fixed in neutral buffered formalin; if blocks are not available, a minimum of 10 to 15 unstained 5-µm slides are required.  Tumor 
ALK status will be assessed by central laboratory before randomization. 
f Optional tumor sample could be taken from the tumor block obtained at screening. 
g At the time of disease progression from progressive lesions. 
h Mandatory blood sample (20 mL) for detection of ALK rearrangements in nucleic acids in plasma collected at baseline only. 
i Blood sample (20 mL) to obtain plasma for exploratory biomarkers will be collected at Visit 0 (baseline), during the study every second visit (i.e., 
every 16 weeks) until disease progression and during post-progression on treatment in case of isolated, asymptomatic CNS progression. 
j This sample is required in all patients in alectinib arm, and in those patients in the crizotinib arm who wish to participate in optional genomics 
sequencing. 
k Tumor assessment consists at minimum of a CT/MRI scan of chest and abdomen (for imaging of liver and adrenal glands).  Patients who are 
known to have bone metastasis or who display clinical or laboratory signs (e.g., serum ALP >1.5 × ULN) of bone metastasis should undergo 
radionuclide bone scan.  Clinical lesions should be assessed with caliper measurement and documented by color photography, including a 
ruler to estimate the size of the lesion. Post-baseline assessments are to be performed within ±1 week for the 8 weekly assessments.  If there is 
suspicion of disease progression on the basis of clinical or laboratory findings, a tumor assessment should be performed as soon as possible 
before the next scheduled evaluation. 
l Screening tumor assessment done within 14 days will be counted as the baseline assessment. 
m Tumor assessment can be performed whenever clinically indicated.  Brain assessment scans should be performed at every systemic imaging 
tumor assessment.  Tumor assessment should continue until disease progression if a patient discontinues treatment prior to PD, regardless of 


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Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 3 
126 
whether they subsequently receive non-study, anti-cancer therapy (a use of subsequent non-study, anti-cancer therapy prior to disease 
progression would be considered a protocol violation).  
n If treatment was permanently discontinued due to disease progression. 
o Pre-dose PK (2 mL) sampling for all patients on alectinib treatment will be performed at each visit during the treatment period and at the final 
study visit.  The pre-dose PK samples should be taken immediately before (within 2 hours) intake of study medication at all study visits. Remind 
the patient not to take a daily dose at home on the day of scheduled study visit.  For a subset of patients on alectinib treatment (10%−15%, or at 
least approximately n = 20) participating in serial/intensive PK sample collection, additional PK will be collected on Visits 0 (baseline) and 1 
(Week 4) at pre-dose (within 2 hours before intake of study medication), 1, 2, 4, 6, and 8 hours post-dose. 
p PRO questionnaires are to be completed every 4 weeks until disease progression and during post-progression on treatment in case of isolated, 
asymptomatic CNS progression; at the post-treatment visit (4 weeks after permanent treatment discontinuation); and every follow up visit (every 
8 weeks) after post-treatment visit for 6 months..  Further guidelines on PRO questionnaire administration will be provided in the study manual. 
q Performed every 8 weeks after post-treatment visit during the first 6 months and then every 12 weeks or performed as appropriate.  The PRO 
assessments should be performed during the first 6 months.  For patients who discontinue treatment for reasons other than disease progression 
and who progress within the first 6 months of survival follow-up, PRO measures will be administered every 4 weeks until disease progression 
and then decreased to every 8 weeks until 6 months post treatment. For patients who discontinue treatment for reasons other than disease 
progression and have not yet progressed at 6 months post treatment, PRO measures will be administered every 4 weeks until disease 
progression and will no longer be required thereafter.  
r Male patients only, using institutional standard assay. The recommended time of day to have a blood sample taken for this test is between 7 a.m. 
and 10 a.m.  Albumin and SHBG measurements are not required when a direct assessment of free testosterone is available.  If free testosterone 
level cannot be directly assessed, it will be calculated from albumin and SHBG using a free testosterone calculator: 
http://www.issam.ch/freetesto.htm. 
s Graded according to NCI CTCAE (version 4.0).  Serious adverse events collection must start from first study-specific procedure. 
t For details on drug dispensing and accountability, see Section 4.3.3. 
 
 


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Appendix 2  
Schedule of Alectinib Pharmacokinetic Assessments 
Visit 
Timepoint 
Visit 0 (baseline) 
Pre-dose (within 2 hours before intake of alectinib)
Visit 1 (Week 4) 
Pre-dose (within 2 hours before intake of alectinib)
Visit 2 (Week 8) 
Pre-dose (within 2 hours before intake of alectinib)
All subsequent visits (every 
8 weeks) until PD or 
death/withdrawal from study prior to 
PD 
Pre-dose (within 2 hours before intake of alectinib)
Visit 0 (baseline) and Visit 1 
(Week 4)a 
Pre-dose (within 2 hours before intake of 
alectinib), 1, 2, 4, 6, and 8 hours post-dose 
PD = progressive disease; PK = Pharmacokinetic 
a For patients participating in the serial/intensive PK sample collection only. 


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Appendix 3  
List of Substrates, Inhibitors, and Inducers of Drug-Metabolizing 
Enzymes and Transporters 
This representative list is not intended to be an exhaustive list.  Each patient’s 
concomitant medications should be carefully considered by the investigator with regard 
to the risk-benefit for the particular patient and appropriate monitoring, including any 
concomitant medication, dose adjustment, or therapeutic alternatives, which should be 
determined by the investigator caring for the patient. 
CYP3A Inducers 
CYP3A Potent Inhibitors 
avasimibe, aminoglutethimide, barbiturates, 
carbamazepine, dexamethasone, efavirenz, 
ethosuximide, garlic supplements, 
glucocorticoids, glutethimide, griseofulvin, 
modafinil, nafcillin, nevirapine, oxcarbazepine, 
phenobarbital, phenytoin, pioglitazone, 
primidone, rifabutin, rifampin, rifapentine, St. 
John’s wort, troglitazone 
aprepitant, atazanavir, boceprevir, 
ciprofloxacin, clarithromycin, conivaptan, 
diltiazem, erythromycin, fluconazole, grapefruit 
juice, indinavir, itraconazole, ketoconazole, 
lopinavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, troleandomycin, verapamil, 
voriconazole 
 
P-gp 
Substrates 
 
Inducers 
aliskiren, ambrisentan, 
colchicine, dabigatran, 
digoxin, everolimus, 
fexofenadine, imatinib, 
lapatinib, maraviroc, nilotinib, 
posaconazole, pravastatin, 
ranolazine, saxagliptin, 
sirolimus, sitagliptin, talinolol, 
tolvaptan, topotecan 
 
avasimibe, carbmazepine, 
phenytoin, rifampin, St John’s 
wort, tipranavir 
Dual UGT1A1/CYP3A 
Substrates 
Inhibitors 
Inducers 
buprenorphine, raltegravir 
atazanavir 
rifampin 
 Levien TL, and Baker DE Cytochrome P450 Drug Interactions. Therapeutic Research Center 
Pharmacist’s Letter/Prescriber’s Letter [resource on the Internet]. 2003. Available from: 
www.pharmacistsletter.com and www.prescribersletter.com. 
 Zhang L. Transporter Mediated Drug-Drug Interactions. FDA. Clinical Pharmacology Advisory 
Committee Meeting Topic 4: Transporter-Mediated Drug-Drug Interactions Atlanta, GA, March 
17, 2010. 
 
This information in this appendix is adapted from Levien and Baker 20031, Zhang 20102, 
and FDA Guidance on Drug-Drug Interactions. 
                                            
 
 


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Appendix 3  
List of Substrates, Inhibitors, and Inducers of Drug-Metabolizing 
Enzymes and Transporters (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 3 
 
129 
Also see: 
• 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dr
ugInteractionsLabeling/ucm080499.htm  
• 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
 
Potent inhibitors of CYP3A are those considered to be “strong CYP3A inhibitors” 
previously shown to result in a ≥ 5-fold increase in the AUC of a concomitantly 
administered CYP3A substrate.  These are based on the available published literature 
and, thus, are not considered exhaustive or inclusive.  See FDA Guidance on Drug-Drug 
Interactions for further detail. 


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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1: Excerpt from Original Publication 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1,1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2 
MEASURABILITY OF TUMOR AT BASELINE 
DEFINITIONS 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below. 
Measurable tumor lesions 
Tumor lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 
• 
10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater than 
5 mm) 
• 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
• 
20 mm by chest X-ray 
Malignant lymph nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
≥ 15 mm in the short axis when assessed by CT scan (CT scan slice thickness is 
recommended to be no greater than 5 mm).  At baseline and follow-up, only the short 
axis will be measured and followed.  See also notes below on “Baseline Documentation 
of Target and Non-Target Lesions” for information on lymph node measurement. 
Non-Measurable tumor lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 
                                            
1  Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors:  
revised REC)ST guideline ȋVersion ͳ.ͳȌ. Eur J Cancer ʹͲͲͻ;Ͷͷ:ʹʹͺ–Ͷ͹. 
2  For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made. 


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Version 1.1: Excerpt from Original Publication (cont.) 
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131 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone lesions 
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions.  However, these techniques 
can be used to confirm the presence or disappearance of bone lesions. 
Lytic bone lesions or mixed lytic−blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques, such as CT or MRI, can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
Blastic bone lesions are non-measurable. 
Cystic lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
TARGET LESIONS: SPECIFICATIONS BY METHODS OF MEASUREMENTS  
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
Method of assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 


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Version 1.1: Excerpt from Original Publication (cont.) 
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132 
Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
clinical lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is required. 
Chest X-Ray 
Chest CT is preferred over chest X-Ray, particularly when progression is an important 
endpoint, because CT is more sensitive than X-Ray, particularly in identifying new 
lesions.  However, lesions on chest X-Ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 
CT, MRI 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  This guideline has defined measurability of lesions on CT 
scan on the basis of the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable.  
If, prior to enrollment, it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease and should be 
optimized to allow for comparison with the prior studies if possible.  Each case should be 
discussed with the radiologist to determine if the substitution of these other approaches 
is possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of non-target disease or new lesions because the same lesion may 
appear to have a different size using a new modality. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. 
Endoscopy, laparoscopy, tumor markers, cytology, histology 
The utilization of these techniques for objective tumor evaluation cannot generally be 
advised. 


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Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 3 
133 
TUMOR RESPONSE EVALUATION 
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least one 
measurable lesion, as detailed above. 
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions, up to a 
maximum of five lesions total and a maximum of two lesions per organ, representative of 
all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be recorded as non-measurable lesions (even if the size is > 10 mm by CT scan).   
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but, in addition, the lesions 
should lend themselves to reproducible repeated measurements.  It may be the case 
that, on occasion, the largest lesion does not lend itself to reproducible measurement, in 
which circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT this is 
almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or 
coronal).  The smaller of these measures is the short axis.  For example, an abdominal 
node that is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node.  In this example, 20 mm should be recorded as the 
node measurement.  All other pathological nodes (those with short axis ≥ 10 mm but 
< 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
< 10 mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 


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Response Evaluation Criteria in Solid Tumors (RECIST) 
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into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
All other lesions or sites of disease, including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression”. 
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). 
RESPONSE CRITERIA 
Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
• 
CR:  Disappearance of all target lesions 
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm. 
• 
PR:  At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum of diameters. 
• 
PD:  At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (nadir), including baseline. 
In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered progression. 
• 
SD:  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum on study. 
 
Special notes on the assessment of target lesions 
Lymph nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to < 10 mm on study.  This means that when 
lymph nodes are included as target lesions, the sum of lesions may not be zero even if 
CR criteria are met, since a normal lymph node is defined as having a short axis of 
< 10 mm. 
Target lesions that become too small to measure 
During the study, all lesions (nodal and non-nodal) recorded at baseline should have 
their actual measurements recorded at each subsequent evaluation, even when very 
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small (e.g., 2 mm).  However, sometimes lesions or lymph nodes that are recorded as 
target lesions at baseline become so faint on the CT scan that the radiologist may not 
feel comfortable assigning an exact measure and may report them as being too small to 
measure.  When this occurs, it is important that a value be recorded on the CRF, as 
follows:   
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
If the lesion is believed to be present and is faintly seen but is too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should be 
ticked.  (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such as 
in the retroperitoneum; however, if a lymph node is believed to be present and is faintly 
seen but is too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well and BML should also be ticked). 
To reiterate:  If the radiologist is able to provide an actual measure, this 
measurement should be recorded, even if it is below 5 mm, and, in that case, BML 
should not be ticked. 
Lesions that split or coalesce on treatment 
When non-nodal lesions fragment, the longest diameters of the fragmented portions 
should be added together to calculate the target lesion sum.  Similarly, as lesions 
coalesce, a plane between them may be maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion.  If the lesions have truly coalesced 
such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximum longest diameter for the coalesced lesion. 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  Whereas some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the protocol. 
• 
CR:  Disappearance of all non-target lesions 
All lymph nodes must be non-pathological in size ( < 10 mm short axis). 
• 
Non-CR/Non-PD:  Persistence of one or more non-target lesions 
• 
PD:  Unequivocal progression of existing non-target lesions 
The appearance of one or more new lesions is also considered progression. 
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Special notes on assessment of progression of non-target disease 
When the patient also has measurable disease 
In this setting, to achieve unequivocal progression on the basis of the non-target 
disease, there must be an overall level of substantial worsening in non-target disease in 
a magnitude that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy.  A modest increase 
in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or PR of target disease will 
therefore be extremely rare. 
When the patient has only non-measurable disease 
This circumstance arises in some Phase III trials when it is not a criterion of study entry 
to have measurable disease.  The same general concepts apply here as noted above; 
however, in this instance, there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden.  Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly 
non-measurable), a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden on the 
basis of the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease, that is, an 
increase in tumor burden representing an additional 73% increase in volume (which is 
equivalent to a 20% increase in diameter in a measurable lesion).  Examples include an 
increase in a pleural effusion from “trace” to “large” or an increase in lymphangitic 
disease from localized to widespread.  Examples may be described in protocols as 
“sufficient to require a change in therapy”.  If unequivocal progression is seen, the 
patient should be considered to have had overall PD at that point.  Though it would be 
ideal to have objective criteria to apply to non-measurable disease, the very nature of 
that disease makes it impossible to do so; therefore, the increase must be substantial. 
New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(e.g., some “new” bone lesions may be simply healing or flare of preexisting lesions).  
This is particularly important when the patient’s baseline lesions show PR or CR (e.g., 
necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, 
which it is not). 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
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If a new lesion is equivocal (e.g., because of its small size) continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan. 
EVALUATION OF RESPONSE 
Timepoint response (overall response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used. 
Table 1 
Timepoint Response: Patients with Target Lesions (with or 
without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
 
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Table 2 
Timepoint Response: Patients with Non-Target Lesions Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised. 
 
Missing assessments and not-evaluable designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned timepoint response.  This would be most likely 
to happen in the case of PD (e.g., if a patient had a baseline sum of 50 mm with three 
measured lesions and during the study only two lesions were assessed, but those gave 
a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution 
of the missing lesion).  
If one or more target lesions were not assessed either because the scan was not done 
or because the scan could not be assessed due to poor image quality or obstructed 
view, the response for target lesions should be “unable to assess” since the patient is 
not evaluable.  Similarly, if one or more non-target lesions are not assessed, 
the response for non-target lesions should be “unable to assess”, except where there is 
clear progression.  Overall response would be “unable to assess” if either the target 
response or the non-target response is “unable to assess”, except where this is clear 
evidence of progression, as this equates with the case being not evaluable at that 
timepoint. 
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Table 3 
Best Overall Response When Confirmation Is Required 
Overall Response at First 
Timepoint 
Overall Response at 
Subsequent Timepoint 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR a 
CR 
SD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
CR 
PD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
CR 
NE 
SD, provided minimum 
duration for SD was met; 
otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
PR 
NE 
SD, provided minimum 
duration for SD was met; 
otherwise, NE 
NE 
NE 
NE 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even 
disease meeting PR criteria relative to baseline, qualifies as PD at that point (since disease 
must have reappeared after CR).  Best response would depend on whether the minimum 
duration for SD was met.  However, sometimes CR may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR, at the 
first timepoint.  Under these circumstances, the original CR should be changed to PR and the 
best response is PR. 
 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (< 10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
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progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Table 1 to Table 3. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes, or necrosis in existing lesions), treatment may continue until the 
next scheduled assessment.  If at the next scheduled assessment, progression is 
confirmed, the date of progression should be the earlier date when progression was 
suspected. 
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or non-target lesion.


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Appendix 5  
Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework or 
office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about > 50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair > 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair 
5 
Dead 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires 
 
 
 
 
 
 
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.)  
 
 


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Appendix 7  
Modification of Diet in Renal Disease (MDRD) Formula 
The estimating glomerular filtration rate (eGFR) will be calculated on the basis of the 
following formula: 
eGFR [mL/min/1.73 m2] = 175 × SCRT -1.154 × AGE -0.203 [× 0.742 if female] 
[× 1.212 if African American] (conventional units) 
 
where SCRT =  serum creatinine in conventional units, i.e. mg/dL. The following 
conversion factor should be used in case the serum creatinine value is provided by the 
lab in μmol/L units:  
Serum creatinine [mg/dL] =  Serum creatinine [μmol/L] × 0.0113 
 
 
References:  
Miller WG. Estimating glomerular filtration rate. Clin Chem Lab Med 2009;47(9):1017−9. 
Heil W., Koberstein R, Zawta B. Reference Ranges for Adults and Children−Pre-
Analytical Considerations. Roche Diagnostics GmbH 2014, 8th edition, p.159.  


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Appendix 8  
Anaplastic Lymphoma Kinase (ALK) Immunohistochemistry 
Overview 
The VENTANA anti-ALK (D5F3) Rabbit Monoclonal Primary Antibody (VENTANA 
anti-ALK [D5F3]) IHC assay will be used to determine anaplastic lymphoma kinase (ALK) 
IHC status and to select patients with positive ALK for enrollment in Study BO28984.  
The anti-ALK (D5F3) rabbit monoclonal antibody IHC assay is currently being developed 
by Ventana Medical Systems as a companion diagnostic to Roche’s ALK inhibitor, 
alectinib.  For Study BO28984, the VENTANA anti-ALK (D5F3) assay will be used for 
investigational purposes only. 
VENTANA anti-ALK (D5F3) is intended for laboratory use in the detection of the ALK 
protein in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) 
tissue stained with using a VENTANA automated slide stainer.  It is indicated as an aid 
in identifying patients eligible for treatment with alectinib. 
Device Description 
The VENTANA anti-ALK (D5F3) IHC assay is an automated IHC staining assay system 
comprising a pre-diluted, ready to-use anti-ALK (D5F3) rabbit monoclonal primary 
antibody, the BenchMark® automated slide staining platform, OptiView DAB detection kit, 
OptiView Amplification kit, Rabbit Monoclonal Negative Control Ig, and VENTANA 
anti-ALK 2-in-1 cell line control slides or other appropriate system run control. 
Scoring System 
The IHC scoring system evaluates specific VENTANA anti-ALK (D5F3) staining in 
NSCLC tumor cells by the presence of a strong, granular, cytoplasmic staining pattern.  
Pathologists must rely on the Negative Reagent Control (NRC) slides to distinguish 
non-specific staining from specific ALK positivity.  Samples must be assessed for 
morphological damage and the presence of viable tumor versus necrosis.  Light, 
granular, cytoplasmic stippling in alveolar macrophages can occur on anti-ALK (D5F3) 
and/or NRC slides as an artifact of the detection system.  This staining artifact should be 
noted on the Slide Evaluation Form comment field but should NOT be interpreted as 
ALK-positive staining.  Some background staining has also been observed on normal 
mucosa in NSCLC specimens, as well as in necrotic tumor areas; this staining also 
should not be interpreted as ALK-positive staining.  Case slide sets failing to show 
specific staining of the case tissue with VENTANA anti-ALK (D5F3) cannot be 
considered ALK-positive.  Refer to VENTANA ALK Scoring Interpretation Guide for non-
small cell lung carcinoma (NSCLC) for additional information. 
 


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Appendix 9  
Drug Metabolism Enzymes, Transporters (DMET), and Liver Injury Polymorphisms 
ABCB1 
CHST13 
CYP3A5 
HNMT 
SLC22A3 
UGT1A4 
ADRB3 
HSP90AA1 
STAT6 
ABCB11 
CHST2 
CYP3A7 
MAOA 
SLC22A4 
UGT1A5 
ALG10B 
IGF1 
TNF 
ABCB4 
CHST3 
CYP46A1 
MAOB 
SLC22A5 
UGT1A6 
APOA1 
IGF2 
TNFRSF1B 
ABCB7 
CHST4 
CYP4A11 
MAT1A 
SLC22A6 
UGT1A7 
APOC3 
IL10 
TXNIP 
ABCC1 
CHST5 
CYP4B1 
METTL1 
SLC22A7 
UGT1A8 
ARHGAP24 
IL22 
UBC 
ABCC2 
CHST6 
CYP4F11 
NAT1 
SLC22A8 
UGT1A9 
ATF3 
IL4 
UCP1 
ABCC3 
CHST7 
CYP4F12 
NAT2 
SLC25A27 
UGT2A1 
ATIC 
IL4R 
VDR 
ABCC4 
CHST8 
CYP4F2 
NNMT 
SLC28A1 
UGT2B11 
BIRC2 
IL6 
 
ABCC5 
CHST9 
CYP4F3 
NQO1 
SLC28A2 
UGT2B15 
BIRC3 
IL8 
 
ABCC6 
COMT 
CYP4F8 
NR1I2 
SLC28A3 
UGT2B17 
C3orf38 
INSR 
 
ABCC8 
CROT 
CYP4Z1 
NR1I3 
SLC29A1 
UGT2B28 
CALCA 
IRS1 
 
ABCC9 
CYP11A1 
CYP51A1 
NR3C1 
SLC29A2 
UGT2B4 
CASP9 
IRS2 
 
ABCG1 
CYP11B1 
CYP7A1 
ORM1 
SLC5A6 
UGT2B7 
CD33 
IRS4 
 
ABCG2 
CYP11B2 
CYP7B1 
ORM2 
SLC6A6 
UGT8 
CD36 
ITPA 
 
ABP1 
CYP17A1 
CYP8B1 
PGAP3 
SLC7A5 
VKORC1 
CD44 
JAK1 
 
ADH1A 
CYP19A1 
DCK 
PNMT 
SLC7A7 
XDH 
CDK4 
JUN 
 
ADH1B 
CYP1A1 
DPYD 
PON1 
SLC7A8 
 
CDK6 
KCNIP4 
 
ADH1C 
CYP1A2 
EPHX1 
PON2 
SLCO1A2 
 
CEBPB 
KRT18 
 
ADH4 
CYP1B1 
EPHX2 
PON3 
SLCO1B1 
 
CEP44 
KRT8 
 
ADH5 
CYP20A1 
FAAH 
POR 
SLCO1B3 
 
CES1 
LEP 
 
ADH6 
CYP21A2 
FMO1 
PPARD 
SLCO2B1 
 
CTLA4 
LEPR 
 
ADH7 
CYP24A1 
FMO2 
PPARG 
SLCO3A1 
 
CYP3A 
LMX1A 
 
AHR 
CYP26A1 
FMO3 
PPP1R9A 
SLCO4A1 
 
EGFR 
LPL 
 


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Appendix 9  
Drug Metabolism Enzymes, Transporters (DMET), and Liver Injury Polymorphisms (cont.) 
 
AKAP9 
CYP26C1 
FMO4 
PRSS53 
SLCO5A1 
 
ETNK2 
MCTP2 
 
ALB 
CYP27A1 
FMO5 
PTGIS 
SPG7 
 
FASLG 
MT-CO2 
 
ALDH1A1 
CYP27B1 
FMO6 
QPRT 
SPN 
 
FMOD 
MTHFR 
 
ALDH2 
CYP2A13 
G6PD 
RALBP1 
SULT1A1 
 
FOS 
NFE2L2 
 
ALDH3A1 
CYP2A6 
GSTA1 
RPL13 
SULT1A2 
 
FPGS 
NOS2 
 
ALDH3A2 
CYP2A7 
GSTA2 
RXRA 
SULT1A3 
 
GGH 
NOS3 
 
AOX1 
CYP2B6 
GSTA3 
SERPINA7 
SULT1B1 
 
GPNMB 
OR5H2 
 
APOA2 
CYP2B7P1 
GSTA4 
SLC10A1 
SULT1C2 
 
GPT 
PARD3B 
 
ARNT 
CYP2C18 
GSTA5 
SLC10A2 
SULT1C4 
 
GPX1 
PRKCZ 
 
ARSA 
CYP2C19 
GSTM1 
SLC13A1 
SULT1E1 
 
GPX3 
RASGRP1 
 
ATP7A 
CYP2C8 
GSTM2 
SLC15A1 
SULT2A1 
 
GPX4 
RB1 
 
ATP7B 
CYP2C9 
GSTM3 
SLC15A2 
SULT2B1 
 
GYS1 
RDH5 
 
CA5P 
CYP2D6 
GSTM4 
SLC16A1 
SULT4A1 
 
GYS2 
RIPK1 
 
CBR1 
CYP2E1 
GSTM5 
SLC19A1 
TBXAS1 
 
HCP5 
SOCS3 
 
CBR3 
CYP2F1 
GSTO1 
SLC22A1 
TPMT 
 
HGF 
SOD1 
 
CDA 
CYP2J2 
GSTP1 
SLC22A11 
TPSG1 
 
HLA-A 
SOD2 
 
CES2 
CYP2S1 
GSTT1 
SLC22A12 
TYMS 
 
HLA-B 
SPP1 
 
CHST1 
CYP39A1 
GSTT2 
SLC22A13 
UGT1A1 
 
HLA-DQA1 
SQSTM1 
 
CHST10 
CYP3A4 
GSTZ1 
SLC22A14 
UGT1A10 
 
HLA-DQB1 
ST6GAL1 
 
CHST11 
CYP3A43 
HMGCR 
SLC22A2 
UGT1A3 
 
HLA-DRB1 
STAT1 
 
 


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Appendix 10  Formulae for the Calculation of QTcF and RR  
 
QtcF  − Fridericia’s correction for QTc measurement (if not provided directly by the ECG machine): 
QTcF (ms) =  QT (ms) 3RR/1000 
 
 
RR Interval Formula (if not provided directly by the ECG machine): 
RR (ms)  =  60000/heart rate (bpm) 
 
 
 
 
 
 
 


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Title
08-Oct-2014 13:34:01
Date and Time (UTC)
Clinical Science Leader
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
PROTOCOL 
TITLE: 
RANDOMIZED, MULTICENTER, PHASE III, OPEN 
LABEL STUDY OF ALECTINIB VERSUS 
CRIZOTINIB IN TREATMENT NAÏVE ANAPLASTIC 
LYMPHOMA KINASE–POSITIVE ADVANCED NON–
SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: BO28984 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2013-004133-33 
IND NUMBER: 
111723 
UTN NUMBER: 
 
TEST PRODUCT: 
Alectinib (RO5424802) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  10 February 2014 
DATE AMENDED: 
Version 2:  See electronic date stamp below. 


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PROTOCOL AMENDMENT, VERSION 2: 
RATIONALE 
Protocol BO28984 has been amended to comply with questions addressed during the 
assessment of the Voluntary Harmonisation Procedure VHP444 (VHP201415), Western 
Institutional Review Board request (dated June 5, 2014) to further specify protocol 
inclusion criterion, FDA request (dated July 10, 2014) to revise crizotinib dose 
modification criteria for non-hematologic toxicities to conform to the most recent 
FDA⎯approved label, as well as feedback from various other Health Authorities/Ethic 
Committees.  Protocol BO28984 has been amended to include the latest clinical and 
safety information. 
The main changes to the protocol are as follows: 
• 
Study rationale (Section 1.3 and Section 3.3.3) supplemented with latest crizotinib 
data from the recently published PROFILE 1014 study that lead to reassessment of 
assumptions for median progression-free survival (PFS) without impacting a target 
HR for the study.  This amendment text was introduced throughout the Protocol and 
Section 6, Statistical Considerations and Analysis Plan. 
• 
Inclusion criteria (Section 4.1.1) of an adequate renal function and Guidelines for 
Management of Specific Adverse Events with Alectinib (Table 2) were modified to 
use measure of an estimated Glomerular Filtration Rate (eGFR) calculated using 
the Modification of Diet in Renal Disease (MDRD) equation. 
• 
Specified inclusion criteria (Section 4.1.1) by adding statement that asymptomatic 
CNS lesions might be treated at the discretion of the investigator as per local clinical 
practice. 
• 
Exclusion criteria (Section 4.1.2) of symptomatic bradycardia have been specified 
by removing the reference to <45 beats per minute. 
• 
Section 4.3.4 amended to describe post-trial access to alectinib 
• 
Permitted Therapy (Section 4.4.1) and Safety of Crizotinib Management of Adverse 
Events (Section 5.1.4, Table 4) revised as per latest prescribing information for 
crizotinib (USPI May 2014; EU SmPC 16 June 2014). 
• 
Local therapy (e.g., stereotactic radiotherapy or surgery) in case of isolated 
asymptomatic CNS progression (e.g., new CNS oligometastases) added to the list 
of Permitted Therapy (Section 4.4.1.) for further clarity. 
• 
Added information on events of bradycardia reported with alectinib (Section 5.1.2.8) 
• 
Based on an updated directive from the European Parliament that was released 
April 2014 superseding the previous Directive (CT3) updated language of the 
Protocol BO28984 (Section 5.3.1 and Section 5.6) referring to a suspected causal 
relationship to the investigational medicinal product that occurs after the end of the 
clinical trial. 
• 
Introduced Section 5.3.5.13, Adverse Events in Individuals Not Enrolled in the Study 


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• 
Section 9.5, Publication of Data and Protection of Trade Secrets, amended to 
further describe publication of data and protection of trade secrets. 
 
Additional minor changes have been made to improve clarity and consistency.  This 
amendment represents cumulative changes to the original protocol. 
 


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PROTOCOL AMENDMENT, VERSION 2: 
SUMMARY OF CHANGES 
GLOBAL CHANGES 
The UTN number 
 was added to the title pages as applicable. 
The protocol was clarified to indicate that the Ventana IHC and the Vysis FISH should be 
used. 
The planned competitive recruitment period was changed from 25 to 24 months.  The 
final analysis of the primary endpoint will occur when 170 patients, instead of 
169 patients, have progressed or died; this is expected to occur at approximately 
33 months, not 31 months. 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.1:  Background on Anaplastic Lymphoma Kinase−Positive 
Non−Small Cell Lung Cancer 
Currently, the only approved medicine treatment for treatment-naïve ALK-positive 
NSCLC is crizotinib (Xalkori®, Pfizer, Inc.), an inhibitor of receptor tyrosine kinases 
including ALK, hepatocyte growth factor receptor (HGFR, c-Met), recepteur d’origine 
nantais (RON), and c-ros oncogene 1 (ROS1) (Sahu et al. 2013).  
SECTION 1.3:  Study Rationale and Benefit-Risk Assessment 
Crizotinib is the only first generation ALK inhibitor that is currently approved and has 
been registered in multiple countries worldwide for the treatment of ALK-positive NSCLC.  
Crizotinib is an oral small-molecule multitargeted tyrosine kinase inhibitor (TKI) targeting 
ALK, MET, RON, and ROS1 tyrosine kinases (Sahu et al. 2013, Shaw et al. 2013).  The 
previous clinical studies reported at present demonstrate that the median PFS with 
crizotinib ranged from 7.7 to 9.7 months (Camidge et al. 2012, Kim et al. 2013, Shaw et 
al. 2013), while published clinical evidence on crizotinib’s efficacy in ALK positive 
NSCLC first line treatment setting is still limited.  The PROFILE 1014 study, a Phase III 
study of crizotinib compared with standard pemetrexed−platinum−based chemotherapy, 
was presented at the ASCO 2014 congress (Mok et al. 2014).  The study met its 
primary objective of prolonging PFS in previously untreated patients with ALK-
positive non-squamous NSCLC with median PFS of 10.9 and 7.0 months (HR: 0.454; 
95% CI: 0.346, 0.596; p < 0.0001) for crizotinib and pemetrexed-platinum-based 
chemotherapy, respectively. 
Altogether, it would be important to compare alectinib to crizotinib as a therapeutic 
option for treatment-naïve ALK-positive advanced NSCLC patients. 


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Alectinib was granted approval in Japan on 4 July 2014 for ALK fusion gene-positive, 
unresectable, recurrent, or advanced NSCLC. 
SECTION 3.1:  DESCRIPTION OF STUDY 
The experimental arm will receive alectinib at 600 mg orally BID, taken with food.  The 
control arm will receive crizotinib at 250 mg orally BID, taken with or without food.  The 
first dose of the study drug should be administered as soon as possible after 
randomization, preferably within 24 hours, and no later than 48 hours after 
randomization. 
Patients will be treated until disease progression, unacceptable toxicity, withdrawal of 
consent, or death.  After disease progression (as per RECIST v1.1), patients should 
discontinue the study medication.  After disease progression, patients will be treated at 
the discretion of the investigator according to local practice.  Information regarding the 
nature and the duration of subsequent therapies will be collected. 
SECTION 3.3.3:  Rationale for Control Group 
There are no publicly available Phase III data yet for crizotinib in the first line setting.  
The randomized Phase III PROFILE 1014 study, which began in January 2011, is 
currently being was conducted to assess the efficacy of crizotinib versus standard 
platinum-based chemotherapy (pemetrexed plus cisplatin or carboplatin) as first-line 
treatment for patients with ALK-positive, non-squamous NSCLC.  The study met its 
primary objective of prolonging PFS in previously untreated patients with ALK-
positive non-squamous NSCLC with median PFS of 10.9 and 7.0 months (HR: 0.454; 
95% CI: 0.346, 0.596; p < 0.0001) for crizotinib and pemetrexed-platinum-based 
chemotherapy, respectively (Mok et al. 2014).  The authors concluded that these 
findings establish crizotinib as the standard of care for patients with previously 
untreated advanced ALK-positive non-squamous NSCLC (Mok et al. 2014). The 
estimated primary completion date of this study is November 2013 (ClinicalTrials.gov), 
with data expected to be reported in 2014.  If PROFILE 1014 reported data will 
drastically differ from previously reported information, the study assumptions might be 
reevaluated. 
SECTION 3.3.5:  Rationale for Primary Endpoint Selection 
The assumed median PFS of patients in the alectinib treatment arm is 15.116.8 months, 
and an OS of more than 30 months is expected, which equates to a post-progression 
survival of at least 135 months.   
SECTION 4.1.1:  Inclusion Criteria 
• 
Adequate renal function: 
An estimated glomerular filtration rate (eGFR) calculated using the 
Modification of Diet in Renal Disease equation of Calculated creatinine 
clearance at least 45 mL/min/1.73 m2 


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• 
Prior brain or leptomeningeal metastases allowed if asymptomatic and (e.g., 
diagnosed incidentally at study baseline).  Asymptomatic CNS lesions might be 
treated at the discretion of the investigator as per local clinical practice.  If patients 
have neurological symptoms or signs due to CNS metastasis, patients need to 
complete whole brain radiation or gamma knife irradiation treatment.  In all cases, 
radiation treatment must be completed at least 14 days before enrollment and 
patients must be clinically stable. 
SECTION 4.1.2:  Exclusion Criteria 
• 
Liver disease characterized by: 
ALT or AST > 3 × ULN (≥ 5 × ULN for patients with concurrent liver metastasis) 
confirmed on two consecutive measurements 
OR 
Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or 
other conditions of decompensated liver disease such as coagulopathy, hepatic 
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal 
varices 
OR 
Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis 
• 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy 
(e.g. radiotherapy) (excluding alopecia), which have not shown improvement and 
are strictly considered to interfere with current study medication. 
• 
History of organ transplant. 
• 
Co-administration of anti-cancer therapies other than those administered in this 
study. 
• 
Patients with baseline QTc > 470 ms or patients with symptomatic bradycardia 
< 45 beats per minute. 
 
SECTION 4.3.1.1:  Alectinib 
Alectinib comes in a hard capsule dosage form containing the following active ingredient: 
[Chemical name] 9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-6,11-
dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride 
Each capsule contains 150 mg of alectinib (as free base) along with lactose 
monohydrate, carmellose calcium, hydroxypropyl cellulose, sodium lauryl sulfate (SLS), 
and magnesium stearate as excipients. 
Alectinib capsules should be stored in accordance with the storage instructions on the 
label. 
Alectinib capsules should be administered orally BID with food (within 30 minutes after a 
meal, in the morning and evening). 


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The formulation contains SLS as an surfactant excipient.  This excipient is known to be 
associated potentially with GI adverse events such as nausea, vomiting, diarrhea, and 
abdominal pain. 
SECTION 4.3.2.2:  Crizotinib 
If a dose is missed, then it should be taken as soon as the patient remembers unless it is 
less than 6 hours until the next dose, in which case the patient should not take the 
missed dose.  Patients should not take 2 doses at the same time to make up for a 
missed dose.  If vomiting occurs after taking a dose of crizotinib, the next dose should 
be taken as scheduled.  
SECTION 4.3.4:  Post-Trial Access to Alectinib 
The Sponsor does not intend to provide alectinib or other study interventions to patients 
after conclusion of the study or any earlier patient withdrawal, under this protocol.The 
Sponsor will offer post-trial access to the study drug alectinib free of charge to eligible 
patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive study drug after the end of the study if all of the following 
conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
would not otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for ALK-positive NSCLC 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for ALK-positive NSCLC 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 


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SECTION 4.4.1:  Permitted Therapy 
Concomitant medication includes any medication (e.g., prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used 
by a patient from 28 days prior to screening to the study completion/discontinuation visit.   
The medications and/or treatments below are permitted: 
• 
Gastric pH−elevating medications (such as proton pump inhibitors, H2 blockers, or 
antacids) 
• 
Local therapy (e.g., stereotactic radiotherapy or surgery) may be given to patients 
with isolated asymptomatic CNS progression (e.g., new CNS oligometastases). 
Caution should be exercised when the following are co-administered with crizotinib: 
• 
Bradycardia has been reported during clinical studies; therefore, the use of 
crizotinib in combination with other agents known to cause bradycardia (e.g., 
beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and 
digoxin) should be avoided to the extent possibleuse crizotinib with caution owing to 
the risk of excessive bradycardia when used in combination with other bradycardic 
agents (e.g., non dihydropyridine calcium channel blockers such as verapamil and 
diltiazem, beta blockers, clonidine, guanfacine, digoxin, mefloquine, 
anticholinesterases, pilocarpine). 
• 
The aqueous solubility of crizotinib is pH dependent, with higher pH resulting in 
lower solubility.  Drugs that elevate the gastric pH (such as proton pump inhibitors, 
H2 blockers, or antacids) may decrease the solubility of crizotinib and subsequently 
reduce its bioavailability. 
• 
The inhibitory effect of crizotinib on uridine 5' diphospho glucuronosyltransferases 
(UGTs), notably UGT1A1, has not been established.  Therefore, caution should be 
exercised when crizotinib and substrates of UGTs, such as paracetamol or 
morphine, are combined. 
 
SECTION 4.5.8.1:  Laboratory Assessments 
• 
Urinalysis: Urine samples will be collected according to the schedule of 
assessments (Appendix 1) (first morning urine sample for baseline and end of 
treatment visit, spot urine for rest of visits).  Urine protein albumin and creatinine will 
be measured by dipstick test in order to assess micro- and 
macroproteinalbuminuria. 
 
SECTION 4.5.8.2:  Pre-Treatment Tumor Samples (Mandatory) 
The tumor sample may also be tested for the presence of EGFR mutations, if requested y 
the investigator. 
SECTION 4.5.8.3:  Pre- and Fresh Post-Treatment Tumor Biopsies (Optional) 
Optional additional pre-treatment tumor samples and fresh post-treatment tumor biopsy 
at disease progression or permanent treatment discontinuation withdrawal from 
treatment (at the last treatment or post-progression visit) may be collected, with proper 
informed consent.   


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SECTION 4.5.8.4:  Blood and Plasma Samples (Mandatory) 
Mandatory blood samples will be obtained to determine: 
• 
ALK mutations assessment in circulating tumor cells.  It will require 2012 mL of 
blood sample to be collected (2 tubes of 106 mL each) at baseline and at disease 
progression (at the last treatment or post-progression visit).  It should match in time 
to tumor progression (CNS and/or systemic disease progression). 
• 
All patients who are randomized in alectinib arm will also participate in retrospective 
pharmacogenomic research to understand inter-individual variability of safety and 
pharmacokinetics of alectinib.  For this purpose, a 3-mL blood sample will be drawn 
at baseline (see Sections 4.5.8.4.1and 4.5.8.5). 
• 
Patients in the crizotinib arm who opt in to optional genomics sequencing will 
provide a 3 mL blood sample.  This 3 mL blood sample will be used as a source of 
healthy tissue.  This sample is required for all patients in the crizotinib arm who wish 
to participate in the optional genomic sequencing (see Section 4.5.8.4.1). 
 
Optional blood samples will be collected to obtain: 
• 
A source of healthy tissue for patients who agreed to participate in the optional 
genomic sequencing assessment.  For patients in the crizotinib arm, a 3-mL blood 
sample will be drawn at baseline.  For patients in the alectinib arm, a source of 
healthy tissue will be used as a portion of the sample for the pharmacogenomics 
research (see Section4.5.8.4.1) 
• 
A portion of this blood sample will also be used as a source of healthy tissue for the 
patients receiving alectinib treatment who agree to participate in the optional 
genomic sequencing research. 
For biomarkers, a total maximum of 4335 mL of blood will be collected at baseline 
(20 mL for plasma purification and determination of mutation status in ALK and other 
escape genes, 2012 mL for ALK fusion detection in circulating tumor cells, and 3 mL for 
pharmacogenomics research), 20 mL of blood (for plasma purification and determination 
of mutation status in ALK and other escape genes) will be collected at Visit 3 (Week 16) 
and subsequently at every second visit (every 16 weeks), and 32 mL will be collected at 
disease progression (CNS and/or systemic disease progression) (20 mL for plasma 
purification for determination of mutation status in ALK and other escape genes and 
2012 mL for ALK fusion detection in circulating tumor cells). 
SECTION 4.5.8.5:  Samples for Pharmacokinetic Assessments 
Patients who permanently discontinue from study drugs will also discontinue from all PK 
assessments.  The procedures for the collection, handling, storage, and shipping of 
plasma samples for the PK analysis are specified in the Laboratory Manual.  Actual 
sampling times will be recorded for each PK sample in the eCRF.  


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SECTION 4.5.9:  Electrocardiograms 
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws, study drug administration) as well as prior 
to meals and should not be obtained within 3 hours after any meal.   
SECTION 4.5.11.3:  Sample Collection 
For RCR purposes, 10 mL of blood will be collected.  Any remaining tissue samples 
from study-related or non−study−related procedures that are performed during the 
study may also be collecte for RCR purposes.  For all samples, dates of consent and 
specimen collection should be recorded on the associated RCR page of the eCRF.  For 
sampling procedures, storage conditions, and shipment instructions, see the laboratory 
manual. 
SECTION 5.1.2.8:  Cardiovascular Effects (QT Interval Prolongation) 
Events of bradycardia have been reported with alectinib.  Preliminary heart rate data 
(based on ECG and pulse measurements) from the ongoing alectinib clinical trials show 
a decrease in heart rate during alectinib treatment, which is mainly asymptomatic.  In 
patients treated with other ALK inhibitors (crizotinib and ceritinib), bradycardia 
adverse events, and decreases in heart rate based on ECG and pulse measurements, have 
also been reported.  
In case of bradycardia, concomitant medications must be evaluated to identify those 
that are known to cause bradycardia, as well as anti-hypertensive medications; 
discontinuation or dose reduction of these concomitant medications must be considered. 
SECTION 5.2:  SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
non-SAEs of special interest, performing ; measurement of protocol-specified safety 
laboratory assessments, measuring ; measurement of protocol-specified vital signs,; and 
conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
SECTION 5.3.1:  Adverse Event Reporting Period 
After initiation of study drug, all AEs, regardless of relationship to study drug, will be 
reported until 4 weeks after the last dose of study drug.  After this period, the investigator 
should report any SAEs that are believed to be related to study drug treatment is not 
required to actively monitor patients for AEs; however, the Sponsor should be notified if 
the investigator becomes aware of any post study SAEs or non SAEs of special interest 
(see Section 5.6). 
SECTION 5.3.5.3:  Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation timepoints.  Such events should only be recorded once on the Adverse Event 
eCRF.  The initial severity (intensity or grade) of the event will be recorded at the time 


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the event is first reported.  If a persistent AE becomes more severe, the most extreme 
intensity severity should also be recorded on the Adverse Event eCRF.   
SECTION 5.3.5.4:  Abnormal Laboratory Values 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only not be repeatedly recorded once on the Adverse Event eCRF (see 
Section5.3.5.3 for details on recording persistent AEs). , unless the etiology changes.  
The initial severity of the event should be recorded, and the severity or seriousness 
should be updated any time the event worsens. 
SECTION 5.3.5.5:  Abnormal Vital Sign Values 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only not be repeatedly recorded one on the Adverse Event eCRF (see 
Section 5.3.5.3 for details on recording persistent adverse events). , unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
SECTION 5.3.5.11:  Adverse Events Associated with an Overdose or Error 
in Drug Administration 
This section header was revised as shown above. 
SECTION 5.3.5.13:  Adverse Events in Individuals Not Enrolled in the 
Study 
If an AE inadvertently occurs in an individual not enrolled in the study, the Adverse 
Event Form provided to investigators should be completed and submitted to Roche or 
its designee, either by faxing or by scanning and emailing the form using the fax 
number or email address provided to investigators. 
SECTION 5.4.2.1:  Events That Occur Prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported.  A paperThe Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form provided to 
investigators and fax cover sheet should be completed and submitted faxed to Roche 
Safety Risk Management or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address numbers provided to investigators (see "Protocol 
Administrative and Contact Information & List of Investigators"). 
SECTION 5.4.2.2:  Events That Occur After Study Drug Initiation 
In the event that the EDC system is unavailable, a paperthe Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators and 
fax cover sheet should be completed and submitted faxed to Roche Safety Risk 
Management or its designee immediately (i.e., no more than 24 hours after learning of 
the event), either by faxing or by scanning and emailing the form using the fax number 
or email address numbers provided to investigators (see "Protocol Administrative and 


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Contact Information & List of Investigators").  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. 
SECTION 5.4.3.1:  Pregnancies in Female Patients 
In the event that the EDC system is unavailable, a paperthe Clinical Trial Pregnancy 
Reporting Form provided to investigators and fax cover sheet should be completed and 
submitted faxed to Roche Safety Risk Management or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), either by faxing or by scanning 
and emailing the form using the fax number or email address numbers provided to 
investigators (see "Protocol Administrative and Contact Information & List of 
Investigators").  Once the EDC system is available, all information will need to be 
entered and submitted via the EDC system. 
SECTION 5.5.1:  Investigator Follow-Up 
If, after follow up, return to baseline status or stabilization cannot be established, an 
explanation should be recorded on the Adverse Event eCRF. 
SECTION 5.6:  POST-STUDY ADVERSE EVENTS 
At the time of study completion or study discontinuation, the investigator should instruct 
each patient to report to the investigator any subsequent AEs that the patient’s personal 
physician believes could be related to prior study drug treatment or study procedures. 
The Sponsor should be notified if the investigator becomes aware of any SAE that 
occurs after the end of the AE reporting period The investigator is not required to 
actively monitor patients for AEs after the end of the AE reporting period (defined as 
4 weeks after the last dose of study drug), if the event is believed to be related to study 
drug treatment.  However, the Sponsor should be notified if the investigator becomes 
aware of any death, other SAE, or non SAE of special interest occurring after the end of 
the AE reporting period, regardless of causality.  The Sponsor should also be notified if 
the investigator becomes aware of the development of cancer or a congenital 
anomaly/birth defect in a subsequently conceived offspring of a female patient exposed 
to study drug or the female partner of a male patient exposed to study drug. 
The investigator should report these events directly to Roche or its designee, either by 
faxing or by scanning and emailing Safety Risk Management via telephone or via fax 
machine using the Serious Adverse Event/Adverse Event of Special Interest Reporting 
Form using the fax number or email address provided to investigatorsand fax cover 
sheet (see "Protocol Administrative and Contact Information & List of Investigators"). 
SECTION 6.1:  DETERMINATION OF SAMPLE SIZE 
At the time of writing the initial protocol, there are were no Phase III data available on 
crizotinib in the first-line setting in ALK-positive patients.  The median PFS for crizotinib 
administered as second-line therapy from the global randomized Phase III PROFILE 
1007 study was 7.7 months (95% CI: 6.0%, 8.8%).  From the Phase II single arm study 


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of patients who had received ≥ 1 line of chemotherapy (with 85% patients having 
received ≥ 2 prior chemotherapy regimens), the median PFS was 8.5 months (95% CI: 
6.2%, 9.9%).  The Phase III PROFILE 1014 study of crizotinib versus standard 
pemetrexed-platinum-based chemotherapy in previously untreated patients with 
ALK-positive non-squamous NSCLC reported a median PFS of 10.9 months for 
crizotinib (Mok et al. 2014). 
Thus, an initial assumption ofA median PFS of 9.8 months for the crizotinib arm has 
been reassessed on the basis of data from the Phase III study PROFILE 1014 to 
10.9 monthsassumed.  An HR of 0.65 for alectinib versus crizotinib (i.e., an increase 
from 9.810.9 months median PFS to 15.116.8 months) will be targeted. 
In this study, 286 patients will be enrolled in a 1:1 randomization allocation.  Enrollment 
will take approximately 245 months on the basis of an assumption of non-linear 
recruitment as follows: 
• 
Month 1:  1 patient per month 
• 
Month 2:  2 patients per month 
• 
Month 3:  4 patients per month 
• 
Month 4:  6 patients per month 
• 
Month 5:  8 patients per month 
• 
Month 6:  10 patients per month 
• 
Month 7:  12 patients per month 
• 
Months 8−12:  13 patients per month 
• 
Months 13−14:  14 patients per month 
• 
Month 15 onwards:  15 patients per month 
A total of 17069 PFS events are required to achieve 80% power at a two-sided alpha 
level of 5%.  This number of PFS events level of enrollment is estimated to occur 
approximately 331 months after the first patient has been enrolled. 
No interim analysis for efficacy or futility is planned. 
A survival follow-up analysis will be performed once approximately 50% of patients 
(i.e., 143 patients) have died.  The median OS in the crizotinib arm is assumed to be 
245 months, and the expected median OS in the alectinib treatment arm is 30 months, 
equating to an HR of 0.83.  On the basis of the sample size (N = 286), the trial will not be 
powered to demonstrate any statistically significant difference in OS of this magnitude.  
At the time of the final analysis of the primary endpoint of PFS, on the basis of the above 
assumptions, 10694 OS events are expected to have occurred.  The survival follow-up 
analysis is expected to occur approximately 42 months after the first patient has been 
enrolled. 


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SECTION 9.5:  PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing information on 
the trial to healthcare professionals and to the public, both at scientific congresses and in peer-
reviewed journals.  The Sponsor will comply with all requirements for publication of study 
results.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
The results of this study may be published or presented at scientific congressesmeetings.  
For all clinical trials in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical trial results within 6 months after the 
availability of the respective clinical study report.  In addition, for all clinical trials in 
patients involving an IMP for which a marketing authorization application has been 
filed or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and 
statistically sound. 
If this is foreseen, tThe investigator must agree to submit all manuscripts or abstracts to 
the Sponsor prior to submission for publication or presentation.  This allows the 
Sponsor to protect proprietary information and to provide comments based on 
information from other studies that may not yet be available to the investigator. 
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
TABLE 2:  Guidelines for Management of Specific Adverse Events with 
Alectinib 
Table 4 has been modified to reflect changes to the protocol. 
TABLE 4:  Crizotinib Dose Modification-Non-Hematologic Toxicities 
Table 4 has been modified to reflect changes to the protocol. 
TABLE 5:  Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in the NCI CTCAE 
The title of Table 5 has been updated. 
APPENDIX 1:  Schedule of Assessments 
The Schedule of Assessments has been revised to reflect the changes to the protocol. 


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APPENDIX 4:  Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication 
• 
CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• 
Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
SAMPLE INFORMED CONSENT FORMS 
The sample Informed Consent Forms have been revised to reflect the changes to the 
protocol. 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 23 
PROTOCOL SYNOPSIS .................................................................................... 24 
1. 
BACKGROUND .......................................................................................... 35 
1.1 
Background on Anaplastic Lymphoma 
Kinase−Positive Non−Small Cell Lung Cancer...................... 35 
1.2 
Background on Alectinib........................................................ 37 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 42 
2. 
OBJECTIVES.............................................................................................. 44 
2.1 
Efficacy Objectives ................................................................ 44 
2.2 
Safety Objectives................................................................... 45 
2.3 
Pharmacokinetic Objectives .................................................. 45 
2.4 
Patient-Reported Outcome Objectives .................................. 45 
2.5 
Exploratory Objectives........................................................... 45 
3. 
STUDY DESIGN ......................................................................................... 46 
3.1 
Description of Study .............................................................. 46 
3.2 
End of Study.......................................................................... 48 
3.3 
Rationale for Study Design.................................................... 48 
3.3.1 
Rationale for Alectinib Dosage .............................................. 48 
3.3.2 
Rationale for Patient Population ............................................ 49 
3.3.3 
Rationale for Control Group................................................... 49 
3.3.4 
Rationale for Open-Label Design .......................................... 50 
3.3.5 
Rationale for Primary Endpoint Selection .............................. 51 
3.3.6 
Rationale for Secondary Endpoint of Time to 
CNS Progression................................................................... 52 
3.3.7 
Rationale for PK Sample Collection Schedule....................... 53 
3.3.8 
Rationale for Biomarker Assessments................................... 54 
3.3.9 
Rationale for PRO Assessments ........................................... 54 
3.4 
Outcome Measures ............................................................... 55 
3.4.1 
Efficacy Outcome Measures.................................................. 55 
3.4.2 
Safety Outcome Measures .................................................... 56 
3.4.3 
Pharmacokinetic Outcome Measures.................................... 56 


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3.4.4 
Patient-Reported Outcome Measures ................................... 57 
3.4.5 
Exploratory Outcome Measures ............................................ 57 
4. 
MATERIALS AND METHODS .................................................................... 57 
4.1 
Patients.................................................................................. 57 
4.1.1 
Inclusion Criteria.................................................................... 57 
4.1.2 
Exclusion Criteria................................................................... 59 
4.2 
Method of Treatment Assignment and Blinding..................... 60 
4.3 
Study Treatment.................................................................... 60 
4.3.1 
Formulation, Packaging, and Handling.................................. 60 
4.3.1.1 
Alectinib................................................................................. 60 
4.3.1.2 
Crizotinib................................................................................ 61 
4.3.2 
Dosage, Administration, and Compliance.............................. 61 
4.3.2.1 
Alectinib................................................................................. 61 
4.3.2.2 
Crizotinib................................................................................ 61 
4.3.3 
Investigational Medicinal Product Accountability ................... 62 
4.3.4 
Post-Trial Access to Alectinib ................................................ 62 
4.4 
Concomitant Therapy ............................................................ 63 
4.4.1 
Permitted Therapy ................................................................. 63 
4.4.2 
Prohibited Therapy ................................................................ 65 
4.4.3 
Prohibited Food ..................................................................... 66 
4.5 
Study Assessments ............................................................... 66 
4.5.1 
Informed Consent Forms and Screening Log........................ 66 
4.5.2 
Medical History and Demographic Data ................................ 66 
4.5.3 
Corticosteroid Use for CNS Metastases ................................ 66 
4.5.4 
Physical Examinations........................................................... 67 
4.5.5 
Vital Signs.............................................................................. 67 
4.5.6 
ECOG Performance Status ................................................... 67 
4.5.7 
Tumor and Response Evaluations......................................... 67 
4.5.8 
Laboratory, Biomarker, and Other Biological 
Sample .................................................................................. 69 
4.5.8.1 
Laboratory Assessments ....................................................... 69 
4.5.8.2 
Pre-Treatment Tumor Samples (Mandatory)......................... 69 


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4.5.8.3 
Pre- and Fresh Post-Treatment Tumor Biopsies 
(Optional)............................................................................... 70 
4.5.8.4 
Blood and Plasma Samples................................................... 70 
4.5.8.5 
Samples for Pharmacokinetic Assessments.......................... 72 
4.5.9 
Electrocardiograms................................................................ 72 
4.5.10 
Patient-Reported Outcomes .................................................. 73 
4.5.11 
Samples for Roche Clinical Repository.................................. 73 
4.5.11.1 
Overview of the Roche Clinical Repository............................ 73 
4.5.11.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 74 
4.5.11.3 
Sample Collection.................................................................. 74 
4.5.11.4 
Confidentiality........................................................................ 74 
4.5.11.5 
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 75 
4.5.11.6 
Withdrawal from the Roche Clinical Repository..................... 75 
4.5.11.7 
Monitoring and Oversight....................................................... 76 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 76 
4.6.1 
Patient Discontinuation.......................................................... 76 
4.6.2 
Study Treatment Discontinuation........................................... 76 
4.6.3 
Study and Site Discontinuation.............................................. 77 
5. 
ASSESSMENT OF SAFETY....................................................................... 77 
5.1 
Safety Plan ............................................................................ 77 
5.1.1 
Adverse Events Collection..................................................... 77 
5.1.2 
Adverse Events Relating to ALK Inhibitors and/or 
the Tyrosine Kinase Inhibitor Class and Alectinib 
Data....................................................................................... 78 
5.1.2.1 
Interstitial Lung Disease ........................................................ 78 
5.1.2.2 
Hepatobiliary Laboratory Test Elevations .............................. 78 
5.1.2.3 
Hematologic Abnormalities.................................................... 78 
5.1.2.4 
Gastrointestinal Disorders ..................................................... 79 
5.1.2.5 
Skin Disorders ....................................................................... 79 
5.1.2.6 
Vision Disorders .................................................................... 79 
5.1.2.7 
Edema ................................................................................... 80 


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5.1.2.8 
Cardiovascular Effects........................................................... 80 
5.1.2.9 
Abnormal Renal Function ...................................................... 80 
5.1.2.10 
Muscular Adverse Events and CPK Elevations ..................... 81 
5.1.3 
Management of Specific Adverse Events with 
Alectinib................................................................................. 82 
5.1.4 
Safety of Crizotinib and Management of Adverse 
Events.................................................................................... 86 
5.2 
Safety Parameters and Definitions ........................................ 89 
5.2.1 
Adverse Events ..................................................................... 89 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 90 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 90 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 91 
5.3.1 
Adverse Event Reporting Period ........................................... 91 
5.3.2 
Eliciting Adverse Event Information ....................................... 91 
5.3.3 
Assessment of Severity of Adverse Events ........................... 91 
5.3.4 
Assessment of Causality of Adverse Events ......................... 92 
5.3.5 
Procedures for Recording Adverse Events............................ 93 
5.3.5.1 
Diagnosis Versus Signs and Symptoms................................ 93 
5.3.5.2 
Adverse Events that are Secondary to Other 
Events.................................................................................... 93 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 93 
5.3.5.4 
Abnormal Laboratory Values ................................................. 94 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 95 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 95 
5.3.5.7 
Deaths ................................................................................... 95 
5.3.5.8 
Preexisting Medical Conditions.............................................. 96 
5.3.5.9 
Lack of Efficacy or Worsening of Non-Small Cell 
Lung Cancer.......................................................................... 96 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 96 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 97 
5.3.5.12 
Patient-Reported Outcome Data ........................................... 97 


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5.3.5.13 
Adverse Events in Individuals Not Enrolled in the 
Study ..................................................................................... 97 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 97 
5.4.1 
Emergency Medical Contacts................................................ 98 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 98 
5.4.2.1 
Events That Occur Prior to Study Drug Initiation ................... 98 
5.4.2.2 
Events That Occur After Study Drug Initiation ....................... 98 
5.4.3 
Reporting Requirements for Pregnancies.............................. 99 
5.4.3.1 
Pregnancies in Female Patients............................................ 99 
5.4.3.2 
Pregnancies in Female Partners of Male Patients................. 99 
5.4.3.3 
Abortions ............................................................................. 100 
5.4.3.4 
Congenital Anomalies/Birth Defects .................................... 100 
5.5 
Follow-Up of Patients after Adverse Events ........................ 100 
5.5.1 
Investigator Follow-Up......................................................... 100 
5.5.2 
Sponsor Follow-Up .............................................................. 100 
5.6 
Post-study Adverse Events.................................................. 101 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 101 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 101 
6.1 
Determination of Sample Size ............................................. 102 
6.2 
Summaries of Conduct of Study.......................................... 103 
6.3 
Summaries of Treatment Group Comparability ................... 104 
6.4 
Efficacy Analyses ................................................................ 104 
6.4.1 
Primary Efficacy Endpoint.................................................... 104 
6.4.2 
Secondary Efficacy Endpoints............................................. 105 
6.4.2.1 
Sensitivity Analyses............................................................. 107 
6.4.2.2 
Subgroup Analyses ............................................................. 107 
6.5 
Safety Analyses................................................................... 107 
6.6 
Pharmacokinetic Analyses................................................... 108 
6.7 
Patient-Reported Outcome Analyses .................................. 109 


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6.7.1 
Time to Deterioration of Patient-Reported Lung 
Cancer Symptoms............................................................... 109 
6.7.2 
Additional Patient-Reported Outcomes ............................... 110 
6.8 
Exploratory Analyses........................................................... 110 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 111 
7.1 
Data Quality Assurance....................................................... 111 
7.2 
Electronic Case Report Forms............................................. 111 
7.3 
Electronic Patient-Reported Outcome Data......................... 112 
7.4 
Source Data Documentation................................................ 112 
7.5 
Use of Computerized Systems ............................................ 113 
7.6 
Retention of Records........................................................... 113 
8. 
ETHICAL CONSIDERATIONS.................................................................. 113 
8.1 
Compliance with Laws and Regulations .............................. 113 
8.2 
Informed Consent ................................................................ 113 
8.3 
Institutional Review Board or Ethics Committee.................. 115 
8.4 
Confidentiality...................................................................... 115 
8.5 
Financial Disclosure ............................................................ 115 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 116 
9.1 
Study Documentation .......................................................... 116 
9.2 
Protocol deviations .............................................................. 116 
9.3 
Site Inspections ................................................................... 116 
9.4 
Administrative Structure....................................................... 116 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 117 
9.6 
Protocol Amendments ......................................................... 118 
10. REFERENCES ......................................................................................... 119 
 
 
LIST OF TABLES 
Table 1 
Overall Response Rates and Time to Response in Patients 
in Part 2 of Study AF-001JP........................................................ 39 
Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib ...................................................................................... 82 


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Table 3 
Crizotinib Dose Modification⎯Hematologic Toxicities 
(Except Lymphopenia) ................................................................ 87 
Table 4 
Crizotinib Dose Modification⎯Non-Hematologic Toxicities......... 88 
Table 5 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in the NCI CTCAE ......................................... 92 
 
 
LIST OF FIGURES 
Figure 1 
Change in Size of Target Lesions as Assessed by the 
Independent Review Committee in Part 2 of Study AF-001JP 
Using RECIST v1.1 (Data Cutoff Date: 18 April 2013)................ 38 
Figure 2 
Duration of Dosing by Cohort in Patients in Part 1 of 
Study NP28761/AF-002JG (Data Cutoff Date: 
12 September 2013) ................................................................... 40 
Figure 3 
Best Percent Change in Size of Target Lesions from 
Baseline as Assessed by the Investigator in Patients in 
Part 1 of Study NP28761/AF-002JG (Data Cutoff Date: 
12 September 2013) ................................................................... 41 
Figure 4 
Summary of Study Design .......................................................... 47 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 124 
Appendix 2 
Schedule of Alectinib Pharmacokinetic Assessments............... 130 
Appendix 3 
List of Substrates, Inhibitors, and Inducers of Drug-
Metabolizing Enzymes and Transporters.................................. 131 
Appendix 4 
Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1: Excerpt from Original Publication.......................... 133 
Appendix 5 
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 144 
Appendix 6 
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires .......... 145 
Appendix 7 
Modification of Diet in Renal Disease (MDRD) Formula ........... 151 
Appendix 8 
Anaplastic Lymphoma Kinase (ALK) Immunohistochemistry.... 152 
Appendix 9 
Drug Metabolism Enzymes, Transporters (DMET), and Liver 
Injury Polymorphisms................................................................ 153 


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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
RANDOMIZED, MULTICENTER, PHASE III, 
OPEN-LABEL STUDY OF ALECTINIB VERSUS 
CRIZOTINIB IN TREATMENT-NAÏVE ANAPLASTIC 
LYMPHOMA KINASE−POSITIVE ADVANCED 
NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: BO28984 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2013-004133-33 
IND NUMBER: 
111723 
UTN NUMBER: 
 
TEST PRODUCT: 
Alectinib (RO5424802) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return a copy of the form to your local study monitor.  Please retain the original 
for your study files. 


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PROTOCOL SYNOPSIS 
TITLE: 
RANDOMIZED, MULTICENTER, PHASE III, OPEN-LABEL STUDY 
OF ALECTINIB VERSUS CRIZOTINIB IN TREATMENT-NAÏVE 
ANAPLASTIC LYMPHOMA KINASE−POSITIVE ADVANCED 
NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: 
BO28984 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2013-004133-33 
IND NUMBER: 
111723 
UTN NUMBER: 
 
TEST PRODUCT: 
Alectinib (RO5424802) 
PHASE: 
Phase III 
INDICATION: 
Anaplastic lymphoma kinase−positive (ALK-positive) non−small cell 
lung cancer (NSCLC) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Efficacy Objectives 
The primary efficacy objective for this study is as follows: 
• 
To evaluate and compare the efficacy of alectinib compared with crizotinib in patients with 
treatment-naïve anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung 
cancer (NSCLC), as measured by investigator-assessed progression-free survival (PFS) 
The secondary efficacy objectives for this study are as follows: 
• 
To evaluate and compare the Objective Response Rate (ORR) and Duration of Response 
(DOR) 
• 
To evaluate and compare the time to progression in the CNS on the basis of Independent 
Review Committee (IRC) review of radiographs by Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 and Revised Assessment in Neuro Oncology (RANO) criteria, as 
well as: 
To evaluate CNS objective response rate (C-ORR) in patients with CNS metastases 
who have measurable disease in the CNS at baseline  
To assess CNS duration of response (C-DOR) in patients who have a CNS Objective 
Response  
To assess CNS progression rates (C-PR) at 6, 12, 18, and 24 months on the basis of 
cumulative incidence  
• 
To evaluate and compare the PFS assessment by the IRC 
• 
To evaluate and compare the overall survival (OS) 
Safety Objective 
The safety objective for this study is as follows: 
• 
To evaluate the safety and tolerability of alectinib compared with crizotinib 


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Pharmacokinetic Objective 
The secondary pharmacokinetic (PK) objective for this study is as follows: 
• 
To characterize the pharmacokinetics of alectinib and metabolite(s) 
Patient-Reported Outcome Objectives 
The secondary patient-reported outcome (PRO) objectives for this study are as follows: 
• 
To evaluate and compare time to deterioration (TTD) in patient-reported lung cancer 
symptoms of cough, dyspnea (single item and multi-item subscales), chest pain, 
arm/shoulder pain, and fatigue as measured by the European Organization for the 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire − Core 
(QLQ-C30) and the supplemental lung cancer module (QLQ-LC13) as well as a composite 
of three symptoms (cough, dyspnea, chest pain). 
• 
To evaluate and compare PROs of health-related quality of life (HRQoL), patient functioning, 
and side effects of treatment as measured by the EORTC QLQ-C30 and EORTC 
QLQ-LC13. 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To evaluate and compare patient's health status as assessed by the EuroQoL 5 Dimension 
(EQ-5D-3L) questionnaire to generate utility scores for use in economic models for 
reimbursement. 
• 
To evaluate and compare an onset of hypogonadism in adult men by measuring total 
testosterone, albumin and sex hormone-binding globulin (SHBG) to calculate free 
testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in 
blood. 
• 
To evaluate and compare efficacy and safety in patients with treatment-naïve ALK-positive 
NSCLC as assessed by the FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott). 
• 
To investigate molecular mechanisms of resistance to ALK inhibitors. 
• 
To investigate detection of ALK mutations in plasma and circulating tumor cells. 
Study Design 
Description of Study 
This is a randomized, active controlled, multicenter Phase III open-label study in patients with 
treatment-naïve ALK-positive advanced NSCLC.  All patients are required to provide 
pretreatment tumor tissue to confirm the presence of ALK rearrangement (by Ventana 
immunohistochemistry [IHC] test).  Patients will be randomized 1:1 into one of the two treatment 
arms to receive either alectinib or crizotinib. 
This study will comprise approximately 180 centers, in around 30 countries worldwide. 
Central randomization will be performed via an interactive voice or web-based response system 
(IxRS) using the following stratification factors:  Eastern Cooperative Oncology Group 
Performance Status (ECOG PS) (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at 
baseline (yes vs. no).  An IxRS manual containing relevant information will be provided to each 
study site. 
The experimental arm will receive alectinib at 600 mg orally twice daily (BID), taken with food.  
The control arm will receive crizotinib at 250 mg orally BID, taken with or without food.  The first 
dose of the study drug should be administered as soon as possible after randomization, 
preferably within 24 hours, and no later than 48 hours after randomization. 
Patients will be treated until disease progression, unacceptable toxicity, withdrawal of consent, 
or death.  After disease progression (as per RECIST v1.1), patients should discontinue the study 
medication.  After disease progression, patients will be treated at the discretion of the 
investigator according to local practice.  Information regarding the nature and the duration of 
subsequent therapies will be collected. 
In case of isolated asymptomatic CNS progression (e.g., new CNS oligometastases) a local 
therapy can be given (e.g., stereotactic radiotherapy or surgery) followed by continuation of 
either alectinib (in alectinib arm) or crizotinib (in crizotinib arm) until systemic disease 
progression and/or symptomatic CNS progression.  The decision to continue the treatment 


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beyond isolated, asymptomatic CNS progression is at the investigator’s discretion for patients 
who can continue to benefit from respective treatment. 
Patients who discontinue treatment prior to disease progression (e.g., due to unacceptable 
toxicity or withdrawal of consent) will continue to be followed until disease progression and for 
OS regardless of whether they subsequently receive non-study anti-cancer therapy.  Data for 
subsequent therapy will be collected for the analysis of OS. 
Number of Patients 
Approximately 286 patients will be randomly assigned in a 1:1 allocation ratio to the two 
treatment arms via a block stratified randomization procedure and over a planned recruitment 
period of 24 months. 
Randomization will guard against systematic selection bias and should ensure the comparability 
of treatment groups.  To assist balance in important prognostic factors, randomization will be 
stratified by ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at baseline 
(yes vs. no). 
Target Population  
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not 
amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive 
as assessed by the Ventana IHC test.  Sufficient tumor tissue to perform ALK IHC and ALK 
FISH is required.  Both tests will be performed at designated central laboratories. 
• 
Age ≥ 18 years old. 
• 
Life expectancy of at least 12 weeks. 
• 
ECOG PS of 0-2. 
• 
Patients had no prior systemic treatment for advanced or recurrent (Stage IIIB not 
amenable for multimodality treatment) or metastatic (Stage IV) NSCLC. 
• 
Adequate hematologic function: 
Platelet count ≥ 100 × 109/L 
ANC ≥ 1500 cells/μL 
Hemoglobin ≥ 9.0 g/dL 
• 
Adequate renal function: 
An estimated glomerular filtration rate (eGFR) calculated using the Modification of 
Diet in Renal Disease equation of at least 45 mL/min/1.73 m2 
• 
Patients must have recovered from effects of any major surgery or significant traumatic 
injury at least 28 days before the first dose of study treatment. 
• 
Measurable disease (by RECIST v1.1) prior to the administration of study treatment. 
• 
Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed 
incidentally at study baseline).  Asymptomatic CNS lesions might be treated at the 
discretion of the investigator as per local clinical practice.  If patients have neurological 
symptoms or signs due to CNS metastasis, patients need to complete whole brain radiation 
or gamma knife irradiation treatment.  In all cases, radiation treatment must be completed 
at least 14 days before enrollment and patients must be clinically stable. 
• 
For all females of childbearing potential, a negative pregnancy test must be obtained within 
3 days before starting study treatment. 


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• 
For women who are not postmenopausal ( ≥ 12 months of non-therapy-induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus):  agreement to remain abstinent or 
use single or combined contraceptive methods that result in a failure rate of  < 1% per year 
during the treatment period and for at least 3 months after the last dose of study drug.  
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  Examples of 
non-hormonal contraceptive methods with a failure rate of < 1% per year include tubal 
ligation, male sterilization, hormonal implants, established, proper use of combined oral or 
injected hormonal contraceptives, and certain intrauterine devices.  Alternatively, two 
methods (e.g., two barrier methods such as a condom and a cervical cap) may be 
combined to achieve a failure rate < 1% per year.  Barrier methods must always be 
supplemented with the use of a spermicide.  
• 
For men:  agreement to remain abstinent or use a condom plus an additional contraceptive 
method that together result in a failure rate of  < 1% per year during the treatment period 
and for at least 3 months after the last dose of study drug.  Abstinence is only acceptable if 
it is in line with the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.   
• 
Able and willing to provide written informed consent prior to performing any study related 
procedures and to comply with the study protocol, including patients must be willing and 
able to use the electronic patient-reported outcome device. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients with a previous malignancy within the past 3 years are excluded (other than 
curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by 
endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered 
to have no impact in PFS and OS for the current NSCLC). 
• 
Any GI disorder that may affect absorption of oral medications, such as mal-absorption 
syndrome or status post-major bowel resection. 
• 
Liver disease characterized by: 
ALT or AST > 3 × ULN (≥ 5 × ULN for patients with concurrent liver metastasis) 
confirmed on two consecutive measurements 
OR 
Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or other 
conditions of decompensated liver disease such as coagulopathy, hepatic 
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices 
OR 
Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis 
• 
National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) 
Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding 
alopecia), which have not shown improvement and are strictly considered to interfere with 
current study medication. 
• 
History of organ transplant. 
• 
Co-administration of anti-cancer therapies other than those administered in this study. 
• 
Patients with baseline QTc > 470 ms or symptomatic bradycardia. 
• 
Administration of strong/potent cytochrome P4503A inhibitors or inducers within 14 days 
prior to the first dose of study treatment and while on treatment with alectinib or crizotinib 
except for oral corticosteroids up to 20 mg of prednisolone equivalent per day  
• 
Administration of agents with potential QT interval prolonging effects within 14 days prior to 
the first administration of study drug and while on treatment.  


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• 
History of hypersensitivity to any of the additives in the alectinib drug formulation (lactose 
monohydrate, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose, 
sodium lauryl sulfate [SLS], magnesium stearate). 
• 
History of hypersensitivity to any of the additives in the crizotinib drug formulation (silica, 
colloidal anhydrous cellulose, microcrystalline calcium hydrogen phosphate, anhydrous 
sodium starch glycolate, magnesium stearate). 
• 
Pregnant or lactating women. 
• 
Known HIV positivity or AIDS-related illness. 
• 
Any clinically significant concomitant disease or condition that could interfere with, or for 
which the treatment might interfere with, the conduct of the study or the absorption of oral 
medications or that would, in the opinion of the Principal Investigator, pose an unacceptable 
risk to the patient in this study. 
• 
Any psychological, familial, sociological, or geographical condition potentially hampering 
compliance with the study protocol requirements and/or follow-up procedures; those 
conditions should be discussed with the patient before trial entry. 
Length of Study 
The time from first patient screened to end of study, defined below, will be approximately 
43 months. 
End of Study 
This study is event-driven, with a recruitment period of approximately 24 months.  The required 
number of events for the final analysis of the primary endpoint is expected approximately 
33 months after the first patient has been enrolled.  Patients are to be treated until disease 
progression, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.  
Follow-up for survival will continue until the survival follow-up analysis or the Sponsor decides to 
end the trial, whichever occurs first.  The study will formally end once the survival follow-up 
analysis is complete. 
A survival follow-up analysis will be performed once approximately 50% of patients 
(i.e., 143 patients) have died, which is estimated to occur approximately 42 months after the first 
patient has been enrolled. 
Outcome Measures 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
• 
PFS, which is defined as the time from randomization to the first documented disease 
progression, as determined by the investigators (primary endpoint) or IRC (secondary 
endpoint) using RECIST v1.1 or death from any cause, whichever occurs first.  Patients 
without an event will be censored at the last tumor assessment either during follow-up or 
during study treatment.  Patients with no post-baseline assessments will be censored at the 
date of randomization. 
• 
ORR, which is defined as the percentage of patients who attain complete response (CR) or 
partial response (PR); response, as determined by the investigators using RECIST v1.1.  
Patients without any assessments will be regarded as non-responders. 
• 
Time to CNS progression, which is defined as the time from randomization to the first 
occurrence of disease progression in the CNS as determined by IRC using RECIST v1.1 
and RANO (separate assessments and analyses), as well as C-ORR in patients with CNS 
metastases who have measurable disease in the CNS at baseline, C-DOR in patients who 
have a CNS Objective Response, and C-PR at 6, 12, 18, and 24 months. 
• 
DOR, which is defined as the time from when response (CR or PR) was first documented to 
first documented disease progression or death (whichever occurs first).  This will only be 
calculated for patients who have a best overall response of CR or PR.  Patients who do not 
progress or die after they have had a response are censored at the date of their last tumor 
measurement. 


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• 
OS, which is defined as the time from randomization to death from any cause.  Patients 
without an event will be censored at the last date known to be alive.  Patients without any 
follow-up information will be censored at the date of randomization. 
Safety Outcome Measures 
The secondary safety outcome measures for this study are as follows: 
• 
Serious and non-serious adverse events 
• 
Safety laboratory tests values 
• 
Vital signs (blood pressure, heart rate), ECG 
• 
Physical examination 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Sparse (pre-dose) PK samples for measurement of alectinib and its major metabolite(s) will 
be collected in all study patients receiving alectinib treatment 
• 
Serial/intensive PK sampling will be collected in a subset of consenting patients enrolled to 
receive alectinib treatment (approximately 10%−15%, at least approximately n = 20) 
• 
PK parameters will be determined as appropriate and where data allow: 
The pharmacokinetics of alectinib (and metabolite[s], if appropriate) will be described, 
and the between-patient variability will be estimated using a population PK approach.  
The potential influence of covariates that contribute significantly to the between-patient 
differences in PK parameters of alectinib will also be explored and quantified. 
Non-compartmental analysis may be conducted in patients undergoing serial/intensive 
PK sample collection, as appropriate and where data allow. 
Patient-Reported Outcome Measures 
The PRO measures for this study are as follows: 
• 
EORTC QLQ-C30 and the EORTC QLQ-LC13 to determine the impact of alectinib 
compared with crizotinib as measured by TTD in patient-reported lung cancer symptoms 
(e.g., cough, dyspnea [single item and multi-item scales], pain in chest, pain in 
arm/shoulder, fatigue). 
• 
The EORTC QLQ-C30 and EORTC QLQ-LC13 to measure PROs of HRQoL, patient 
functioning, and side effects of therapy compared between patients treated with alectinib 
and those treated with crizotinib. 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
EQ-5D-3L to generate utility scores for use in economic models for reimbursement. 
• 
Total testosterone, albumin and SHBG to calculate free testosterone level, FSH, and LH, in 
blood to measure an onset of hypogonadism in adult men. 
• 
The FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) to evaluate and compare 
efficacy and safety in patients with treatment-naïve NSCLC that is ALK-positive by FISH 
test. 
• 
Post progression tumor mutation status to study molecular mechanisms of resistance to 
ALK inhibitors. 
• 
ALK mutation status in plasma DNA to monitor efficacy and disease progression. 
• 
ALK fusion status in circulating tumor cells in blood. 
Investigational Medicinal Products 
Test Product 
Alectinib comes in a hard capsule dosage form containing the following active ingredient: 
[Chemical name] 9-Ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-6, 
11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride 


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Each capsule contains 150 mg of alectinib (as free base) along with lactose monohydrate, 
carmellose calcium, hydroxypropyl cellulose, SLS, and magnesium stearate. 
Alectinib capsules should be stored in accordance with the storage instructions on the label.  
Alectinib capsules should be administered orally BID with food (within 30 minutes after a meal, 
in the morning and evening). 
Comparator 
Crizotinib comes in a hard capsule dosage form.  Each capsule contains 250 mg or 200 mg 
crizotinib.  Crizotinib hard capsules should be stored in accordance with the storage instructions 
on the label.  Crizotinib capsules should be administered orally BID. 
For further details, see the local prescribing information for crizotinib (Xalkori®). 
Non-Investigational Medicinal Products 
Standard-of-care therapy administered to all patients in addition to test product or comparator. 
Statistical Methods 
Primary Analysis 
PFS is defined as the time from date of randomization to the date of first documented disease 
progression or death, whichever occurs first.  The primary endpoint of PFS will be determined 
on the basis of investigator assessment of progression using RECIST v1.1.  Patients who have 
not experienced disease progression or death at the time of analysis will be censored at the last 
tumor assessment date either during study treatment or during follow-up.  Patients with no post-
baseline tumor assessment will be censored at the date of randomization. 
Patients who discontinue treatment prior to disease progression (e.g., due to toxicity) will 
continue on study and will be followed until disease progression and for OS regardless of 
whether they subsequently receive anti-cancer therapy. 
The treatment comparison of PFS will be based on a stratified log-rank test at the 5% level of 
significance (two-sided).  The stratification factors are the randomization stratification factors:  
ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at baseline (yes vs. no), 
as recorded on the eCRF.  Results from an unstratified log-rank test will also be presented. 
The Kaplan-Meier method will be used to estimate the median PFS for each treatment arm with 
95% confidence limits, and a Kaplan-Meier curve will be constructed to provide a visual 
description of the difference between the treatment arms.  A stratified Cox proportional 
regression model will be used including treatment in order to provide an estimate of the 
treatment effect expressed as a hazard ratio (HR) (alectinib vs. crizotinib), as well as a 95% CI. 
The difference between the two treatment groups will be assessed and tested for the following 
hypothesis:  the survival distribution function (SDF) of PFS of the alectinib treatment group is 
the same as for the crizotinib treatment group versus the alternative that the two distributions 
are different:  
H0:  SDF (alectinib) = SDF (crizotinib) 
versus 
H1:  SDF (alectinib) ≠ SDF (crizotinib) 
where SDF denotes the survival distribution function of the parameter PFS. 
Determination of Sample Size   
The focus of this clinical trial is hypothesis testing, and the primary endpoint of PFS was used to 
determine the sample size of the study. 
At the time of initially writing the protocol, there were no Phase III data available on crizotinib 
in the first line setting in ALK-positive patients.  The median PFS for crizotinib administered as 
second line therapy from the global randomized Phase III PROFILE 1007 study was 7.7 months 
(95% CI: 6.0%, 8.8%).  From the Phase II single arm study of patients who had received ≥ 1 line 
of chemotherapy (with 85% patients having received ≥ 2 prior chemotherapy regimens), the 
median PFS was 8.5 months (95% CI: 6.2%, 9.9%).  The Phase III PROFILE 1014 study of 
crizotinib versus standard pemetrexed-platinum-based chemotherapy in previously untreated 
patients with ALK-positive non-squamous NSCLC reported a median PFS of 10.9 months for 
crizotinib (Mok et al. 2014). 


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Thus, an initial assumption of median PFS of 9.8 months for the crizotinib arm has been 
reassessed based on data from the Phase III study PROFILE 1014 to 10.9 months.  An HR of 
0.65 for alectinib versus crizotinib (i.e., an increase from 10.9 months median PFS to 
16.8 months) will be targeted.  In this study, 286 patients will be enrolled in a 1:1 randomization 
allocation.  Enrollment will take approximately 24 months on the basis of an assumption of non-
linear recruitment as follows: 
• 
Month 1:  1 patient per month 
• 
Month 2:  2 patients per month 
• 
Month 3:  4 patients per month 
• 
Month 4:  6 patients per month 
• 
Month 5:  8 patients per month 
• 
Month 6:  10 patients per month 
• 
Month 7:  12 patients per month 
• 
Months 8−12:  13 patients per month 
• 
Months 13−14:  14 patients per month 
• 
Month 15 onwards:  15 patients per month 
A total of 170 PFS events are required to achieve 80% power at a two-sided alpha level of 5%.  
This number of PFS events is estimated to occur approximately 33 months after the first patient 
has been enrolled. 
Interim Analyses 
No interim analysis for efficacy or futility is planned. 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
AUC 
area under the concentration−time curve 
BID 
twice daily 
Cmax 
maximum concentration 
C-DOR 
CNS duration of response 
C-ORR 
CNS objective response rate 
C-PR 
CNS progression rate 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DOT 
duration of treatment 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EGFR 
epidermal growth factor receptor 
EML4 
echinoderm microtubule-associated protein-like 4 
EORTC  
European Organization for the Research and Treatment of Cancer  
ePRO 
electronic patient-reported outcome 
EQ-5D-3L 
EuroQoL 5 Dimension 
FDA 
U.S. Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FPP 
FISH Positive Population 
FSH 
follicle-stimulating hormone 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
HRQoL 
health-related quality of life 


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Abbreviation 
Definition 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITT 
intent to treat 
IxRS 
interactive voice or web-based response system 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
LH 
luteinizing hormone 
MET 
mesenchymal-epithelial transition factor 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCA 
non-compartmental analysis 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
not evaluable 
NSCLC 
non−small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
P-gp 
P-glycoprotein 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PRO 
patient-reported outcome 
QLQ-C30 
Quality of Life Questionnaire−Core 
QLQ-LC13 
Quality of Life Questionnaire lung cancer module 
RANO 
Revised Assessment in Neuro Oncology 
RCR 
Roche Clinical Repository 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROS1 
c-ros oncogene 1 
SAE 
serious adverse event 
SAP 
Safety Analysis Population 


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Abbreviation 
Definition 
SD 
stable disease 
SDF 
survival distribution function 
SLS 
sodium lauryl sulfate 
TKI 
tyrosine kinase inhibitor 
TTD 
time to deterioration 
UGT 
uridine 5'-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 


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1. 
BACKGROUND 
1.1 
BACKGROUND ON ANAPLASTIC LYMPHOMA 
KINASE−POSITIVE NON−SMALL CELL LUNG CANCER 
Non−small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality 
worldwide.  Lung cancer was estimated to cause 160,340 deaths in the United States 
in 2012, accounting for 28% of all cancer-related deaths according to the report from the 
American Lung Association (Lung Cancer Fact Sheet).  There is an annual incidence of 
310,000 cases of NSCLC in men in the Europe with a mortality of 276,000 deaths 
(GLOBOCAN 2008).  Among women in the Europe, there is an annual incidence of 
107,000 cases and a mortality of 91,000 deaths.  In total, there are 417,000 cases of 
NSCLC and 367,000 deaths in Europe each year, which represents a major health 
problem.  Survival rates for lung cancer tend to be much lower than other common 
cancers because of its late diagnosis and limited effective therapy in the advanced stage.  
The expected 5-year survival rate for all patients in whom lung cancer is diagnosed is 
16.3% compared with 65.2% for colon cancer, 90.0% for breast cancer, and 99.9% for 
prostate cancer (Siegel et al. 2012).  Conventional anti-cancer therapies are far from 
satisfactory, and there is an unmet medical need for the development of new therapies 
for NSCLC. 
Recent progress in the identification of genetic mutations or chromosomal 
rearrangements in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral 
oncogene homolog (KRAS), mesenchymal-epithelial transition factor (MET), and other 
genes has provided new opportunities to use targeted therapeutic agents for the 
treatment of NSCLC, when the tumor is identified as having these mutations 
(Katayama et al. 2011; Doebele et al. 2012). 
Approximately 5% of NSCLC cases have been shown to harbor the echinoderm 
microtubule-associated protein-like 4 (EML4)−anaplastic lymphoma kinase (ALK) fusion 
gene as a result of a chromosomal inversion at 2p21 and 2p23 (Choi et al. 2010; 
Ou et al. 2012).  The formation of the resulting ALK fusion protein results in activation 
and dysregulation of the gene’s expression and signaling, which can contribute to 
increased cell proliferation and survival in tumors expressing these genes.  This is 
further supported by reports that the TFG and KIF5B genes can also serve as ALK 
fusion partners in some NSCLC patients.  Expression of these ALK fusion genes in 
mouse 3T3 fibroblasts causes their transformation and enhanced proliferation.  ALK 
gene alterations are generally in a mutually exclusive relationship with mutations in 
EGFR or KRAS (Soda et al. 2007; Inamura et al. 2008; Inamura et al. 2009; 
Wong et al. 2009), although EGFR mutations may develop as a resistance mechanism 
after treatment with crizotinib (Doebele et al. 2012).  Inhibition of ALK activity in Ba/F3 
cells transfected with the EML4-ALK fusion protein resulted in inhibition of cell growth 
(Ou et al. 2012), whereas a small molecule inhibitor of ALK demonstrated anti-tumor 
efficacy in two xenograft models in athymic mice, namely, the H3122 NSCLC and 
Karpas299 anaplastic large cell lymphoma models harboring the EML4-ALK and 


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nucleophosmin-ALK fusion proteins, respectively.  Hence, ALK appears to be a suitable 
therapeutic target for NSCLC with ALK gene rearrangements. 
Wild-type ALK is hardly expressed at all in most normal human tissues, being expressed 
at higher levels in a few limited types of tissue such as developing and mature nervous 
system tissue (glial cells, neurons, endothelial cells, and pericytes) (Pulford et al. 1997).  
By contrast, an aberrant ALK with constitutively active kinase results from the formation 
of the EML4-ALK fusion gene by chromosomal translocation. 
Currently, the only approved medicine for treatment-naïve ALK-positive NSCLC is 
crizotinib (Xalkori®, Pfizer, Inc.), an inhibitor of receptor tyrosine kinases including ALK, 
hepatocyte growth factor receptor (HGFR, c-Met), recepteur d’origine nantais (RON), 
and c-ros oncogene 1 (ROS1) (Sahu et al. 2013).  
Crizotinib was first granted accelerated approval by the U.S. Food and Drug 
Administration (FDA) for the treatment of patients with locally advanced or metastatic 
NSCLC that is positive for ALK as detected by an FDA-approved test in August 2011.  
The approval was based on two single-arm trials.  The primary endpoint of both trials 
was ORR as assessed by the investigator.  In one study, the ORR was 50% 
(95% CI: 42%, 59%) with a median response duration of 42 weeks, and, in other study, 
the ORR was 61% (95% CI: 52%, 70%) with a median response duration of 48 weeks 
(Camidge et al. 2012; Kim et al. 2012).  In November 2013, the FDA granted regular 
approval for crizotinib on the basis of demonstrating superior progression-free survival 
(PFS) and ORR for crizotinib compared with chemotherapy in patients with ALK-positive 
NSCLC whose disease progressed after platinum-based doublet chemotherapy 
(PROFILE 1007 study).  An open-label active-controlled multinational randomized trial 
enrolled 347 patients with ALK-positive metastatic NSCLC.  Patients were required to 
have disease progression following platinum-based chemotherapy.  The trial 
demonstrated significantly prolonged PFS with crizotinib treatment compared with 
chemotherapy (HR = 0.49 [95% CI: 0.37, 0.64], p < 0.0001).  Median PFS was 7.7 months 
for patients treated with crizotinib and 3.0 months for patients treated with chemotherapy.  
The ORR was significantly higher for patients treated with crizotinib (65% vs. 20%), with 
median response durations of 7.4 months for patients treated with crizotinib and 5.6 
months for patients treated with chemotherapy.  No difference in overall survival (OS) 
was noted between the two groups (HR = 1.02 [95% CI: 0.68%, 1.54%]) in a planned 
interim analysis (Shaw et al. 2013).  Common adverse reactions in clinical trials with 
crizotinib, occurring at an incidence of 25% or higher, included visual disorders, nausea, 
diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue (National 
Cancer Institute 2013).  These results showed that an ALK inhibitor is effective in 
patients with NSCLC harboring ALK fusion genes.  Crizotinib has subsequently been 
approved in other countries, such as Japan, Korea, Canada, and Switzerland.  In the 
European Union, crizotinib was conditionally approved in October 2012 for the treatment 
of adults with previously treated ALK positive NSCLC. 


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Although substantial benefit has been observed with crizotinib therapy, relapse remains 
the norm.  Studies with patients who had progression with crizotinib treatment reveal two 
main reasons for treatment failure: the development of resistance because of secondary 
(e.g., gatekeeper) mutations (predominantly in ALK or occasionally in other genes, such 
as EGFR, cKIT, or KRAS) (Katayama et al. 2011; Doebele et al. 2012; Kim et al. 2013) 
and CNS relapse (crizotinib has impaired control of brain metastases in comparison to 
other sites of systemic disease).  The CNS is the primary site of initial treatment failure in 
46% of patients with ALK-positive NSCLC treated with crizotinib (Costa et al. 2011; 
Chun et al. 2012; Weickhardt et al. 2012).  Significant morbidity is associated with brain 
metastases as a function of brain involvement, and because of treatment (corticosteroids, 
surgery, and radiation) required for disease control. 
A new generation of ALK inhibitors will have the potential to overcome these two major 
limitations of crizotinib treatment to offer patients a better chance of prolonged remission 
and minimize the development of CNS metastases and the attendant comorbidity. 
1.2 
BACKGROUND ON ALECTINIB 
Alectinib (also RO5424802 or CH5424802) is a newly developed small molecule, highly 
selective, and potent oral next-generation ALK inhibitor with a benzo[b]carbazole 
scaffold.  In enzyme inhibition assays performed in vitro, this compound has been shown 
to selectively inhibit ALK.  The compound also shows high antitumor activity both in vitro 
and in vivo against tumor cell lines with some type of ALK gene alteration, including 
NSCLC and anaplastic large cell lymphoma lines harboring an ALK translocation and a 
neuroblastoma line harboring amplified ALK gene. 
Nonclinical pharmacology studies showed that alectinib is efficacious in a model of 
tumors expressing an ALK fusion bearing the L1196M mutation, which is associated with 
resistance to crizotinib, and alectinib is effective in mouse NCI H2228 NSCLC xenografts 
that are already maximally suppressed by crizotinib.  Alectinib also prolongs survival in 
an intracerebral NCI H2228 implantation model, and it reduces tumor growth in an 
intracranial model monitored using bioluminescence. 
The clinical development program for alectinib, to date, comprises three ongoing 
Phase I/II studies in patients with ALK-positive NSCLC.  The ongoing Phase I/II studies 
are as follows:  Study AF-001JP, which is being conducted in Japan; 
Study NP28761/AF-002JG, which is being conducted in United States and Canada; and 
Study NP28673, which is being conducted globally. 
The first-in-human study AF-001JP is an open-label Phase I/II study being conducted in 
Japan.  This study is assessing the pharmacokinetics, safety, and efficacy of alectinib in 
patients with ALK-positive NSCLC who are crizotinib-naïve and have disease 
progression after at least one line of chemotherapy.  This study has completed 
enrollment, but it is still ongoing.  A total of 70 patients were included (24 patients in the 
Phase I portion and 46 patients in the Phase II portion of the study).  In the Phase I 


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portion of the study, at the data cutoff date of 31 July 2012, 24 patients were treated at 
doses of 20−300 mg twice daily (BID).  No dose-limiting toxicities (DLTs) or adverse 
events of Grade 4 were noted up to the highest dose; thus, 300 mg BID was evaluated 
in the Phase II portion of the study without further escalating the dose.  In the Phase II 
portion of the study, 46 patients were treated with the highest evaluated dose of 300 mg 
BID, of whom 43 achieved an objective response (93.5%; 95% CI: 82.1%, 98.6%) and 
7 patients had a complete response (CR) on the basis of an independent radiological 
review in the 12-month follow-up analysis (data cutoff for response data: 18 April 2013).  
The median duration of treatment (DOT) in the study has not been achieved at that date 
because 86% of patients were still on treatment in the study, but the projected median 
DOT is more than 14 months as data mature. 
Figure 1 shows the waterfall plot of the best change from baseline in the size of target 
lesions by an independent radiological review.  Table 1 shows the objective response 
rate (ORR) by time interval.  The majority (86%) of patients had a time to response of 
within 6 weeks after administration of the first dose. 
Figure 1 Change in Size of Target Lesions as Assessed by the 
Independent Review Committee in Part 2 of Study AF-001JP 
Using RECIST v1.1 (Data Cutoff Date: 18 April 2013) 
 


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Two of 7 patients who were assessed as having a CR had lymph nodes as the target 
lesions.  Per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), 
the percent change from baseline for patients with CR can be less than 100% when 
lymph nodes are identified as the target lesions.  Therefore, they were assessed as 
having CR, although their tumor change from baseline was less than 100%. 
Table 1 
Overall Response Rates and Time to Response in Patients 
in Part 2 of Study AF-001JP 
Response (Data Cutoff Date: 18 April 2013) 
IRC Assessment (N = 46) 
Complete response 
7 
Partial response 
36 
Stable disease 
1 
Progressive disease 
0 
Not evaluable 
2 
Total response 
43 
Overall response rate (95% CI) 
93.5% (82.1%, 98.6%) 
Time to Response 
IRC Assessment (N = 43) 
0 to ≤ 3 weeks 
22 (51%) 
> 3 to ≤ 6 weeks 
15 (35%) 
> 6 to ≤ 9 weeks 
3 (7%) 
> 9 weeks 
3 (7%) 
IRC = Independent Review Committee. 
 
In Study NP28761/AF-002JG (crizotinib-failed ALK-positive NSCLC patients), the 
Phase I portion has completed enrollment.  Two ‘bridging’ cohorts of patients receiving 
alectinib using the 150-mg capsule at 600 and 900 mg BID were included in 
Study NP28761/AF-002JG to transition/facilitate the planned formulation for the Phase II 
trials.  A total of 47 patients were enrolled in Phase I (Part 1).  There does not appear to 
be any substantial difference in pharmacokinetics between the two formulations 
(20/40-mg capsule and the 150-mg capsule) at the 600-mg dose on the basis of 
available data. 
The radiological imaging analysis performed in 44 evaluable patients who had a baseline 
scan and at least one follow-up scan (data cutoff date: 12 September 2013) has shown 
that 2 of 7 patients in the 300-mg BID dosage cohort, 5 of 7 patients in the 460-mg BID 
dosage cohort, 4 of 10 patients in the 600-mg BID dosage cohort, and 4 of 13 patients 
(including 1 patient with CR) in the 900-mg BID dosage cohort have achieved a 
confirmed partial response (PR), as assessed by the investigator.  Three of 10 patients 
in the 600-mg BID dosage cohort, 2 of 7 patients in the 760-mg BID dosage cohort, and 
4 of 13 patients in the 900-mg BID dosage cohort have achieved a PR, as assessed by 
the investigator, which is still to be confirmed.  Three patients (all in the 600-mg BID 






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both systemic disease and CNS progression).  No patient discontinued because of CNS 
progression alone. 
In addition, 2 patients with leptomeningeal carcinomatosis received benefit from alectinib 
treatment.  One patient with leptomeningeal spread in Study NP28761/AF-002JG 
achieved PR after 6 weeks of treatment.  Another patient with leptomeningeal 
carcinomatosis but without systemic lesions was treated under a single-patient 
Investigational New Drug (IND) application because of ineligibility to enter either of the 
two Phase II alectinib studies (because of the high intake of dexamethasone for 
symptom control).  After 6 weeks of treatment, this patient achieved CR as 
demonstrated by complete disappearance of gadolinium enhancement on magnetic 
resonance imaging (MRI) and disappearance of positive CSF cytology.  This patient has 
been able to reduce corticosteroids to physiological replacement dose only. 
See the Alectinib Investigator's Brochure for additional details on nonclinical and clinical 
studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Over the past 10 years, the treatment of NSCLC has become increasingly focused on 
guiding treatment based on the presence or absence of an actionable mutation.  
Numerous oncogenes have now been identified in NSCLC, including mutations in the 
genes coding for EGFR, KRAS, phosphoinositide-3-kinase, catalytic, α polypeptide, and 
human EGFR 2 (Pao and Girard 2011).  As described in previous sections, a 
translocation in the gene encoding the receptor tyrosine kinase ALK, leading to the 
expression of ALK fusion proteins, was identified as an oncogenic driver in a subset of 
patients with NSCLC (Soda et al. 2007).  ALK rearrangements are found in 
approximately 4.6% of unselected patients with NSCLC (Koivunen et al. 2008; 
Takeuchi et al. 2008; Boland et al. 2009; Wong et al. 2009; Bang 2011; Kim et al. 2011; 
Paik et al. 2011; Cardarella et al. 2012; Dai et al. 2012; Fukui et al. 2012;). 
Crizotinib is the first ALK inhibitor that is approved and has been registered in multiple 
countries worldwide for the treatment of ALK-positive NSCLC.  Crizotinib is an oral 
small-molecule multitargeted tyrosine kinase inhibitor (TKI) targeting ALK, MET, RON, 
and ROS1 tyrosine kinases (Sahu et al. 2013, Shaw et al. 2013).  The previous clinical 
studies reported that the median PFS with crizotinib ranged from 7.7 to 9.7 months 
(Camidge et al. 2012, Kim et al. 2013, Shaw et al. 2013).  The PROFILE 1014 study, a 
Phase III study of crizotinib compared with standard pemetrexed−platinum−based 
chemotherapy, was presented at the ASCO 2014 congress (Mok et al. 2014).  The study 
met its primary objective of prolonging PFS in previously untreated patients with 
ALK-positive non-squamous NSCLC with median PFS of 10.9 and 7.0 months (HR: 
0.454; 95% CI: 0.346, 0.596; p < 0.0001) for crizotinib and pemetrexed-platinum-based 
chemotherapy, respectively. 


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Although substantial benefit has been observed with crizotinib therapy, relapse 
eventually occurs.  Two main reasons for this are the development of resistance 
because of secondary (e.g., gatekeeper) mutations or CNS relapse 
(Katayama et al. 2011; Doebele et al. 2012; Kim et al. 2013).  This could be due to the 
fact that crizotinib is a P-gp substrate and has a low penetration in the CNS.  Thus 
ALK-positive NSCLC treated with crizotinib has impaired control of brain metastases 
relative to other sites of systemic disease, with 46% of progressions in patients treated 
with crizotinib involving the CNS (Costa et al. 2011; Weickhardt et al. 2012).  The CNS 
becomes a sanctuary site for ALK-positive NSCLC treated with crizotinib⎯a physiologic 
and anatomic mechanism of drug resistance. 
Alectinib is a highly selective and potent, oral next generation ALK inhibitor.  Clinical 
data from the Phase II portion of the still ongoing Study AF-001JP, assessing alectinib in 
patients with ALK-positive NSCLC who are crizotinib-naïve and have disease 
progression after at least one line of chemotherapy, reported that the median treatment 
duration in the study has not been achieved as 86% of patients were still active on the 
study, but the projected median DOT is estimated to be at least 14 months as data 
mature (Inoue et al. 2013). 
Moreover, alectinib is lipophilic drug and not a P-glycoprotein (P-gp) substrate, thus, 
could penetrate through the blood-brain barrier and has the potential to reach higher 
concentration in brain as compared with substrates of the P-gp, such as crizotinib.  This 
has been shown in the nonclinical setting on the basis of the prolongation of survival in a 
mouse model with implanted CNS lesions and in a tissue distribution study with a single 
oral dose of [14C]-alectinib at 1 mg/kg to albino rats (Ou et al. 2013).  Preliminary clinical 
data from the Phase I/II studies show consistent therapeutic efficacy of alectinib in brain 
metastases. 
The clinical efficacy data is compelling given the shown activity for a longer progression 
free interval with alectinib and improved activity in the CNS, thus delaying the impact of 
CNS metastases on neurologic function along with the morbidities associated with 
treatment like brain radiation, surgery and corticosteroid use required for disease control.  
The currently available clinical safety data is supportive for an acceptable safety and 
tolerability profile with alectinib.  Altogether, it would be important to compare alectinib to 
crizotinib as a therapeutic option for treatment-naïve ALK-positive advanced NSCLC 
patients. 
Alectinib was granted approval in Japan on 4 July 2014 for ALK fusion gene-positive, 
unresectable, recurrent, or advanced NSCLC. 
In this proposed Phase III study, treatment-naïve patients with ALK-positive advanced 
NSCLC will be enrolled and will be randomized to receive either crizotinib or alectinib 
treatment.  The results of this study will determine whether alectinib treatment has 
superior efficacy compared with crizotinib. 


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The first Phase I dose-escalation study of alectinib conducted only in Japan 
(Study AF001-JP), with a dose schedule of 20, 40, 80, 160, 240, and 300 mg BID orally, 
showed that alectinib was generally well tolerated without major toxicities.  Of the 
58 patients who received treatment with 300 mg BID alectinib in Study AF-001JP, 
27 experienced Grade 3 adverse events and 9 experienced serious adverse events.  No 
deaths were reported during this study and up to 28 days after treatment discontinuation.  
There were 5 adverse events leading to treatment discontinuation in Part 2 (brain edema, 
sclerosing cholangitis, interstitial lung disease [ILD], ALT increased, and tumor 
hemorrhage).  Alectinib was well tolerated at all doses investigated in this study.  Its 
adverse event profile was consistent with the one known to be associated with TKIs.  In 
the Phase II Study NP28761/AF-002JG, alectinib was well tolerated, with no DLTs or 
treatment-related dose modifications up to 600 mg BID.  Two DLTs were reported at 
900 mg BID.  The recommended alectinib Phase II dosage of 600 mg BID was chosen 
as having the best balance between clinical safety, efficacy, and pharmacokinetic (PK) 
data as observed in the Phase I/II studies (see Section 3.3.1). 
On the basis of available preliminary data, the estimated benefits of alectinib treatment 
outweigh the risks, specifically: 
• 
Available nonclinical and clinical data demonstrate that alectinib is active in NSCLC 
in crizotinib-naïve patients as well as after progression on prior crizotinib therapy 
• 
Clinical safety data in humans up to 900 mg BID demonstrate that its safety profile 
is consistent to the one known to be associated with TKIs. 
Identified and potential risks associated with alectinib treatment will continue to be 
closely monitored throughout the clinical program.  Patient safety during the alectinib 
program is ensured by:  targeting the most appropriate patient population, stringent 
safety monitoring by the Sponsor and Independent Data Monitoring Committee (IDMC), 
and by protocol-specified study drug interruption criteria. 
2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The primary efficacy objective for this study is as follows: 
• 
To evaluate and compare the efficacy of alectinib compared with crizotinib in 
patients with treatment-naïve ALK-positive advanced NSCLC, as measured by 
investigator-assessed PFS 
 
The secondary efficacy objectives for this study are as follows: 
• 
To evaluate and compare the Objective Response Rate (ORR) and Duration of 
Response (DOR) 


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• 
To evaluate and compare the time to progression in the CNS on the basis of IRC 
review of radiographs by RECIST v1.1 and Revised Assessment in Neuro Oncology 
(RANO) criteria, as well as: 
To evaluate CNS objective response rate (C-ORR) in patients with CNS 
metastases who have measurable disease in the CNS at baseline  
To assess CNS duration of response (C-DOR) in patients who have a CNS 
Objective Response  
To assess CNS progression rates (C-PR) at 6, 12, 18, and 24 months on the 
basis of cumulative incidence  
• 
To evaluate and compare the PFS assessment by the IRC 
• 
To evaluate and compare the OS 
 
2.2 
SAFETY OBJECTIVES 
The secondary safety objective for this study is as follows: 
• 
To evaluate the safety and tolerability of alectinib compared with crizotinib 
 
2.3 
PHARMACOKINETIC OBJECTIVES 
The secondary PK objective for this study is as follows: 
• 
To characterize the pharmacokinetics of alectinib and metabolite(s) 
 
2.4 
PATIENT-REPORTED OUTCOME OBJECTIVES 
The secondary patient-reported outcome (PRO) objectives for this study are as follows: 
• 
To evaluate and compare time to deterioration (TTD) in patient-reported lung cancer 
symptoms of cough, dyspnea (single item and multi-item subscales), chest pain, 
arm/shoulder pain, and fatigue as measured by the European Organization for the 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire−Core 
(QLQ-C30) and the supplemental lung cancer module (QLQ-LC13) as well as a 
composite of three symptoms (cough, dyspnea, chest pain). 
• 
To evaluate and compare PROs of (HRQoL), patient functioning, and side effects of 
treatment as measured by the EORTC QLQ-C30 and EORTC QLQ-LC13. 
 
2.5 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To evaluate and compare patient’s health status as assessed by the EuroQoL 5 
Dimension (EQ-5D-3L) questionnaire to generate utility scores for use in economic 
models for reimbursement. 
• 
To evaluate and compare an onset of hypogonadism in adult men by measuring 
total testosterone, albumin and sex hormone-binding globulin (SHBG) to calculate 
free testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) 
levels in blood. 


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• 
To evaluate and compare efficacy and safety in patients with treatment-naïve 
ALK-positive NSCLC as assessed by the FISH Vysis® ALK Break Apart FISH Probe 
Kit (Abbott). 
• 
To investigate molecular mechanisms of resistance to ALK inhibitors. 
• 
To investigate detection of ALK mutations in plasma and circulating tumor cells. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a randomized, active-controlled, multicenter Phase III open-label study in patients 
with treatment-naïve ALK-positive advanced NSCLC.  All patients are required to 
provide pretreatment tumor tissue to confirm the presence of ALK rearrangement (by 
Ventana immunohistochemistry [IHC] test).  Patients will be randomized 1:1 into one of 
the two treatment arms to receive either alectinib or crizotinib. 
This study will comprise approximately 180 centers, in around 30 countries worldwide. 
The primary endpoint of the study is investigator-assessed PFS. 
Central randomization will be performed via an interactive voice or web-based response 
system (IxRS) using the following stratification factors:  Eastern Cooperative Oncology 
Group Performance Status (ECOG PS) (0/1 vs. 2), race (Asian vs. non-Asian), and CNS 
metastases at baseline (yes vs. no).  An IxRS manual containing relevant information 
will be provided to each study site. 
The experimental arm will receive alectinib at 600 mg orally BID, taken with food.  The 
control arm will receive crizotinib at 250 mg orally BID, taken with or without food.  The 
first dose of the study drug should be administered as soon as possible after 
randomization, preferably within 24 hours, and no later than 48 hours after 
randomization. 
Patients will be treated until disease progression, unacceptable toxicity, withdrawal of 
consent, or death.  After disease progression (as per RECIST v1.1), patients should 
discontinue the study medication.  After disease progression, patients will be treated at 
the discretion of the investigator according to local practice.  Information regarding the 
nature and the duration of subsequent therapies will be collected. 
In case of isolated asymptomatic CNS progression (e.g., new CNS oligometastases), 
local therapy can be given (e.g., stereotactic radiotherapy or surgery) followed by 
continuation of either alectinib (in alectinib arm) or crizotinib (in crizotinib arm) until 
systemic disease progression and/or symptomatic CNS progression.  The decision to 
continue the treatment beyond isolated, asymptomatic CNS progression is at the 
investigator’s discretion for patients who can continue to benefit from their respective 
treatment. 




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3.2 
END OF STUDY 
This study is event-driven, with a recruitment period of approximately 24 months.  The 
required number of events for the final analysis of the primary endpoint is expected 
approximately 33 months after the first patient has been enrolled.  Patients are to be 
treated until disease progression, unacceptable toxicity, withdrawal of consent, or death, 
whichever occurs first.  Follow-up for survival will continue until the survival follow-up 
analysis or the Sponsor decides to end the trial, whichever occurs first.  The study will 
formally end once the survival follow-up analysis is complete. 
A survival follow-up analysis will be performed once approximately 50% of patients 
(i.e., 143 patients) have died, which is estimated to occur approximately 42 months after 
the first patient has been enrolled. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Alectinib Dosage 
Selection of the alectinib dose for the study is based on the clinical safety, efficacy, and 
PK data observed in the Phase I/II studies, AF-001JP and NP28761/AF-002JG, and the 
supportive nonclinical data for alectinib. 
The first-in-human study, AF-001JP evaluated escalating doses of alectinib in an 
accelerated titration scheme to rapidly identify the maximum tolerated dose (MTD).  All 
doses, including the highest evaluated dose in the study, 300 mg BID, were well 
tolerated with no DLTs observed at any dose.  The highest tested dose, 300 mg BID, 
was further evaluated in the Phase II portion of the study and demonstrated robust 
efficacy and good safety with an ORR by IRC of 93.5% (43/46 patients; 95% CI: 82.1%, 
98.6%). 
With no MTD determined in Study AF-001JP, dose escalation progressed in the United 
States Study NP28761/AF-002JG using a modified 3 + 3 design, where 3 patients were 
assessed for DLT evaluation whereas additional patients were enrolled for PK evaluation.  
The starting dose in Study NP28761/AF-002JG was the highest dosage evaluated in 
Study AF-001JP, 300 mg BID.  Following multiple dosages of alectinib at 300 mg BID in 
Study NP28761/AF-002JG, median alectinib exposure (area under the concentration 
time curve [AUC] from 0 to 10 hours) appeared to be approximately two-fold lower 
compared with that in patients from Study AF-001JP, which demonstrated the robust 
efficacy and safety.  Dose escalation progressed with evaluation of higher doses of 
alectinib up to 900 mg BID. 
In Study NP28761/AF-002JG, no DLTs were observed in the dose escalation cohorts, 
up to dose-level of 900 mg BID.  However, 2 patients in the subsequent 900 mg BID 
bridging cohort experienced a DLT; 1 patient had Grade 3 headache and 1 patient had 
Grade 3 neutropenia, and both patients continued study treatment at a reduced dosage 
of 600 mg BID.  Overall, alectinib was well tolerated in the study population.   


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Importantly, administration of 600 mg BID provides systemic exposures that meet or 
exceed exposures achieved in patients receiving 300 mg BID in Study AF-001JP, 
demonstrating its robust efficacy and safety in crizotinib-naïve patients.  Further, in 
Study NP28761/AF-002JG, the 600-mg BID regimen has demonstrated promising 
activity in crizotinib-resistant patients, including activity in patients with CNS metastases 
while being tolerated by patients.  On the basis of available preclinical data, 
administration of alectinib 600 mg BID provides systemic exposures within the expected 
range (on the basis of regression of available data) for tumor regression observed in 
mouse xenograft models. 
Thus, on the basis of nonclinical and clinical data, a dosing regimen of 600 mg BID of 
alectinib has been chosen as the optimal therapeutic dose level with the best balance 
between efficacy and safety. 
Alectinib 600 mg should be administered orally BID with food (within 30 minutes after a 
meal, in the morning and evening). 
3.3.2 
Rationale for Patient Population 
The study population will comprise patients with non-resectable, locally advanced and 
metastatic NSCLC who have been shown to be ALK-positive by Ventana IHC test 
performed at central laboratories specially designated for the study.  Patients should not 
have received any prior treatment for advanced NSCLC (treatment-naïve). 
Both experimental (alectinib) and control (crizotinib) treatments are ALK-targeted 
therapies.  The clinical practice guidelines recommend targeted treatment for patients 
with metastatic, oncogene-driven disease as first-line systemic therapy (i.e., 
EGFR-inhibitors for EGFR-positive NSCLC and ALK-inhibitors for ALK-positive NSCLC) 
(NCCN 2014).  
To be eligible for the study, determination of ALK positivity will be performed centrally by 
the IHC assay (see Appendix 8) that is being developed by Ventana Medical Systems as 
a companion diagnostic to alectinib.  IHC may replace fluorescence in situ hybridization 
(FISH)-based identification of ALK rearrangement as the standard companion diagnostic 
in the future.  IHC is faster, easier to perform in local laboratories, and requires less 
equipment compared with the FISH assay.  In addition, IHC has high concordance with 
FISH and a lower false-negative rate (Kim et al. 2011). 
3.3.3 
Rationale for Control Group 
Targeted therapy (including ALK-targeted therapy) is likely to have a greater antitumor 
effect than standard chemotherapy, offering patients a higher response rate and longer 
durability of response with less toxicity compared with any potential chemotherapy 
options (Mok et al. 2009; Rosell et al. 2012; Sequist et al. 2013; Shaw et al. 2013). 


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Crizotinib (Xalkori) is an oral small-molecule multi-targeted TKI targeting ALK, MET, 
RON, and ROS1 tyrosine kinases (Sahu et al. 2013, Shaw et al. 2013).  It is the only 
first-generation ALK inhibitor that has been approved in multiple countries worldwide for 
the treatment of ALK-positive NSCLC. 
In the United States, in November 2013, crizotinib has been granted a regular approval 
for ALK-positive NSCLC setting, regardless of treatment line (XALKORI® U.S. Package 
Insert), whereas in Europe, crizotinib is currently approved conditionally for patients with 
previously treated ALK-positive NSCLC (Crizotinib SmPC). 
The NCCN guidelines recommend crizotinib as first-line therapy for patients with 
advanced ALK-positive NSCLC (NCCN 2014). 
The randomized Phase III PROFILE 1014 study was conducted to assess the efficacy of 
crizotinib versus standard platinum-based chemotherapy (pemetrexed plus cisplatin or 
carboplatin) as first-line treatment for patients with ALK-positive, non-squamous NSCLC.  
The study met its primary objective of prolonging PFS in previously untreated patients 
with ALK-positive non-squamous NSCLC with median PFS of 10.9 and 7.0 months 
(HR: 0.454; 95% CI: 0.346, 0.596; p < 0.0001) for crizotinib and 
pemetrexed-platinum-based chemotherapy, respectively (Mok et al. 2014).  The authors 
concluded that these findings establish crizotinib as the standard of care for patients 
with previously untreated advanced ALK-positive non-squamous NSCLC 
(Mok et al. 2014).  
Crizotinib will be dosed as per standard dose recommendations from prescribing 
information—patients in the crizotinib arm will receive crizotinib at 250 mg orally BID with 
or without food until disease progression, unacceptable toxicity, withdrawal of consent, 
or death.  See Section 5.1.4 for criteria for dosing interruption and/or dose reduction for 
treatment with crizotinib.  
3.3.4 
Rationale for Open-Label Design 
An open-label study design is more appropriate for patients enrolled in this particular trial 
for a number of reasons defined below, and with the ultimate goal to ensure patient 
compliance as much as possible. 
For a blinded study design, all enrolled patients would be required to take five large 
capsules twice per day.  This high pill count results from the difference in capsule size 
between crizotinib (size 0) and alectinib (size 1).  Each dose would comprise one 250 
mg capsule of crizotinib or matching placebo and four 150 mg capsules of alectinib or 
matching placebo.  In order to blind, crizotinib capsules must be over-encapsulated.  
That furthermore increase the size of a capsule – from size 0 to size 00 (double zero).  
Size 00 is usually the largest capsule size used orally for humans.  For some patients 
size 00 capsules are too large to swallow.  This high pill count of large capsules is 


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considered to be a significant burden to patients and increases the risk of non-
compliance. 
Additionally, a blinded study would increase the complexity of standard dose reductions.  
Dose interruption or dose reduction may be required on the basis of individual safety and 
tolerability.  The standard dose reductions for crizotinib would be 200 mg BID (different 
capsule, size 1), followed by 250 mg QD.  Dose reductions for alectinib would occur in 
150 mg steps.  In a double blind study, these multiple step dose reductions introduce a 
high level of complexity and potential for error. 
In order to avoid a significant burden to patients with high pill count, increased risk of 
non-compliance, and complexity of standard dose reductions, adequate steps have been 
taken to ensure the validity of the data in an open-label study design.  These include 
performing a supportive analysis of efficacy on the basis of determining progression by 
an IRC, performing sensitivity analyses to demonstrate the robustness of the primary 
endpoint, defining progression using established response evaluation criteria 
(RECIST v1.1), performing tumor assessment at the same frequency in both arms and 
adhering to protocol-defined schedules, and finalizing before trial start the strategy for 
the final analysis of the primary endpoint, including predefined methods for handling 
missing data and censoring rules.  Efficacy analyses will only be performed at the pre-
specified analysis timepoints in the protocol (final analysis once 170 PFS events have 
occurred and survival follow-up analysis at 143 events). 
3.3.5 
Rationale for Primary Endpoint Selection 
The investigator-assessed PFS (which will be supported by IRC-assessed PFS analysis, 
one of the secondary endpoints of the study) is the primary endpoint for this trial. 
PFS, as an endpoint, can reflect tumor growth and can be assessed before the 
determination of a survival benefit, and its determination is not generally confounded by 
subsequent therapies.  Whether an improvement in PFS represents a direct clinical 
benefit or a surrogate for clinical benefit depends on the magnitude of the effect and the 
risk-benefit of the new treatment compared with available therapies (Guidance for 
Industry 2007; European Medicines Agency 2012).  A PFS HR of 0.65 will be targeted, 
which constitutes a clinically meaningful benefit in this patient population as it will delay 
the use of platinum-based chemotherapy and will potentially reduce the frequency of 
CNS relapse and the morbidity associated with treating CNS metastases. 
The assumed median PFS of patients in the alectinib treatment arm is 16.8 months, and 
an OS of more than 30 months is expected, which equates to a post-progression 
survival of at least 13 months.  Patients with ALK-positive NSCLC treated with crizotinib 
in the second-line setting had a median PFS of 7.7 months and an interim median OS of 
20.3 months (Shaw et al. 2013), which equated to a post-progression survival of 
12.6 months.  This lengthy post-progression survival provides an opportunity for 


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subsequent treatment with other ALK inhibitors, several additional lines of chemotherapy, 
or participation in additional clinical trials. 
Patients in both study arms who experience disease progression on study treatment will 
likely be treated with other subsequent treatment options, including ALK inhibitors.  
The availability of crizotinib on the market, as well as the likely availability of other 
next-generation ALK TKIs, and the availability of other investigational agents in clinical 
trials offer potential treatment options to patients in the study who will eventually have 
disease progression.  Subsequent therapies frequently confound the detection of an OS 
benefit, particularly in a setting with a long post-progression survival, such as 
ALK-positive NSCLC.  This has been observed in trials for EGFR TKIs, in which strong 
PFS benefits were observed without evidence of OS benefit (Rosell et al. 2009; 
Fukuoka et al. 2011). 
The long post-progression survival and the confounding effects of subsequent lines of 
therapy indicate that it would be difficult to detect an OS benefit in this setting.  
Nevertheless, OS is one of the study’s secondary endpoints.  The crossover from the 
crizotinib arm to alectinib will not be allowed in this study, with the aim of preserving the 
trial’s ability to potentially demonstrate some degree of treatment benefit of alectinib in 
OS.  However, the study will not be powered to demonstrate any statistically significant 
difference in the secondary endpoint of OS. 
To ensure the validity of the PFS as the primary endpoint, a number of measures have 
been implemented: full IRC assessment to support the analysis of the primary endpoint, 
a substantial target magnitude of benefit (target HR = 0.65) and study assessments that 
will allow a robust evaluation of risk-benefit (standard RECIST criteria to define 
progression with fixed assessment intervals that are identical in both treatment arms and 
a robust definition of PFS and prospectively defined methods to assess, quantify, and 
analyze PFS, including censoring methods and sensitivity analyses). 
3.3.6 
Rationale for Secondary Endpoint of Time to CNS Progression 
Lung cancer is the most common type of cancer to spread to the brain, with at least 40% 
of people with lung cancer developing brain metastases at some point during their 
disease.  ALK-positive NSCLC has a propensity to metastasize to the brain, and 
crizotinib has impaired control of brain metastases in comparison to other sites of 
systemic disease (Chun et al. 2012). 
Delaying or preventing the development of CNS metastases would provide patients with 
clinically meaningful benefit by avoiding consequences of neurological deficits from brain 
metastasis or by delaying/preventing long-term side effects associated with steroid use 
and brain irradiation. 


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Preliminary evidence of CNS benefit with alectinib has been observed in patients in the 
two ongoing Phase II studies.  See Section 1.2 and Alectinib Investigator's Brochure for 
additional details. 
Time to CNS progression is defined as the time from randomization until radiographic 
evidence of CNS progression is documented.  The aim of the pre-specified analysis will 
be to evaluate whether alectinib significantly delays or prevents the development of CNS 
metastases. 
Randomization of the Phase III study will be stratified by the presence or absence of 
CNS metastasis at baseline. 
Imaging analysis by consistently used uniform image acquisition technique (MRI scans) 
will be performed routinely at baseline and at subsequent follow-up assessments along 
with every systemic imaging tumor assessment or whenever clinically indicated (i.e., 
clinical suspicion of CNS metastasis) in order to achieve an accurate determination of 
time to CNS progression.  This ensures that early brain metastatic lesions are detected 
and that assessment bias between the two arms is avoided by having regularly 
scheduled scans. 
An independent central radiological review will be performed for all patients and the 
analysis of time to CNS progression, or response will be based on the data from the 
independent review.  The review will be based on the standard RECIST v1.1 criteria to 
assess the CNS lesions, and a second independent review on the basis of the RANO 
criteria, which are typically used to assess brain tumors (Wen et al. 2010), will be 
performed.  The assessment will be performed independently from the overall disease 
progression assessment. 
3.3.7 
Rationale for PK Sample Collection Schedule 
To date, the pharmacokinetics of alectinib have been characterized in 
chemotherapy-failed, crizotinib-naïve patients with NSCLC in Study AF-001JP and in 
patients who have failed chemotherapy and crizotinib treatment in Study NP28761/AF-
002JG and Study NP28673.  In order to better understand the pharmacokinetics of 
alectinib and to further support the development of a robust population PK model for 
alectinib in order to better understand, identify, and characterize variables which lead to 
changes in exposure, characterization of alectinib pharmacokinetics will be done in this 
study.  This study will include PK assessment of alectinib in ALK inhibitor treatment-
naïve patients with ALK-positive advanced NSCLC by collecting trough samples from all 
patients receiving alectinib.  Serial/intensive PK samples will be collected from a subset 
of patients (10%−15% [at least n = 20] of patients receiving alectinib) to facilitate the PK 
assessment.  The data that will be collected from this study will enable more robust 
understanding of alectinib pharmacokinetics in the global crizotinib-naïve population 
including investigation and potential identification of sources of variability influencing 
alectinib pharmacokinetics and/or response to alectinib therapy.  Results from PK data 


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collection in this study and analyses of PK data could help support optimal use of 
alectinib therapy. 
3.3.8 
Rationale for Biomarker Assessments 
There are several molecular mechanisms of resistance to crizotinib reported in the 
literature: increased copy number of ALK gene, increased expression of ALK mRNA, 
secondary mutations in ALK (e.g., gatekeeper mutation), and changes (e.g., increased 
copy number, increased phosphorylation, or point mutations) in escape genes like EGFR, 
cKIT, or KRAS (Katayama et al. 2011; Doebele et al. 2012; Kim et al. 2013).  In order to 
investigate molecular mechanisms of resistance to ALK inhibitors and ALK mutation 
status, tumor samples will be collected before treatment and at the time of disease 
progression with the goal of sequencing nucleic acids.  Two types of approaches will be 
used: 1) targeted sequencing of a panel of genes known to be involved in cancer and 2) 
unbiased genomic sequencing.  
ALK rearrangements can be monitored in circulating tumor cells in blood (Ilie et al. 2012; 
Pailler et al. 2013).  Intact tumor cells are released into the circulation; hence, using 
specific surface markers, it is possible to selectively separate them from the remaining 
cells in the blood.  This allows downstream analysis like IHC or FISH, and in rare 
occasions, there is enough material to perform reverse transcription–polymerase chain 
reaction or sequencing to detect mutant mRNA.  The presence of ALK rearrangements 
will be investigated in circulating tumor cells before treatment and at the end of study.  
This information will be used to investigate the use of blood as a surrogate of tumor for 
diagnostic purposes and to monitor the presence of ALK rearrangements in circulating 
tumor cells in the blood before and after treatment. 
Mutations in cancer genes appearing from drug resistance can be monitored in 
circulating nucleic acids in plasma (Forshew et al. 2012).  Tumor nucleic acids are shed 
into circulation in amounts that allow direct amplification by polymerase chain reaction 
and sequencing.  Plasma samples will be collected before treatment and at certain 
timepoints during treatment, to monitor mutations in ALK and other genes involved in 
resistance to ALK inhibitors.  Information from mutated genes in the tumor will be 
correlated with mutations in plasma DNA. 
Determination of ALK positivity will be initially performed by Ventana IHC (see 
Appendix 8).  In addition, the Abbott Vysis FISH test will be used as an exploratory 
assay, after patients have been enrolled in this study.  Results from these analyses will 
be used to quantify the degree of correlation between FISH and IHC for the detection of 
ALK-positive NSCLC.  For exploratory purposes, other methods to determine ALK 
positivity (e.g., reverse transcription-polymerase chain reaction) may also be used. 
3.3.9 
Rationale for PRO Assessments 
In the treatment of lung cancer, it is important to both increase survival and palliate 
symptoms because disease symptoms have negative impacts on HRQoL 


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(Hyde and Hyde 1974; Hopwood and Stephens 1995; Sarna et al. 2008).  This is 
especially true for trials that use PFS as a primary endpoint, where it is important to 
translate the delay in disease progression into an endpoint that is meaningful to patients. 
Pain (chest; arm/shoulder), dyspnea, cough, and fatigue have been regarded as the 
most frequent and clinically relevant disease-related symptoms experienced by patients 
with NSCLC.  The BR.21 study (erlotinib vs. chemotherapy in second- or third-line 
NSCLC) demonstrated that longer TTD in the pain, dyspnea, and cough scales of the 
EORTC QLQ-C30 and QLQ-LC13 was consistent with superior PFS, OS, and 
quality-of-life benefits in the erlotinib arm as compared with the placebo arm 
(Aaronson et al. 1993; Bergman et al. 1994; Bezjak et al. 2006).  Additionally, patients in 
the crizotinib PROFILE 1005 trial reported clinically significant (10 points) improvements 
in the pain, cough, dyspnea, and fatigue symptom scales seen as early as 2 weeks on 
treatment (Crinò et al. 2011). 
The EORTC QLQ-C30 and QLQ-LC13 were used in the Phase III PROFILE 1007 study 
(second-line crizotinib vs. chemotherapy).  The study reported significantly greater 
overall reduction from baseline in the symptoms of alopecia, cough, dyspnea, fatigue, 
chest pain, arm or shoulder pain, and pain in other parts of the body with crizotinib than 
with chemotherapy (p < 0.001 for all comparisons, without adjustment for multiple testing).  
Patients treated with crizotinib also had a significantly greater delay in the worsening of 
symptoms.  There was also a significantly greater overall improvement from baseline in 
the global quality of life among patients who received crizotinib treatment than among 
those who received chemotherapy (p < 0.001).  In all domains measuring functioning, 
except for the domain measuring cognitive functioning, there was a significantly greater 
overall improvement from baseline among patients in the crizotinib group than among 
patients in the chemotherapy group (Shaw et al. 2013). 
Therefore, to assess the quality of life of patients in this trial, PRO data will be collected 
from patients enrolled in this study using the validated questionnaires EORTC QLQ-C30 
and QLQ-LC13. 
3.4 
OUTCOME MEASURES 
3.4.1 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
• 
PFS, which is defined as the time from randomization to the first documented 
disease progression, as determined by the investigators (primary endpoint) or IRC 
(secondary endpoint) using RECIST v1.1 or death from any cause, whichever 
occurs first.  Patients without an event will be censored at the last tumor 
assessment either during follow-up or during study treatment.  Patients with no 
post-baseline assessments will be censored at the date of randomization. 


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• 
ORR, which is defined as the percentage of patients who attain CR or PR; response, 
as determined by the investigators using RECIST v1.1.  Patients without any 
assessments will be regarded as non-responders. 
• 
Time to CNS progression, which is defined as the time from randomization to the 
first occurrence of disease progression in the CNS as determined by IRC using 
RECIST v1.1 and RANO (separate assessments and analyses), as well as C-ORR 
in patients with CNS metastases who have measurable disease in the CNS at 
baseline, C-DOR in patients who have a CNS Objective Response, and C-PR at 6, 
12, 18, and 24 months. 
• 
DOR, which is defined as the time from when response (CR or PR) was first 
documented to first documented disease progression or death (whichever occurs 
first).  This will only be calculated for patients who have a best overall response of 
CR or PR.  Patients who do not progress or die after they have had a response are 
censored at the date of their last tumor measurement. 
• 
OS, which is defined as the time from randomization to death from any cause.  
Patients without an event will be censored at the last date known to be alive.  
Patients without any follow-up information will be censored at the date of 
randomization. 
 
3.4.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Serious and non-serious adverse events 
• 
Safety laboratory tests values 
• 
Vital signs (blood pressure, heart rate), ECG 
• 
Physical examination 
 
3.4.3 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Sparse (pre-dose) PK samples for measurement of alectinib and its major 
metabolite(s) will be collected in all study patients receiving alectinib treatment.  See 
Appendix 1 and Appendix 2 for PK sampling times. 
• 
Serial/intensive PK sampling will be collected in a subset of consenting patients 
enrolled to receive alectinib treatment (approximately 10%−15%, at least 
approximately n = 20).  See Appendix 1 and Appendix 2 for PK sampling times. 
• 
PK parameters will be determined as appropriate and where data allow: 
The pharmacokinetics of alectinib (and metabolite[s], if appropriate) will be 
described, and the between-patient variability will be estimated using a 
population PK approach.  The potential influence of covariates that contribute 
significantly to the between-patient differences in PK parameters of alectinib will 
also be explored and quantified. 
Non-compartmental analysis (NCA) may be conducted in patients undergoing 
serial/intensive PK sample collection, as appropriate and where data allow. 


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3.4.4 
Patient-Reported Outcome Measures 
The PRO measures included for this study are as follows and will be administered to 
patients every 4 weeks until disease progression and during post-progression on 
treatment in case of isolated, asymptomatic CNS progression; at the post-treatment visit 
(4 weeks after permanent treatment discontinuation); and every follow-up visit (every 8 
weeks) after post-treatment visit for 6 months: 
• 
The EORTC QLQ-C30 and EORTC QLQ-LC13 to determine the impact of alectinib 
compared with crizotinib as measured by TTD in patient-reported lung cancer 
symptoms (e.g., cough, dyspnea [single item and multi-item scales], pain in chest, 
pain in arm/shoulder, fatigue). 
• 
The EORTC QLQ-C30 and EORTC QLQ-LC13 to measure PROs of HRQoL, 
patient functioning, and side effects of therapy compared between patients treated 
with alectinib and those treated with crizotinib. 
 
3.4.5 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
EQ-5D-3L to generate utility scores for use in economic models for reimbursement. 
• 
Total testosterone, albumin and SHBG to calculate free testosterone, FSH, and LH, 
in blood to measure an onset of hypogonadism in adult men. 
• 
The FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) to evaluate and compare 
efficacy and safety in patients with treatment-naïve NSCLC that is ALK-positive by 
FISH test. 
• 
Post-progression tumor mutation status to study molecular mechanisms of 
resistance to ALK inhibitors. 
• 
ALK mutation status in plasma DNA to monitor efficacy and disease progression. 
• 
ALK fusion status in circulating tumor cells in blood. 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Target population is patients with treatment-naïve ALK-positive non-resectable, locally 
advanced and metastatic NSCLC. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage 
IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that 
is ALK-positive as assessed by the Ventana IHC test.  Sufficient tumor tissue to 
perform ALK IHC and ALK FISH is required.  Both tests will be performed at 
designated central laboratories. 
• 
Age ≥ 18 years old. 


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• 
Life expectancy of at least 12 weeks. 
• 
ECOG PS of 0−2. 
• 
Patients had no prior systemic treatment for advanced or recurrent (Stage IIIB not 
amenable for multimodality treatment) or metastatic (Stage IV) NSCLC. 
• 
Adequate hematologic function: 
Platelet count ≥ 100 × 109/L 
ANC ≥ 1500 cells/μL 
Hemoglobin ≥ 9.0 g/dL 
• 
Adequate renal function: 
An estimated glomerular filtration rate (eGFR) calculated using the 
Modification of Diet in Renal Disease equation of at least 45 mL/min/1.73 m2 
• 
Patients must have recovered from effects of any major surgery or significant 
traumatic injury at least 28 days before the first dose of study treatment. 
• 
Measurable disease (by RECIST v1.1) prior to the administration of study treatment. 
• 
Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed 
incidentally at study baseline).  Asymptomatic CNS lesions might be treated at the 
discretion of the investigator as per local clinical practice.  If patients have 
neurological symptoms or signs due to CNS metastasis, patients need to complete 
whole brain radiation or gamma knife irradiation treatment.  In all cases, radiation 
treatment must be completed at least 14 days before enrollment and patients must 
be clinically stable. 
• 
For all females of childbearing potential, a negative pregnancy test must be 
obtained within 3 days before starting study treatment. 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to 
remain abstinent or use single or combined contraceptive methods that result in a 
failure rate of < 1% per year during the treatment period and for at least 3 months 
after the last dose of study drug.  Abstinence is only acceptable if it is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.  Examples of non-hormonal contraceptive 
methods with a failure rate of < 1% per year include tubal ligation, male sterilization, 
hormonal implants, established, proper use of combined oral or injected hormonal 
contraceptives, and certain intrauterine devices.  Alternatively, two methods (e.g., 
two barrier methods such as a condom and a cervical cap) may be combined to 
achieve a failure rate of < 1% per year.  Barrier methods must always be 
supplemented with the use of a spermicide.  
• 
For men:  agreement to remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of < 1% per year during the 
treatment period and for at least 3 months after the last dose of study drug.  
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of 


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the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception.   
• 
Able and willing to provide written informed consent prior to performing any 
study-related procedures and to comply with the study protocol, including patients 
must be willing and able to use the electronic patient-reported outcome (ePRO) 
device. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients with a previous malignancy within the past 3 years are excluded (other than 
curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer 
by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is 
considered to have no impact in PFS and OS for the current NSCLC). 
• 
Any GI disorder that may affect absorption of oral medications, such as 
mal-absorption syndrome or status post-major bowel resection. 
• 
Liver disease characterized by: 
ALT or AST > 3 × ULN (≥ 5 × ULN for patients with concurrent liver metastasis) 
confirmed on two consecutive measurements 
OR 
Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or 
other conditions of decompensated liver disease such as coagulopathy, hepatic 
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal 
varices 
OR 
Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis 
• 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy 
(e.g. radiotherapy) (excluding alopecia), which have not shown improvement and 
are strictly considered to interfere with current study medication. 
• 
History of organ transplant. 
• 
Co-administration of anti-cancer therapies other than those administered in this 
study. 
• 
Patients with baseline QTc > 470 ms or symptomatic bradycardia. 
• 
Administration of strong/potent cytochrome P450 (CYP)3A inhibitors or inducers 
within 14 days prior to the first dose of study treatment and while on treatment with 
alectinib or crizotinib (see Appendix 3) except for oral corticosteroids up to 20 mg of 
prednisolone equivalent per day. 
• 
Administration of agents with potential QT interval prolonging effects within 14 days 
prior to the first administration of study drug and while on treatment.  (See 
Section 4.4.2 for further details.) 


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• 
History of hypersensitivity to any of the additives in the alectinib drug formulation 
(lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, 
hydroxypropyl cellulose, sodium lauryl sulfate [SLS], magnesium stearate). 
• 
History of hypersensitivity to any of the additives in the crizotinib drug formulation 
(silica, colloidal anhydrous cellulose, microcrystalline calcium hydrogen phosphate, 
anhydrous sodium starch glycolate, magnesium stearate). 
• 
Pregnant or lactating women. 
• 
Known HIV positivity or AIDS-related illness. 
• 
Any clinically significant concomitant disease or condition that could interfere with, 
or for which the treatment might interfere with, the conduct of the study or the 
absorption of oral medications or that would, in the opinion of the Principal 
Investigator, pose an unacceptable risk to the patient in this study. 
• 
Any psychological, familial, sociological, or geographical condition potentially 
hampering compliance with the study protocol requirements and/or follow-up 
procedures; those conditions should be discussed with the patient before trial entry. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label trial, for which the rationale is described in Section 3.3.4. 
Approximately 286 patients will be randomly assigned in a 1:1 allocation ratio to the two 
treatment arms via a block-stratified randomization procedure and over a planned 
recruitment period of 24 months. 
Randomization will guard against systematic selection bias and should ensure the 
comparability of treatment groups.  To assist balance in important prognostic factors, 
randomization will be stratified by ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and 
CNS metastases at baseline (yes vs. no). 
Central randomization and drug pack number allocations will be performed and 
managed by an IxRS.  Further details will be provided in an IxRS manual. 
The independent review of scans for the secondary endpoints of PFS on the basis of 
IRC and time to CNS progression will be performed in a blinded fashion. 
4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Alectinib 
Alectinib comes in a hard capsule dosage form containing the following active ingredient: 
[Chemical name] 9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-6,11-
dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride 


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Each capsule contains 150 mg of alectinib (as free base) along with lactose 
monohydrate, carmellose calcium, hydroxypropyl cellulose, sodium lauryl sulfate (SLS), 
and magnesium stearate as excipients. 
Alectinib capsules should be stored in accordance with the storage instructions on the 
label. 
Alectinib capsules should be administered orally BID with food (within 30 minutes after a 
meal, in the morning and evening). 
The formulation contains SLS as an excipient.  This excipient is known to be associated 
potentially with GI adverse events such as nausea, vomiting, diarrhea, and abdominal 
pain. 
For further details, see the alectinib Investigator's Brochure. 
4.3.1.2 
Crizotinib 
Crizotinib comes in a hard capsule dosage form.  Each capsule contains 250 mg or 
200 mg crizotinib.  Crizotinib hard capsules should be stored in accordance with the 
storage instructions on the label.  Crizotinib capsules should be administered orally BID. 
For further details, see the local prescribing information for crizotinib (XALKORI® U.S. 
Package Insert). 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Alectinib 
Alectinib 600 mg (four 150-mg capsules) should be administered orally BID with food 
(within 30 minutes after a meal, in the morning and evening). 
If a patient misses a dose, it can be taken within 4 hours of the scheduled time.  If the 
time is greater than 4 hours, or if the patient vomits the dose, the patient should wait until 
the next scheduled time and take the next scheduled dose.  Patients should not take 
two doses at the same time to make up for a missed dose. 
Guidelines for dosage modifications and treatment interruptions or discontinuation due to 
specified adverse events are provided in Section 5.1.3. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF. 
4.3.2.2 
Crizotinib 
Crizotinib 250 mg (one 250-mg capsule) should be administered orally BID with or 
without food (in the morning and evening). 


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If a dose is missed, then it should be taken as soon as the patient remembers unless it is 
less than 6 hours until the next dose, in which case the patient should not take the 
missed dose.  Patients should not take 2 doses at the same time to make up for a 
missed dose.  If vomiting occurs after taking a dose of crizotinib, the next dose should 
be taken as scheduled.  
If dose reduction is necessary, then the dose of crizotinib should be reduced to 200 mg 
taken BID.  If further dose reduction is necessary, then the dose should be modified to 
250 mg taken once daily.  Guidelines for dosage modification and treatment interruption 
or discontinuation are provided in Section 5.1.4. 
Any overdose or incorrect administration of crizotinib should be noted on the crizotinib 
Administration eCRF.  Adverse events associated with an overdose or incorrect 
administration of crizotinib should be recorded on the Adverse Event eCRF. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(alectinib and crizotinib) will be provided by the Sponsor where required by local health 
authority regulations.  The study site will acknowledge receipt of IMPs and confirm the 
shipment condition and content.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Post-Trial Access to Alectinib 
The Sponsor will offer post-trial access to the study drug alectinib free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive study drug after the end of the study if all of the following 
conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 


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A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
would not otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for ALK-positive NSCLC 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for ALK-positive NSCLC 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy 
Concomitant medication includes any medication (e.g., prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used 
by a patient from screening to the study completion/discontinuation visit.  All concomitant 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
All therapy and/or medication administered to manage adverse events should be 
recorded on the Adverse Event eCRF. 
The medications and/or treatments below are permitted: 
• 
Anticoagulants and antithrombotic agents (i.e., coumadin-derived anticoagulants, 
unfractionated heparin or low-molecular heparins, aspirin (≤ 325 mg/day), and 
clopidogrel. 
• 
Systemic corticosteroid should be no more than oral 20 mg prednisone equivalent 
daily.  Inhalation corticosteroid is allowed.  Steroid equivalence converter could be 
found at: http://www.medcalc.com/steroid.html 
• 
Acetaminophen up to 2 g/day 
• 
Gastric pH−elevating medications (such as proton pump inhibitors, H2 blockers, or 
antacids) 
• 
Local therapy (e.g., stereotactic radiotherapy or surgery) may be given to patients 
with isolated asymptomatic CNS progression (e.g., new CNS oligometastases). 
 


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Caution should be exercised when the following are co-administered with alectinib: 
• 
For medications that are substrates of P-gp transporter or breast cancer resistance 
protein transporter, the investigator should use caution and monitoring when 
considering concomitant use of alectinib.  Alectinib has been shown to have 
potential for inhibition of these transporters.  Substrates with a narrow therapeutic 
index (e.g., methotrexate, digoxin) should be avoided.  If co-administration cannot 
be avoided, it is recommended that drug levels and/or signs for toxicity are carefully 
monitored (see Appendix 3). 
• 
For medications that are inhibitors of P-gp transporter, the investigator should use 
caution and monitoring when considering concomitant use of alectinib.  The major 
metabolite of alectinib, M4, has been shown to be a substrate of this transporter.  
Strong inhibitors of P-gp should be avoided, if possible (see Appendix 3). 
• 
For medications that are metabolized by CYP3A and CYP2C8, the investigator 
should use caution and monitoring when considering concomitant use of alectinib.  
Alectinib has been shown to have potential for inhibition of CYP3A and CYP2C8, 
including potential time-dependent inhibition.  Sensitive CYP3A and CYP2C8 
substrates should be avoided.  If co-administration cannot be avoided, it is 
recommended that drug levels and/or signs for toxicity are carefully monitored 
(see Appendix 3). 
 
Caution should be exercised when the following are co-administered with crizotinib: 
• 
Crizotinib has been shown to be a moderate inhibitor of CYP3A.  Dose reduction 
maybe needed for co-administered drugs that are predominantly metabolized by 
CYP3A in patients receiving crizotinib.  Concurrent use of CYP3A substrates with 
narrow therapeutic indices should be avoided (see Appendix 3). 
• 
On the basis of an in vitro study, crizotinib is predicted to inhibit intestinal P-gp.  
Therefore, administration of crizotinib with medicinal products that are substrates of 
P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin) may increase their 
therapeutic effect and adverse reactions (see Appendix 3).  Close clinical 
surveillance is recommended when crizotinib is administered with these medicinal 
products. 
• 
Bradycardia has been reported during clinical studies; therefore, the use of 
crizotinib in combination with other agents known to cause bradycardia (e.g., 
beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and 
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• 
In vitro studies in human hepatocytes indicated that crizotinib may induce 
pregnane X receptor and constitutive androstane receptor–regulated enzymes 
(e.g., CYP3A4, CYP2B6, CYP2C8, CYP2C9, UGT1A1).  However, there was no 
observed induction in vivo when crizotinib was coadministered with the CYP3A 
probe substrate midazolam.  Caution should be exercised in administering crizotinib 
in combination with medicinal products that are predominantly metabolized by these 
enzymes.  Of note, the effectiveness of concomitant administration of oral 
contraceptives may be altered. 
• 
In vitro studies indicated that crizotinib is an inhibitor of CYP2B6.  Therefore, 
crizotinib may have the potential to increase plasma concentrations of 
coadministered drugs that are metabolized by CYP2B6 (e.g., bupropion, efavirenz). 
 
4.4.2 
Prohibited Therapy 
Use of the following therapies (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) is prohibited during the study and for at 
least 14 days prior to initiation of study treatment (either alectinib or crizotinib), unless 
otherwise specified below.  Exceptions to the below listed concomitant therapies 
restrictions (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, nutritional supplements) may be made if the rationale is discussed and 
documented between the investigator and the Sponsor’s Clinical Pharmacologist. 
• 
Potent inducers of CYP3A (e.g., rifampin, rifabutin, phenobarbital, phenytoin, 
carbamazepine, and St. John’s wort [Hypericum perforatum]) within 2 weeks or 
5 half-lives (whichever is longer) before the first dose of study drug treatment and 
while on treatment with study drugs (see Appendix 3). 
• 
Potent inhibitors of CYP3A (e.g., ketoconazole) within 2 weeks or 5 half-lives 
(whichever is longer) before the first dose of study drug treatment and while on 
treatment with study drug (see Appendix 3). 
• 
Any concomitant medications known to affect QT interval duration, including but not 
limited to the following drugs: amiodarone, cisapride, clarithromycin, methadone, 
and quinidine, within 2 weeks before the first dose of study drug treatment and while 
on treatment with study drugs and through the end of the study. 
• 
Systemic immunosuppressive drugs, cytotoxic or chemotherapeutic agents 
(other than study drug treatment), ergot derivatives, probenecid, and bile 
acid-binding resins while on study treatment. 
• 
Systemic chemotherapy. 
• 
Radiotherapy/radionuclide therapy except for palliative radiotherapy to bone lesions 
or for pain control.  If palliative radiation is indicated for bone metastases, palliative 
radiation may start within 24 hours of the last dose of alectinib, unless, in the 
judgment of the investigator, patient safety will require a longer washout period prior 
to palliative therapy.  Dosing of alectinib may resume with the resolution of any 
radiation toxicity to  ≤ Grade 1. 
• 
Additional investigational drug (except for during the follow-up period). 
 


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The above lists of medications are not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication 
as well as the Internet references provided below when determining whether a certain 
medication is metabolized by or strongly inhibits or induces CYP3A.  In addition, the 
investigator should contact the Medical Monitor if questions arise regarding medications 
not listed above. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM292362.pdf 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
 
4.4.3 
Prohibited Food 
Use of grapefruit or grapefruit juice should be avoided during the study and for at least 
14 days prior to the initiation of study treatment (either alectinib or crizotinib) because it 
is a potent CYP3A inhibitor and may increase plasma concentration of either alectinib or 
crizotinib. 
4.5 
STUDY ASSESSMENTS 
See Appendix 1 for the schedule of assessments performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 28 days prior 
to the screening visit. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Corticosteroid Use for CNS Metastases 
For patients with CNS metastases requiring corticosteroid use, the corticosteroid intake 
should be captured at all tumor assessment visits and compared with the corticosteroid 
intake at the time of the last disease assessment.  The changes will be recorded as 


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Increased, Unchanged, or Decreased.  Increases and decreases in corticosteroid intake 
should be clinically justified.  Increases in corticosteroid dose for reasons other than for 
CNS metastases control do not need to be taken into consideration when making this 
comparison.  As per Section 4.4.1 of the protocol, systemic corticosteroid use cannot 
exceed oral 20 mg of prednisone equivalent daily. 
4.5.4 
Physical Examinations 
A complete physical examination at screening and baseline should include an evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, GI, genitourinary, and neurological systems as well as 
height and weight.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
Note:  for patients with known CNS metastases, a neurological examination must be 
performed at each tumor assessment visit and compared with the neurological 
examination performed at the time of the last disease assessment.  Definition of clear 
neurological worsening is difficult to describe because progression in the CNS can 
present in numerous ways.  Accordingly, evaluation of neurological function at each 
disease assessment will be based purely on the investigator’s assessment of the 
patient’s neurological state compared with the neurological function at the time of the 
last disease assessment.  Neurological status will be recorded as Improved, Stable, or 
Worsened. 
4.5.5 
Vital Signs 
Vital signs will include measurements of respiratory rate, oxygen saturation, pulse rate, 
and systolic and diastolic blood pressure while the patient is in a seated position, and 
temperature. 
4.5.6 
ECOG Performance Status 
PS will be measured using the ECOG Performance Status Scale (see Appendix 5).  It is 
recommended, where possible, that a patient’s PS be assessed by the same person 
throughout the study. 
4.5.7 
Tumor and Response Evaluations 
Disease burden must be documented at screening and re-assessed at each subsequent 
tumor evaluation.  Response will be assessed by the investigator on the basis of physical 
examinations, computed tomography (CT) scans, and other modalities (e.g., MRI, brain 
scans), using RECIST v1.1 (see Appendix 4).  For assessing response in patients with 
measurable disease, the preferred radiologic tumor response assessment is CT scan 


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with intravenous contrast.  If intravenous contrast is contraindicated, a 
non-contrast-enhanced chest CT scan will be acceptable for chest lesions, and MRI can 
be used for non-chest lesions.  If contrast-enhanced MRI is contraindicated, then 
non-contrast-enhanced MRI will suffice.  Positron emission tomography (PET) scan, bone 
scan, and ultrasound cannot be used to measure lesion as per RECIST v1.1 
(see Appendix 4).   
The same radiographic procedure used to define measurable disease sites at screening 
must be used throughout the study (e.g., the same contrast protocol for CT scans).  
Assessments should be performed by the same evaluator to ensure internal consistency 
across visits. 
CT/MRI scans of chest and abdomen, and MRI scans of the brain should be performed 
for all patients as described in Schedule of Assessments (see Appendix 1) at screening 
then every 8 weeks subsequently until disease progression and during post-progression 
on treatment in case of isolated, asymptomatic CNS progression and at the 
post-treatment visit (4 weeks after permanent treatment discontinuation).  CT/MRI scans 
of the neck bone and pelvis should be included if clinically indicated.  At the investigator’s 
discretion, CT/MRI scans may be repeated at any time if PD is suspected. 
Note: Brain imaging should be performed using MRI with the following image acquisition 
requirements: 
• 
Minimum sequences required: 
Pre-contrast T1, T2/FLAIR 
Post-contrast T1, with two orthogonal planes (or a volume acquisition) 
recommended 
• 
Recommended slice thickness ≤ 5 mm with no gap 
 
Patients with known or suspected bone metastases should undergo radionuclide bone 
scan at screening.  Bone scan, PET scan, or plain films are not considered adequate 
imaging techniques to measure bone lesions and do not need to be repeated routinely 
but can be used to confirm the presence or disappearance of bone lesions.  Lytic bone 
lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be 
evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
measurable lesions of the soft tissue component and meets the definition of measurability 
and should be followed by cross-sectional imaging. 


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4.5.8 
Laboratory, Biomarker, and Other Biological Sample 
4.5.8.1 
Laboratory Assessments 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Hematology (hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
absolute differential count [neutrophils, eosinophils, lymphocytes, monocytes, 
basophils, other cells]) 
• 
Coagulation (PT [or INR], and aPTT) 
• 
Serum chemistry (sodium, potassium, chloride, bicarbonate, fasting glucose, BUN 
or urea, creatinine [including calculated eGFR using the Modification of Diet in 
Renal Disease formula, see Appendix 7]; CPK; gamma-glutamyl transferase (GGT); 
calcium; total and direct bilirubin; total protein; albumin; ALT; AST; alkaline 
phosphatase [ALP]; phosphorus; magnesium; thyroid-stimulating hormone; and total 
testosterone, albumin and SHBG to calculate free testosterone, FSH, and LH [for 
male patients only]) 
• 
Urinalysis: Urine samples will be collected according to the schedule of 
assessments (Appendix 1) (first morning urine sample for baseline and end of 
treatment visit, spot urine for rest of visits).  Urine protein will be measured by 
dipstick test in order to assess micro- and macroproteinuria. 
• 
Pregnancy test.  All women who are not postmenopausal (≥ 12 months of 
non-therapy-induced amenorrhea) or surgically sterile will have a serum pregnancy 
test at screening, within 3 days of dosing.  Urine pregnancy tests will be performed 
anytime during the course of the study, as per investigator’s discretion.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
 
4.5.8.2 
Pre-Treatment Tumor Samples (Mandatory) 
Mandatory pre-treatment tumor samples will be collected to centrally examine ALK 
status by Ventana IHC (eligibility criteria) and Vysis FISH.  Tumor blocks (formalin-fixed, 
preferred 10% neutral-buffered formalin) are the preferred source, but if blocks are not 
available, unstained slides (ten to fifteen 5-µm slides cut less than 3 months before 
screening) are also accepted.  Remaining tumor blocks will be returned to the sites; 
slides will not be returned. 
For fresh tumor biopsies (guided by ultrasound or CT scan), acceptable methods include 
core biopsies for lung and liver lesions and bronchoscopic biopsies for lung lesions.  The 
minimum size for the biopsy needle recommended is 20G. 
Central ALK testing to determine or confirm patient ALK status will be performed at a 
Sponsor designated central laboratory.  After completion of ALK testing for enrollment 
with a pre-specified ALK test by Ventana IHC (see Appendix 8), patient samples will also 
be centrally tested by FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) for possible 
companion diagnostic development.  Additionally, other ALK assays may be used for 
testing patient samples to establish performance characteristics of these assays for 


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diagnostic development.  Testing may be performed on all screened patients (screen-
failed and enrolled).  These additional testing data will have no impact on eligibility, and 
testing will be performed only after eligibility is established for each patient.  In addition, 
local ALK test information, baseline demographic, and disease-related characteristic 
data for all screened patients may be collected in order to support potential registration 
of a companion diagnostic assay for alectinib. 
The tumor sample may also be tested for the presence of EGFR mutations, if requested 
by the investigator. 
Pre-treatment tumor samples may be used, after proper informed consent is obtained, 
for genomic sequencing. 
For sample handling procedures, storage conditions and shipment instructions, see the 
laboratory manual. 
4.5.8.3 
Pre- and Fresh Post-Treatment Tumor Biopsies (Optional) 
Pre-treatment tumor samples (preferably formalin-fixed blocks but if not available a 
minimum of 10-15 unstained 5 µm slides) for ALK testing is a mandatory requirement for 
this study.  Optional additional pre-treatment tumor samples and fresh post-treatment 
tumor biopsy at disease progression or permanent treatment discontinuation (at the last 
treatment or post-progression visit) may be collected, with proper informed consent.  
These samples will be used to help to understand molecular mechanisms of resistance 
to ALK inhibitors by genomic sequencing.  Remaining tumor blocks will be returned to 
the sites, slides will not be returned. 
These specimens will be destroyed within 5 years after the date of final closure of the 
clinical database.  Other residual tissue material (slides, extracts, etc.) will be destroyed 
within 5 years after the date of final closure of the clinical database. 
On the basis of continuous analysis of the data in this study and other studies, or on the 
basis of data from literature, collection of optional tumor biopsies with exploratory 
purposes may be stopped at any time if the data from the samples collected do not 
produce useful information. 
4.5.8.4 
Blood and Plasma Samples 
Mandatory plasma samples will be obtained to determine: 
• 
Mutations status in ALK and other escape genes (e.g., EGFR, KRAS).  It will require 
20 mL of blood to be collected at baseline, treatment Visit 3 (Week 16), and 
subsequently at every second treatment visit (every 16 weeks) (see Appendix 1 for 
detailed information) until disease progression and during post-progression on 
treatment in case of isolated, asymptomatic CNS progression.  For sample handling 
procedures, storage conditions and shipment instructions, see the laboratory 
manual.  These samples will not be taken in countries where regulatory agency or 
Institutional Review Board (IRB) does not allow genetic testing. 


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Mandatory blood samples will be obtained to determine: 
• 
ALK mutations assessment in circulating tumor cells.  It will require 20 mL of blood 
sample to be collected (2 tubes of 10 mL each) at baseline and at disease 
progression (at the last treatment or post-progression visit).  It should match in time 
to tumor progression (CNS and/or systemic disease progression). 
• 
All patients who are randomized in alectinib arm will also participate in retrospective 
pharmacogenomic research to understand inter-individual variability of safety and 
pharmacokinetics of alectinib.  For this purpose, a 3-mL blood sample will be drawn 
at baseline (see Section 4.5.8.4.1). 
 
Optional blood samples will be collected to obtain: 
• 
A source of healthy tissue for patients who agreed to participate in the optional 
genomic sequencing assessment.  For patients in the crizotinib arm, a 3-mL blood 
sample will be drawn at baseline.  For patients in the alectinib arm, a source of 
healthy tissue will be used as a portion of the sample for the pharmacogenomics 
research (see Section 4.5.8.4.1) 
• 
A portion of this blood sample will also be used as a source of healthy tissue for the 
patients receiving alectinib treatment who agree to participate in the optional 
genomic sequencing research. 
For biomarkers, a maximum of 43 mL of blood will be collected at baseline (20 mL for 
plasma purification and determination of mutation status in ALK and other escape genes, 
20 mL for ALK fusion detection in circulating tumor cells, and 3 mL for 
pharmacogenomics research), 20 mL of blood (for plasma purification and determination 
of mutation status in ALK and other escape genes) will be collected at Visit 3 (Week 16) 
and subsequently at every second visit (every 16 weeks), and 32 mL will be collected at 
disease progression (CNS and/or systemic disease progression) (20 mL for plasma 
purification for determination of mutation status in ALK and other escape genes and 
20 mL for ALK fusion detection in circulating tumor cells). 
Details of sample handling procedures, sample storage and shipment will be described 
in a separate laboratory manual. 
On the basis of continuous analysis of the data in this study and other studies, or on the 
basis of data from literature, collection of plasma and circulating tumor cell samples with 
exploratory purposes may be stopped at any time if they are deemed not informative. 
4.5.8.4.1 
Samples for Pharmacogenomic Assessments 
One sample (approximately 3 mL of whole blood) will be collected from all patients on 
alectinib treatment.  Samples will be used for the evaluation of genetic polymorphisms of 
drug metabolic enzymes including, but not limited to, CYP2C9, CYP3A4/5, and UGT1A1, 
and transporters (e.g., organic anion transporter polypeptide 1B1) and for genetic 
variants that could contribute to potentially drug-related liver safety assessments 
(including but not limited to human leukocyte antigen, see Appendix 9 for more details). 


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For sample handling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Only in circumstances where there is concern for collection of this 
genetic material for above evaluations can this assessment be considered not 
mandatory as part of study assessments in this study.  Results of any analyses from 
these samples will be reported outside the clinical study report. 
4.5.8.5 
Samples for Pharmacokinetic Assessments 
PK samples will be collected in all patients on alectinib treatment, as indicated in 
Appendix 1 and Appendix 2 for the analysis of alectinib and its major metabolite(s) 
(RO5468924, RO5507197, and/or others, if applicable and if appropriate, and if assays 
are available).  Residual samples following PK analysis may be used to evaluate 
profiling for alectinib metabolite(s). 
All trough/pre-dose PK samples should be collected within 2 hours BEFORE the 
morning doses of study medications.  
Serial/intensive samples will be collected in a subset of patients (10%–15% [at least 
n = 20] of patients receiving alectinib) on Visit 0 (baseline, after the first dose) and Visit 1 
(Week 4) at the timepoints specified in Appendix 2. 
Plasma concentrations for alectinib and its metabolite(s), if applicable, will be measured 
by specific and validated liquid chromatography tandem mass spectrometry methods. 
For each sample, approximately 2 mL of venous blood will be collected for alectinib PK 
analysis at the timepoints specified in the PK schedule in Appendix 1 and Appendix 2. 
Patients who permanently discontinue from study drugs will also discontinue from all PK 
assessments.  The procedures for the collection, handling, storage, and shipping of 
plasma samples for the PK analysis are specified in the Laboratory Manual. 
These samples will be destroyed when the final Clinical Study Report is complete. 
On the basis of continuous analysis of the data in this study and other studies, any 
sample type collection may be stopped at any time if the data from the samples collected 
do not produce useful information or at the discretion of the Sponsor. 
4.5.9 
Electrocardiograms 
An ECG will be recorded at specified timepoints as outlined in the schedule of 
assessments (see Appendix 1) at screening, Visit 0 (baseline), Visit 1 (Week 4), Visit 4 
(Week 24), Visit 8 (Week 56), and at the last treatment visit and as clinically indicated 
throughout the study.  All ECG recordings must be performed using a standard high-
quality, high-fidelity digital electrocardiograph machine equipped with computer-based 
interval measurements.  All ECGs are to be obtained prior to other procedures 
scheduled at that same time (e.g., vital sign measurements, blood draws, study drug 


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administration) as well as prior to meals.  Circumstances that may induce changes in 
heart rate, including environmental distractions (e.g., television, radio, conversation), 
should be avoided during the pre-ECG resting period and during ECG recording. 
Patients must have been in a supine or semi-supine position for at least 5 minutes prior 
to the recording being taken.  The same recording position (supine or semi-supine) and 
the same equipment should be used for each patient throughout the study.  The ECG 
printout must be (1) reviewed by a medically qualified member of the study team at the 
site, (2) annotated to indicate any clinical finding, and (3) dated and signed by this 
person and filed in the patient notes.  ECG parameters will be entered on the ECG 
eCRF.  The following parameters should be captured on the eCRF: heart rate, RR, PQ, 
QRS and QT duration, and QT interval corrected using Fridericia’s formula. 
If any ECG abnormality is associated with an adverse event, it must be recorded and 
managed as described in Section 5.  Management of QT interval prolongation should be 
done according to guidance provided in Section 5.1.3.  
If considered appropriate by the Sponsor, ECGs may be analyzed retrospectively at a 
central laboratory.  Guidance for abnormal ECG results (QT prolongation) is provided in 
Table 2. 
4.5.10 
Patient-Reported Outcomes 
PROs (EORTC QLQ-C30, QLQ-L13, and EQ-5D) will be collected to more fully 
characterize the clinical profile of alectinib.  The instruments will be translated as 
required in the local language.  To ensure instrument validity and that data standards 
meet health authority requirements, the PROs scheduled for administration during a 
clinic visit (EORTC QLQ-C30, QLQ-L13, and EQ-5D) should be completed prior to the 
performance of non-PRO assessments and the administration of study treatment. 
Patients will use an ePRO device to capture PRO data.  The ePRO device and 
instructions for completing the PRO questionnaires electronically will be provided by the 
investigator staff.  The data will be transmitted via pre-specified transmission method 
(e.g., web or wireless) automatically after entry to a centralized database at the ePRO 
vendor.  The data can be accessed by appropriate study personnel securely via the 
Internet. 
4.5.11 
Samples for Roche Clinical Repository 
4.5.11.1 
Overview of the Roche Clinical Repository 
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future. 


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Specimens for the RCR will be collected from patients who give specific consent to 
participate in optional research.  RCR specimens will be used to achieve the following 
objectives: 
• 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.11.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's IRB or Ethics Committee (EC) and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval for RCR sampling, 
this section of the protocol (Section 4.5.11) will not be applicable at that site. 
4.5.11.3 
Sample Collection 
For RCR purposes, 10 mL of blood will be collected.  Any remaining tissue samples 
from study-related or non−study−related procedures that are performed during the 
study may also be collecte for RCR purposes.  For all samples, date of consent should 
be recorded on the associated RCR page of the eCRF.  For sampling procedures, 
storage conditions, and shipment instructions, see the laboratory manual. 
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below. 
4.5.11.4 
Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 


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database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
4.5.11.5 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether the patient has given consent to participate 
by completing the RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research. 
4.5.11.6 
Withdrawal from the Roche Clinical Repository 
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 


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Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study BO28984 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study BO28984. 
4.5.11.7 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients who withdraw consent for treatment should continue to be 
followed for tumor assessments until progression and for OS, provided they have not 
withdrawn consent for the study.  However, patients will not be followed for any reason 
after consent for the study has been withdrawn.  Patients who withdraw from the study 
will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Pregnancy 
• 
Inability to tolerate study medication on the basis of the investigator judgment 
See guidelines for managing adverse events and for comprehensive guidance on study 
drug discontinuation in Section 5.1.3. 


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Patients who discontinue study drug prematurely will be asked to return to the clinic for 
tumor assessments until progression as per study schedule (see Appendix 1). 
The primary reason for premature study drug discontinuation should be documented on 
the appropriate eCRF.  Patients who discontinue study drug prematurely will not be 
replaced. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
5.1.1 
Adverse Events Collection 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events (SAEs) caused by a protocol-mandated intervention should be 
reported (e.g., SAEs related to invasive procedures such as biopsies).  After the first 
dose of study treatment and up to the 4-week follow-up after the last dose of study 
treatment, all adverse events (AEs) regardless of seriousness, causality assessment, or 
actions taken reported by the investigator or designated medically qualified study site 
personnel will be collected as described below.  At each visit, the investigator or 
designated medically qualified study personnel will ask the patient if any untoward 
medical event occurred since the last visit.  It is the investigator’s responsibility to record 
all AEs in the source patient’s medical records. 
All serious and non-SAEs will be reported on the standard AE/SAE eCRF. 


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5.1.2 
Adverse Events Relating to ALK Inhibitors and/or the Tyrosine 
Kinase Inhibitor Class and Alectinib Data 
Events described in Section 5.1.2.1 through Section 5.1.2.10 will be closely monitored 
and represent selected AEs for this study. 
A more detailed safety profile of alectinib is provided in the alectinib Investigator's 
Brochure. 
5.1.2.1 
Interstitial Lung Disease 
TKIs, including ALK inhibitor crizotinib, have been associated with the occurrence of 
treatment-related ILD (including fatalities). 
See Section 5.1.3 for management and follow-up. 
5.1.2.2 
Hepatobiliary Laboratory Test Elevations 
Hepatobiliary findings were observed in both the rat and monkey 4- and 13-week toxicity 
studies with alectinib, and findings in the 13-week studies were similar to those of the 
4-week studies.  The findings were at or close to clinically relevant exposures.  
Hepatobiliary effects included increased hepatic ALP, direct bilirubin, GGT and liver 
weight, vacuolation/degeneration/necrosis of bile duct epithelium, inflammatory cell 
infiltration in Glisson’s sheath, enlargement/focal necrosis of hepatocytes, and 
enlargement of Kupffer cells. 
Abnormal hepatobiliary laboratory test values, such as increased ALT, AST, or bilirubin 
levels, have been observed after alectinib administration.  AST, ALT, and total bilirubin 
levels temporarily increased in the initial stages of treatment and then improved.  
In patients treated with other tyrosine kinase ALK inhibitor drugs, abnormal liver function 
tests and fatal cases of hepatic failure have been reported. 
See Section 5.1.3 for management and follow-up. 
5.1.2.3 
Hematologic Abnormalities 
Hematologic findings were observed in both the rat and monkey 4- and 13-week toxicity 
studies with alectinib, and findings in the 13-week studies were similar to those of the 
4-week studies.  Findings were at or close to clinically relevant exposures.  Hematologic 
adverse effects such as anemia, thrombocytopenia, bleeding, and neutropenia have 
been observed with most TKIs, including ALK inhibitor crizotinib. 
Hematologic abnormalities of neutropenia, leukopenia, thrombocytopenia, and anemia 
have been reported with alectinib administration.  Neutrophil counts generally decreased 
early and remained stable thereafter. 
See Section 5.1.3 for management and follow-up. 


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5.1.2.4 
Gastrointestinal Disorders 
GI disorders such as nausea, vomiting, constipation, and diarrhea have been reported 
with alectinib.  Similar GI disorders have been observed with other TKIs, including ALK 
inhibitor crizotinib. 
SLS (sodium lauryl sulfate, syn. sodium dodecyl sulfate) is a surfactant excipient in the 
clinical formulation at a concentration of 50% (w/w SLS to active pharmaceutical 
ingredient).  This excipient is a known GI irritant and may be associated with GI AEs 
including nausea, vomiting, diarrhea, and abdominal pain.  Of note, GI tract toxicity as 
the safety determinant of SLS is not because of systemic toxicity, but a consequence of 
local irritation to the GI tract.  In general, when mixed with diet, higher levels of SLS⎯a 
known GI tract mucosal irritant⎯are tolerated versus gavage administrations. 
See Section 5.1.3 for management and follow-up. 
5.1.2.5 
Skin Disorders 
Results of an in vitro phototoxicity study indicated that alectinib may have phototoxic 
potential. 
Skin rash has been reported with majority of TKIs including those targeting the ALK 
receptor (Hartmann et al. 2009). 
Cases of skin rash and photosensitivity have been reported with alectinib and were 
generally Grade 1 or 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.6 
Vision Disorders 
In the rat quantitative whole body autoradiography study, tissue radioactivity 
disappeared over time, following a time course comparable to that of plasma 
radioactivity, except for melanin-containing tissues such as uveal tract of eyes, which 
had much higher and more sustained exposure in pigmented rats.  This is consistent 
with what is commonly observed for lipophilic basic drugs. 
Vision disorders, including diplopia, photopsia, blurred vision, visual impairment, and 
vitreous floaters, have been reported with several TKIs, including ALK inhibitors 
(crizotinib) (Shaw et al. 2013). 
Vision disorders, such as dry eye, blepharitis, conjunctivitis, blurred vision, and vision 
impaired, have been reported with alectinib and were generally Grades 1 and 2. 
See Section 5.1.3 for management and follow-up. 


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5.1.2.7 
Edema 
Most TKIs, including ALK inhibitor crizotinib, have been associated with edema.  Events 
of edema have been reported with alectinib, mostly Grade 1 or 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.8 
Cardiovascular Effects 
QT interval prolongation appears to be an off-target class effect of some TKIs, including 
ALK inhibitor crizotinib (Shah et al. 2013; XALKORI® U.S. Package Insert).  Many TKIs 
have been associated with bradycardia and hypertension. 
In the in vitro study of the cardiovascular system, alectinib inhibited the hERG current 
(IC20: 58 ng/mL; IC50: 217 ng/mL).  Because plasma protein binding by alectinib is ≥ 99%, 
the plasma concentration of alectinib required to induce the same inhibition in vivo would 
be 100 or more times greater than the concentration required in vitro.  In the monkey 
telemetry study, there were no effects on the ECG, any of the other cardiovascular 
parameters or body temperature at doses up to 15 mg/kg (mean maximum 
concentration [Cmax]: 279 ng/mL). 
In a preliminary non- Good Laboratory Practice telemetry study in conscious cynomolgus 
monkeys, a slight hypotensive effect (approximately 10 mmHg) was seen when alectinib 
was administered at 20 and 60 mg/kg orally with no effects on ECG or heart rate.  The 
hypotensive effect of alectinib observed in monkeys was considered to likely be caused 
by vasodilatation induced by L-type Ca2+ channel inhibition. 
Events of bradycardia have been reported with alectinib.  Preliminary heart rate data 
(based on ECG and pulse measurements) from the ongoing alectinib clinical trials show 
a decrease in heart rate during alectinib treatment, which is mainly asymptomatic.  In 
patients treated with other ALK inhibitors (crizotinib and ceritinib), bradycardia 
adverse events, and decreases in heart rate based on ECG and pulse measurements, have 
also been reported.  
In case of bradycardia, concomitant medications must be evaluated to identify those 
that are known to cause bradycardia, as well as anti-hypertensive medications; 
discontinuation or dose reduction of these concomitant medications must be considered. 
See Section 5.1.3 for management and follow-up. 
5.1.2.9 
Abnormal Renal Function 
In the 2-week non-human primate study at 60 mg/kg, an increase in creatinine was 
observed but no changes were observed in histopathology.  In all other non-human 
primate studies, no changes in creatinine were observed. 
Serum creatinine increases have been reported with alectinib treatment and were 
generally Grades 1 and 2. 


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See Section 5.1.3 for management and follow-up. 
5.1.2.10 
Muscular Adverse Events and CPK Elevations 
Postmarketing experience with some TKIs includes reports of myopathy and 
rhabdomyolysis (Hohenegger 2012). 
Blood CPK increases, generally Grades 1 and 2, and muscular AEs have been reported 
with alectinib treatment. 
See Section 5.1.3 for management and follow-up and Table 2  for guidelines for 
managing AEs. 


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5.1.3 
Management of Specific Adverse Events with Alectinib 
Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib 
Event 
Action to Be Taken 
Interstitial lung disease 
• 
Patients should be monitored for pulmonary symptoms 
indicative of pneumonitis.  
• 
Study drug should be permanently discontinued in patients 
diagnosed with interstitial lung disease. 
Hepatobiliary AE and 
laboratory test elevations 
 
Liver test laboratory abnormalities are to be reported as AEs only if 
fulfilling the criteria listed in Section 5.3.5.4 and Section 5.3.5.6. 
• 
If ALT or AST  > 3 × baseline, repeat testing of ALT, AST, 
ALP, and total bilirubin within 48–72 hours, with inquiry 
about symptoms.  If upon repeat testing the transaminases 
remain > 3 × baseline, but are not > 5 × baseline or not 
accompanied with bilirubin increases or do not match any 
other rule for permanent discontinuation, then monitoring 
can continue as per investigator judgment, and dose 
modification is not necessary. 
• 
At any time during the study treatment, if symptoms compatible 
with liver injury are observed, liver enzymes should be 
measured as soon as possible.  
• 
Study drug treatment has to be permanently discontinued if 
any of the following occurs: 
First observation of ALT or AST  > 8 × ULN 
ALT or AST > 5 × ULN for more than 2 weeks 
First observation of ALT or AST > 3 × ULN and total 
bilirubin > 2 × ULN  
First observation of ALT or AST > 3 × ULN and the 
appearance of jaundice or signs of hepatic dysfunction or 
other symptoms (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or 
eosinophilia [> 5%]). 
• 
Following study drug discontinuation, weekly monitoring of 
laboratory values should continue until the abnormal values 
have normalized to pre-treatment levels and/or an adequate 
explanation of the abnormal value is found. 
• 
Resumption of study drug is not allowed in patients 
discontinuing because of any of the above criteria. 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
Hematologic abnormalities Hematologic laboratory abnormalities are to be reported as AEs 
only if fulfilling the criteria listed in Section 5.3.5.4. 
• 
In case of hematologic toxicity:  Grade 4 (neutropenia, 
thrombocytopenia):  
Give supportive treatment per treating physician. 
First episode:  Temporarily interrupt alectinib until ANC is 
above 1200/µL and platelets are above 75 K/µL.  Upon 
resumption, reduce alectinib dose by 150 mg (1 capsule) 
BID (450 mg BID). 
Second episode:  Reduce dose by another 150 mg 
(1 capsule) BID (300 mg BID).  
Third episode:  Permanently discontinue alectinib. 
• 
In case of hematologic toxicity:  Grade 3 (neutropenia, 
thrombocytopenia):  
Temporarily interrupt alectinib until ANC is above 1200/µL 
and platelets are above 75 K/µL. 
Give supportive treatment per treating physician. 
If improvement to Grade ≤ 2 does not occur within 
3 weeks, permanently discontinue alectinib. 
• 
In case of hematologic toxicity:  Grade 1 or 2 (neutropenia, 
thrombocytopenia) no action is required. 
Gastrointestinal tract AEs 
(e.g., nausea, vomiting, 
diarrhea) 
The events are expected to be minimized by taking the study drug 
with meal.  In case GI events occur, appropriate measures should 
be taken in accordance with local clinical practice guidelines.  If GI 
toxicities are observed and not tolerable, treatment with study drug 
should be temporarily interrupted until recovery to Grade 1 or lower.
Skin disorder AEs 
(e.g., phototoxicity, rash) 
Patients should be advised to avoid prolonged sun exposure while 
taking alectinib and for at least 5 days after study drug 
discontinuation.  Patients should also be advised to use a 
broad-spectrum sun screen and lip balm of at least SPF > 30 to help 
protect against potential sunburn 
Vision disorders 
Investigators should consider referring the patients for an 
ophthalmological evaluation according to local clinical practice 
guidelines, if vision disorders persist or worsen in severity, and to 
advise patients to exercise caution when driving or operating 
machinery due to the risk of developing a vision disorder. 
Edema 
Physical examinations will be performed routinely in clinical trials.  
In case edema events occur, appropriate measures should be taken 
in accordance with local clinical practice guidelines 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
QT prolongation 
• 
Grade 1 (450–480 ms):  no action required 
• 
Grade 2 (481–500 ms): 
First and second episodes:  Continue study medication 
and monitoring 
Third episode:  Decrease the current dose of alectinib by 
150 mg (1 capsule) BID (450 mg BID) 
• 
Grade 3 ( ≥ 501 ms on at least two separate ECGs): 
Temporarily interrupt alectinib and refer patient to a 
cardiologist 
First episode:  If improvement to Grade ≤ 1 or baseline, 
restart with a dose of alectinib decreased by 150 mg 
(1 capsule) BID (450 mg BID) 
Second episode:  If improvement to Grade ≤ 1 or baseline, 
restart with a dose of alectinib decreased by 150 mg 
(1 capsule) BID (300 mg BID) 
Third episode:  Permanently discontinue alectinib 
• 
Grade 4 (≥ 501 ms or > 60 ms change from baseline and 
Torsade de pointes or polymorphic ventricular tachycardia or 
signs/symptoms of serious arrhythmia): 
Discontinue alectinib permanently and admit patient into 
the hospital for monitoring 
Abnormal kidney function 
AEs 
Kidney function laboratory abnormalities are to be reported as AEs 
only if fulfilling the criteria listed in Section 5.3.5.4. 
• 
If, at any time during the study treatment, eGFR decreases 
by > 50% of the baseline visit value, the patient has to be 
carefully monitored.  All of the underlying factors that may 
have acutely impacted serum creatinine levels need to be 
evaluated and corrected (e.g., dehydration, recent exposure 
to contrast media, increased amount of cooked meat in diet, 
concomitant medications affecting renal function as 
appropriate, etc.). 
• 
Any eGFR decrease by > 50% of the baseline visit value 
requires repeat testing. 
If, at the repeat test, the eGFR decrease is still  > 50% of 
the baseline visit value, the treatment with alectinib should 
be interrupted. 
• 
Alectinib treatment may be resumed with caution if the 
eGFR value has increased to approximately the baseline 
visit value. 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
Muscular AEs and/or CPK 
elevations 
CPK laboratory abnormalities are to be reported as AEs only if 
fulfilling the criteria listed in Section 5.3.5.4. 
• 
Myopathy should be considered in any patient with diffuse 
myalgia, muscle tenderness or weakness, and/or marked 
elevations of CPK levels.  Patients should promptly report 
unexplained muscle pain, tenderness, or weakness, 
particularly if accompanied by malaise or fever.  CPK levels 
should be assessed in patients reporting these symptoms. 
• 
At the first occurrence of any of asymptomatic CPK values 
(> 10 × ULN, symptomatic CPK  > 5 × ULN, or in the presence of 
severe muscular symptoms with CPK > ULN but  ≤ 5 × ULN) at 
any time during the study treatment, the patient requires 
monitoring of the CPK values until they are normalized to 
pre-treatment levels or a reasonable explanation for the CPK 
elevation and the symptoms is established. 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
Other AEs (including 
bradycardia) or laboratory 
abnormalities: 
• 
Grade 3 or 4: 
Temporarily interrupt alectinib for a maximum of 3 weeks. 
If improvement to Grade ≤ 1 or baseline does not occur 
within 3 weeks, permanently discontinue alectinib. 
First episode:  If improvement to Grade ≤ 1 or baseline 
within 21 days, decrease the current dose of alectinib by 
150 mg (1 capsule) BID (450 mg BID).  
Second episode:  If improvement to Grade ≤ 1 or baseline 
within 21 days, decrease the current dose of alectinib by 
another 150 mg (1 capsule) BID (300 mg BID). 
Third episode:  Permanently discontinue alectinib. 
• 
Grade 2 (except any symptoms and signs that can be 
corrected with supportive care): 
Temporarily interrupt alectinib and resume if recovering to 
Grade ≤ 1 or baseline if clinically indicated. 
First episode:  If improvement to Grade ≤ 1 or baseline 
within 10 days, continue same dose of alectinib.  If 
improvement occurs after 10 days, decrease the current 
dose of alectinib by 150 mg (1 capsule) BID when 
resuming treatment (450 mg BID). 
Second episode:  If improvement to Grade ≤ 1 or baseline 
within 10 days, decrease the current dose of alectinib by 
150 mg (1 capsule) BID (450 mg BID or 300 mg BID if 
after first episode dose was reduced to 450 mg BID).  If 
improvement occurs after 10 days, decrease the current 
dose of alectinib by 300 mg (2 capsules) when resuming 
treatment (300 mg BID or 150 mg BID if after first episode 
dose was reduced to 450 mg BID). 
Third episode:  Permanently discontinue alectinib. 
• 
Grade 1:  no action required 
ANC = absolute neutrophil count; eGFR = estimated glomerular filtration rate.  
Note:  Diarrhea, nausea, and vomiting should be handled with best supportive care first before 
considering dose modification.  Preexisting pleural effusion will not be considered as an adverse 
event. 
 
5.1.4 
Safety of Crizotinib and Management of Adverse Events  
Dosing interruption and/or dose reduction may be required on the basis of individual 
safety and tolerability.  If dose reduction is necessary, then the dose of crizotinib should 
be reduced to 200 mg taken BID.  If further dose reduction is necessary, then the dose 
should be modified to 250 mg taken once daily on the basis of individual safety and 
tolerability (XALKORI® U.S. Package Insert; Crizotinib SmPC).  Dose reduction 
guidelines for hematologic and non-hematologic toxicities are provided in Table 3  and 
Table 4. 


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Table 3 
Crizotinib Dose Modification⎯Hematologic Toxicities (Except 
Lymphopenia) 
CTCAEa Grade 
Crizotinib Dosing 
Grade 3 
Withhold until recovery to Grade ≤ 2, then resume at 
the same dose schedule 
Grade 4 
Withhold until recovery to Grade ≤ 2, then resume at 
200 mg twice dailyb 
a National Cancer Institute Common Terminology Criteria for Adverse Events 
b In case of second episode, dosing should be withheld until recovery to Grade ≤ 2, then dosing 
should be resumed at 250 mg once daily.  Crizotinib must be permanently discontinued in case 
of a third episode of Grade 4 hematologic toxicity. 
 


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Table 4 
Crizotinib Dose Modification⎯Non-Hematologic Toxicities 
Criteria 
Crizotinib Dosing 
ALT or AST elevation  > 5 × ULN with total 
bilirubin ≤1.5 × ULN 
Withhold until recovery to baseline 
or  ≤ 3 × ULN, then resume at reduced dose.  
Crizotinib must be permanently discontinued 
in case of recurrence. 
ALT or AST elevation  > 3 × ULN with 
concurrent total bilirubin 
elevation  > 1.5 × ULN (in the absence of 
cholestasis or hemolysis) 
Permanently discontinue 
Any Grade drug-related ILD/pneumonitis 
Permanently discontinue 
QTc  > 500 ms on at least 2 separate ECGs 
Withhold until recovery to baseline or  < 481 
ms, then resume at reduced dose.  Crizotinib 
must be permanently discontinued in case of 
recurrence (i.e., QTc  > 500 ms on at least 2 
separate ECGs). 
QTc  > 500 ms or  ≥ 60 ms change from 
baseline with torsade de pointes or 
polymorphic ventricular tachycardia or 
signs/symptoms of serious arrhythmia 
Permanently discontinue 
Bradycardia (heart rate < 60 bpm, 
symptomatic, may be severe and medically 
significant, medical intervention indicated) 
Withhold until recovery to asymptomatic 
bradycardia or to a heart rate  ≥ 60 bpm.  
Evaluate concomitant medications known to 
cause bradycardia, as well as 
anti-hypertensive medications.  If a 
contributing concomitant medication is 
identified and discontinued or its dose is 
adjusted, resume crizotinib at previous dose 
upon recovery to asymptomatic bradycardia or 
to a heart rate  ≥ 60 bpm. 
If no contributing concomitant medication is 
identified or if contributing concomitant 
medication is identified but not discontinued 
or its dose was not modified, resume crizotinib 
at reduced dose upon recovery to 
asymptomatic bradycardia or to a heart rate 
of  ≥ 60 bpm. 
Bradycardia (heart rate < 60 bpm, 
life-threatening consequences, urgent 
intervention indicated) 
Permanently discontinue if no contributing 
concomitant medication is identified.  If 
contributing concomitant medication is 
identified and discontinued, or its dose is 
adjusted, resume at 250 mg once daily upon 
recovery to asymptomatic bradycardia or to a 
heart rate of  ≥ 60 bpm, with frequent 
monitoring.  Crizotinib must be permanently 
discontinued in case of recurrence. 
 
 


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Gastrointestinal events were commonly reported with crizotinib in clinical trials.  Nausea, 
diarrhea, vomiting, and constipation were the most commonly reported gastrointestinal 
events and were primarily Grade 1 in severity.  Supportive care for gastrointestinal 
events may include standard antiemetic and/or antidiarrheal or laxative medicinal 
products.  In clinical studies with crizotinib, events of gastrointestinal perforations 
were reported (XALKORI® U.S. Package Insert; Crizotinib SmPC). 
Blood counts and liver function tests including ALT, AST, and total bilirubin should 
be monitored per local prescribing information for crizotinib. 
See local prescribing information for further crizotinib safety information. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
non-SAEs of special interest, performing protocol-specified safety laboratory 
assessments, measuring protocol-specified vital signs, and conducting other protocol-
specified tests that are deemed critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical occurrence in a clinical investigation where a patient is administered a 
pharmaceutical product, regardless of causal attribution.  An AE can therefore be any of 
the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition). 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as 
biopsies) 
 


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5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
An SAE is any AE that meets any of the following criteria: 
• 
Is fatal (i.e., the AE actually causes or leads to death) 
• 
Is life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death) 
This does not include any AE that had it occurred in a more severe form or was 
allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.9) 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an AE (e.g., rated as mild, moderate, or severe, or according to National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] criteria; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF. 
SAEs are required to be reported by the investigator to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2 for reporting 
instructions). 
5.2.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-SAEs of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  AEs of special interest for this study are the 
following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.6) 


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• 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs (see Section 5.2.1 for definition) 
are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Sections 5.4−5.6.  For each AE recorded 
on the Adverse Event eCRF, the investigator will make an assessment of seriousness 
(see Section 5.2.2 for seriousness criteria), severity (see Section 5.3.3), and causality 
(see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on AEs at each patient contact.  All AEs, whether 
reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
SAEs caused by a protocol-mandated intervention (e.g., invasive procedures such as 
biopsies, discontinuation of medications) should be reported (see Section 5.4.2 for 
instructions for reporting SAEs). 
After initiation of study drug, all AEs will be reported until 4 weeks after the last dose 
of study drug.  After this period, the investigator should report any SAEs that are 
believed to be related to study drug treatment (see Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient evaluation timepoints.  Examples of non-directive questions 
include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The AE severity grading scale for the NCI CTCAE (v4.0) will be used for assessing AE 
severity.  Table 5 will be used for assessing severity for AEs that are not specifically 
listed in the NCI CTCAE. 


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Table 5 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in the NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  On the basis of the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
AE is considered to be related to the study drug, indicating "yes" or "no" accordingly.  
The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 


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5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs on 
the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 
5.3.5.1 
Diagnosis Versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported AEs based on 
signs and symptoms should be nullified and replaced by one AE report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events that are Secondary to Other Events 
In general, AEs that are secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events.  A medically significant secondary AE that is separated in 
time from the initiating event should be recorded as an independent event on the 
Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation timepoints.  Such events should only be recorded once on the Adverse Event 
eCRF.  The initial severity (intensity or grade) of the event will be recorded at the time 
the event is first reported.  If a persistent AE becomes more severe, the most extreme 
severity should also be recorded on the Adverse Event eCRF.  If the event becomes 


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serious, it should be reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 
to "serious," providing the date that the event became serious, and completing all data 
fields related to SAEs. 
A recurrent AE is one that resolves between patient evaluation timepoints and 
subsequently recurs.  Each recurrence of an AE should be recorded as a separate event 
on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE.  A laboratory test result must be 
reported as an AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
Note: For oncology trials, certain abnormal values may not qualify as AEs. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5 times the ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the AE.  For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent AEs). 


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5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported 
as an AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment 
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded one on the Adverse Event eCRF (see Section 5.3.5.3 for details 
on recording persistent adverse events). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an AE the occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which  ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as an SAE or a non-SAE of special interest (see Section 5.4.2). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified AE reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of NSCLC should be recorded only on the Study 
Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and 


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immediately reported to the Sponsor (see Section 5.4.2).  An independent monitoring 
committee will monitor the frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. 
During survival follow-up, deaths attributed to progression of NSCLC should be recorded 
only on the Survival eCRF. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such 
events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., "more 
frequent headaches"). 
5.3.5.9 
Lack of Efficacy or Worsening of Non-Small Cell Lung Cancer 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs.  These data will be captured as 
efficacy assessment data only.  In most cases, the expected pattern of progression will 
be based on RECIST criteria v1.1 (Appendix 4).  In rare cases, the determination of 
clinical progression will be based on symptomatic deterioration.  However, every effort 
should be made to document progression using objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an AE. 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization (i.e., in-patient admission to a hospital) or 
prolonged hospitalization should be documented and reported as an SAE (per the 
definition of SAE in Section 5.2.2), except as outlined below. 


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The following hospitalization scenarios are not considered to be AEs: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an AE 
• 
Hospitalization due solely to progression of the underlying cancer 
 
5.3.5.11 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an AE, but it may result in an AE.  All AEs associated with an overdose or incorrect 
administration of study drug should be recorded on the Adverse Event eCRF.  If the 
associated AE fulfills seriousness criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.3.5.12 
Patient-Reported Outcome Data 
AE reports will not be derived from PRO data by the Sponsor, and safety analyses will 
not be performed using PRO data.  However, if any PRO responses suggestive of a 
possible AE are identified during site review of the PRO data, the investigator will 
determine whether the criteria for an AE have been met and, if so, will report the event 
on the Adverse Event eCRF. 
5.3.5.13 
Adverse Events in Individuals Not Enrolled in the Study 
If an AE inadvertently occurs in an individual not enrolled in the study, the Adverse 
Event Form provided to investigators should be completed and submitted to Roche or 
its designee, either by faxing or by scanning and emailing the form using the fax 
number or email address provided to investigators. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
SAEs 


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• 
Non-SAEs of special interest 
• 
Pregnancies 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting SAEs to the local 
health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor (Roche Medical Responsible) Contact Information 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk as 
well as Medical Monitor contact information will be distributed to all investigators. 
This list can be generated using contact numbers found at the following link: 
http://gcpcenter.roche.com/synergy/portal/view/pdq-spi/gcpcenter/34-64711453. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
5.4.2.1 
Events That Occur Prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported.  The Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators 
should be completed and submitted to Roche or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur After Study Drug Initiation 
After initiation of study drug, SAEs and non-SAEs of special interest will be reported until 
4 weeks after the last dose of study drug.  Investigators should record all case details 
that can be gathered immediately (i.e., within 24 hours after learning of the event) on the 
Adverse Event eCRF and submit the report via the electronic data capture (EDC) system.  


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A report will be generated and sent to Roche Safety Risk Management by the EDC 
system. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to Roche or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system. 
Instructions for reporting post-study AEs are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 3 months after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Roche Safety Risk Management.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any SAEs associated 
with the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF. 
In the event that the EDC system is unavailable, the Clinical Trial Pregnancy Reporting 
Form provided to investigators should be completed and submitted to Roche or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Once the EDC system is available, all information will 
need to be entered and submitted via the EDC system. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
3 months after the last dose of study drug.  A Pregnancy Report eCRF should be 
completed by the investigator immediately (i.e., no more than 24 hours after learning of 
the pregnancy) and submitted via the EDC system.  Attempts should be made to collect 
and report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  The pregnant partner will need to sign an Authorization 
for Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy.  Once the authorization has been signed, the investigator will update the 


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Pregnancy Report eCRF with additional information on the course and outcome of the 
pregnancy.  An investigator who is contacted by the male patient or his pregnant partner 
may provide information on the risks of the pregnancy and the possible effects on the 
fetus, to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 
5.4.3.3 
Abortions 
Any abortion should be classified as an SAE (as the Sponsor considers abortions to be 
medically significant), recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as an SAE, recorded on the Adverse Event eCRF, and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or 
the patient withdraws consent.  Every effort should be made to follow all SAEs considered 
to be related to study drug or trial-related procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.5.2 
Sponsor Follow-Up 
For SAEs, non-SAEs of special interest, and pregnancies, the Sponsor or a designee 
may follow up by telephone, fax, electronic mail, and/or a monitoring visit to obtain 
additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 


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5.6 
POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the investigator becomes aware of any SAE that 
occurs after the end of the AE reporting period (defined as 4 weeks after the last dose 
of study drug), if the event is believed to be related to study drug treatment. 
The investigator should report these events directly to Roche or its designee, either by 
faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided to 
investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all SAEs and non-SAEs of special interest against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators, IRBs, ECs, and applicable health authorities based on 
applicable legislation. 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference documents: 
• 
Alectinib Investigator's Brochure 
• 
Local prescribing information for crizotinib 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The primary analysis population for efficacy is the intent-to-treat (ITT) population defined 
as all randomized patients.  Patients will be assigned to the treatment group to which 
they were randomized. 
The primary analysis population for safety is the Safety Analysis Population (SAP) 
defined as all patients who received at least one dose of study medication.  Patients will 
be assigned to treatment groups as treated, and all patients who received any dose of 
alectinib will be included in the alectinib treatment arm. 
A secondary analysis population for efficacy and safety is the FISH Positive Population 
(FPP).  For efficacy, this is defined as all patients in the ITT population who were 
ALK-positive using the Vysis FISH assay.  Patients will be assigned to the treatment 


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group to which they were randomized.  For safety, this is defined as all patients in the 
SAP who were ALK-positive using the Vysis FISH assay.  Patients will be assigned to 
treatment groups as treated.  This analysis population will be used to perform a 
supportive analysis of the study data based on the Vysis FISH assay rather than the 
Ventana IHC.  This population may be used for registration purposes in the unlikely 
event of registrational failure of the Ventana IHC companion diagnostic, in which case all 
analyses will be based on this population and the same prespecified testing strategy of 
secondary endpoints defined in Section 6.4.2 will be applied. 
The final analysis of the primary endpoint of PFS will occur when 170 PFS events have 
occurred, on the basis of the investigators’ assessments.  On the basis of the 
assumptions outlined in Section 6.1, this is estimated to occur approximately 33 months 
after the first patient has been enrolled.  A survival follow-up analysis will be performed 
once approximately 50% of patients (i.e., 143 patients) have died, which is estimated to 
occur approximately 42 months after the first patient has been enrolled. 
Hypothesis tests will be two-sided unless otherwise indicated. 
The baseline value of any variable will be defined as the last available value recorded 
prior to the first administration of alectinib or crizotinib. 
Further details of all analyses will be provided in the Statistical Analysis Plan. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The focus of this clinical trial is hypothesis testing (Section 6.4.1), and the primary 
endpoint of PFS was used to determine the sample size of the study. 
At the time of writing the initial protocol, there were no Phase III data available on 
crizotinib in the first-line setting in ALK-positive patients.  The median PFS for crizotinib 
administered as second-line therapy from the global randomized Phase III PROFILE 
1007 study was 7.7 months (95% CI: 6.0%, 8.8%).  From the Phase II single arm study 
of patients who had received ≥ 1 line of chemotherapy (with 85% patients having 
received ≥ 2 prior chemotherapy regimens), the median PFS was 8.5 months (95% CI: 
6.2%, 9.9%).  The Phase III PROFILE 1014 study of crizotinib versus standard 
pemetrexed-platinum-based chemotherapy in previously untreated patients with 
ALK-positive non-squamous NSCLC reported a median PFS of 10.9 months for 
crizotinib (Mok et al. 2014). 
Thus, an initial assumption of median PFS of 9.8 months for the crizotinib arm has 
been reassessed on the basis of data from the Phase III study PROFILE 1014 to 
10.9 months.  An HR of 0.65 for alectinib versus crizotinib (i.e., an increase from 
10.9 months median PFS to 16.8 months) will be targeted. 


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In this study, 286 patients will be enrolled in a 1:1 randomization allocation.  Enrollment 
will take approximately 24 months on the basis of an assumption of non-linear 
recruitment as follows: 
• 
Month 1:  1 patient per month 
• 
Month 2:  2 patients per month 
• 
Month 3:  4 patients per month 
• 
Month 4:  6 patients per month 
• 
Month 5:  8 patients per month 
• 
Month 6:  10 patients per month 
• 
Month 7:  12 patients per month 
• 
Months 8−12:  13 patients per month 
• 
Months 13−14:  14 patients per month 
• 
Month 15 onwards:  15 patients per month 
A total of 170 PFS events are required to achieve 80% power at a two-sided alpha level 
of 5%.  This number of PFS events is estimated to occur approximately 33 months after 
the first patient has been enrolled. 
No interim analysis for efficacy or futility is planned. 
A survival follow-up analysis will be performed once approximately 50% of patients 
(i.e., 143 patients) have died.  The median OS in the crizotinib arm is assumed to be 
24 months, and the expected median OS in the alectinib treatment arm is 30 months, 
equating to an HR of 0.83.  On the basis of the sample size (N = 286), the trial will not be 
powered to demonstrate any statistically significant difference in OS of this magnitude.  
At the time of the final analysis of the primary endpoint of PFS, on the basis of the above 
assumptions, 106 OS events are expected to have occurred.  The survival follow-up 
analysis is expected to occur approximately 42 months after the first patient has been 
enrolled. 
A follow-up analysis will be performed based on the FPP.  This will occur once 170 PFS 
events have occurred in the FPP to ensure 80% power of the log-rank test assuming a 
hazard ratio of 0.65 in this sub-population.  Based on a potential discrepancy/technical 
failure rate of 10% between the Ventana IHC assay and the Vysis FISH assay, 257 
patients would be eligible for the FPP analysis, which is estimated to occur 
approximately 35 months after the first patient has been enrolled (i.e., 2 months after the 
primary IHC analysis) based on the above assumptions. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Study enrollment, study treatment administration, reasons for discontinuation from study 
treatment, and reasons for study termination will be summarized by treatment arm for all 


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randomized patients.  Violations of inclusion and exclusion criteria, on the basis of 
information captured on the eCRF, will be reported and summarized by treatment arm. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Summaries of treatment group comparability will be based on the ITT population. 
Demographic, baseline disease characteristics and lung cancer history will be 
summarized by treatment arm for all randomized patients, including the randomization 
stratification factors.  Descriptive baseline summaries of continuous data will present the 
group mean, standard deviation, median, minimum, and maximum.  Descriptive 
summaries of discrete data will present the category counts as frequency and 
percentages. 
Previous and concomitant cancer therapy will also be summarized, as well as 
anti-cancer subsequent therapy.  Previous and concurrent diseases and medications will 
also be summarized. 
6.4 
EFFICACY ANALYSES 
The primary population for all primary and secondary efficacy analyses will be the ITT 
population. 
6.4.1 
Primary Efficacy Endpoint 
PFS is defined as the time from date of randomization to the date of first documented 
disease progression or death, whichever occurs first.  The primary endpoint of PFS will 
be determined on the basis of investigator assessment of progression using 
RECIST v1.1.  Patients who have not experienced disease progression or death at the 
time of analysis will be censored at the last tumor assessment date either during study 
treatment or during follow-up.  Patients with no post-baseline tumor assessment will be 
censored at the date of randomization. 
Patients who discontinue treatment prior to disease progression (e.g., due to toxicity) will 
continue on study and will be followed until disease progression and for OS regardless 
of whether they subsequently receive anti-cancer therapy. 
The treatment comparison of PFS will be based on a stratified log-rank test at the 
5% level of significance (two-sided).  The stratification factors are the randomization 
stratification factors:  ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS 
metastases at baseline (yes vs. no), as recorded on the eCRF.  Results from an 
unstratified log-rank test will also be presented. 
The Kaplan-Meier method will be used to estimate the median PFS for each treatment 
arm with 95% confidence limits, and a Kaplan-Meier curve will be constructed to provide 
a visual description of the difference between the treatment arms.  A stratified Cox 
proportional regression model will be used including treatment in order to provide an 


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estimate of the treatment effect expressed as an HR (alectinib vs. crizotinib), as well as 
a 95% CI. 
The difference between the two treatment groups will be assessed and tested for the 
following hypothesis:  the survival distribution function (SDF) of the alectinib treatment 
group is the same as for the crizotinib treatment group versus the alternative that the two 
distributions are different:  
H0:  SDF (alectinib) = SDF (crizotinib) 
versus 
H1:  SDF (alectinib) ≠ SDF (crizotinib) 
where SDF denotes the survival distribution function of the parameter PFS. 
6.4.2 
Secondary Efficacy Endpoints 
If the primary endpoint of PFS is statistically significant at a two-sided 5% significance 
level, the following secondary endpoints will be tested in the following sequential order, 
each at a two-sided 5% significance level: 
• 
PFS by IRC 
• 
Time to CNS progression 
• 
ORR 
• 
OS 
 
PFS by IRC 
An analysis of PFS on the basis of the IRC assessments will be performed using the 
same methodology as specified for PFS on the basis of investigator assessment. 
Time to CNS Progression 
Time to CNS progression is defined as the time from randomization until radiographic 
evidence of CNS progression.  An independent central radiological review will be 
performed for all patients, and the analysis of CNS progression or response will be on 
the basis of the data from the independent review.  All patients will be included in the 
analysis regardless of their baseline status of CNS metastases.  CNS progression is 
defined as progression due to newly developed CNS lesions and/or progression of 
preexisting baseline CNS lesions.  On the basis of RECIST v1.1, this is defined as a new 
post-baseline CNS/brain lesion(s) and/or an increase of ≥ 20% in the sum of longest 
diameters of the measurable baseline CNS lesions compared to nadir and/or 
unequivocal progression of non-measurable baseline CNS lesions. 
In order to account for the competing risks inherent in such an analysis, HRs, including 
statistical inference on the basis of a two-sided log-rank test, to compare the risk of CNS 
progression between the alectinib and crizotinib treatment groups, will be computed on 
the basis of cause-specific hazard functions. 


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The probability of CNS progression, non-CNS progression, and death will each be 
estimated using cumulative incidence functions. 
For descriptive purposes, estimates of the CNS progression rates over time with 
95% CIs on the basis of cumulative incidence functions will be presented.  A Gray’s test 
to compare the risk of CNS progression between alectinib and crizotinib will also be 
performed as a supportive analysis. 
An exploratory analysis of CNS Time to Progression on the basis of RANO criteria will 
also be performed on the basis of the IRC assessments. 
In the subgroup of patients with measurable CNS lesions at baseline, an exploratory 
analysis of C-ORR defined as the percentage of patients who achieve a best overall 
response of CR or PR (defined by RECIST v1.1 as a 30% decrease in the sum of 
longest diameters of measurable CNS lesions referencing baseline) will also be 
performed.  Duration of CNS response will be listed and may be analyzed if there are a 
sufficient number of CNS responses.  An exploratory analysis of these endpoints will 
also be performed on the basis of RANO criteria assessed by the IRC. 
Objective Response Rate 
ORR, on the basis of investigator assessment, is defined as the percentage of patients 
who attain a CR or PR.  Per RECIST v1.1, confirmation of objective response is not 
required for this secondary endpoint.  Patients without a post-baseline tumor 
assessment will be considered non-responders, as will patients with a best overall 
response of stable disease (SD), PD, or NE (not evaluable). 
An estimate of ORR and its two-sided 95% CI will be calculated using the 
Clopper-Pearson method for each treatment arm.  Response rates in the treatment 
groups will be compared using a stratified Mantel-Haenszel test on the basis of the 
randomization stratification factors.  The difference in ORR between the two treatment 
arms will be presented together with a two-sided 95% CI on the basis of a normal 
approximation to the binomial distribution. 
DOR 
For patients who have experienced an objective response (CR or PR) during the study 
as assessed by the investigator, DOR is defined as the duration from the first tumor 
assessment that supports the patient’s objective response (CR or PR, whichever is first 
recorded) to first documented disease progression or death due to any causes, 
whichever occurred first.  Patients who have not progressed or died at the time of 
analysis will be censored at the last tumor assessment date.  Because the determination 
of DOR is based on a non-randomized subset of patients, formal hypothesis testing will 
not be performed.  DOR will be estimated using Kaplan-Meier methodology and a HR on 
the basis of a Cox proportional regression model will be calculated. 


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Overall Survival 
OS is defined as the time from the date of randomization to the date of death due to any 
cause.  Patients who are not reported as having died at the time of analysis will be 
censored at the date when they were last known to be alive.  Patients who do not have 
post-baseline information will be censored at the date of randomization.  OS will be 
analyzed using the same methodology as specified for the primary endpoint.  A survival 
follow-up will be performed based on more mature data. 
6.4.2.1 
Sensitivity Analyses 
The following sensitivity analyses will be performed on the primary endpoint of PFS: 
• 
The effect of non−protocol-specified anti-cancer therapy prior to progression will be 
assessed by censoring patients at the last adequate tumor assessment prior to the 
start of non−protocol-specified anti-cancer therapy. 
• 
The effect of missing tumor assessments will be assessed if the number of missing 
assessments in either arm is > 5%.  For patients with progression determined 
following one or more missing tumor assessments, the progression will be 
backdated to the first missing tumor assessment. 
• 
The effect of loss to follow-up will be assessed depending on the number of patients 
who are lost to follow-up.  If > 5% of patients are lost to follow-up for PFS in either 
treatment arm, a “worst-case” analysis will be performed in which patients who are 
lost to follow-up will be considered to have progressed at the last date they were 
known to be progression-free. 
 
6.4.2.2 
Subgroup Analyses 
Subgroup analyses of PFS will be performed for patients with baseline CNS metastases 
and for patients without baseline CNS metastases.  In addition, a subgroup analysis of 
Time to CNS Progression will be performed, excluding patients who had pre-treatment 
radiation therapy for CNS lesions. 
All other subgroup analyses will be specified in the SAP. 
6.5 
SAFETY ANALYSES 
The primary population for all safety analyses will be the SAP as defined in Section 6. 
All safety parameters will be summarized in tables to evaluate and compare the safety 
profile of patients treated with alectinib versus crizotinib in terms of: 
• 
Adverse events including adverse events leading to dose modifications or 
interruptions, study drug withdrawal, and death  
• 
Severe, serious, and selected adverse events 
• 
Deaths 
• 
Laboratory parameters and abnormalities 
• 
Vital signs 


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• 
ECGs 
• 
ECOG PS 
Adverse events will be coded using MedDRA and summarized by mapped term and 
appropriate thesaurus level.  All adverse events and routine laboratory parameters will 
be assessed according to the NCI CTCAE v4.0 grading system.  For adverse events, the 
most extreme severity will be used for reporting.  Adverse events will be described by 
individual listings and by body system, as well as by severity.  In tables showing the 
overall incidence of adverse events, patients who experienced the same event on more 
than one occasion are counted only once in the calculation of the event frequency. 
Laboratory values will be summarized by treatment arm including summary tables for the 
shifts in grades from baseline to the worst grade observed during treatment.  In order to 
evaluate and compare hypogonadism in the two treatment arms, testosterone levels in 
the blood will be summarized for males by treatment arm over time (for details, see 
Section 6.8). 
Descriptive summary tables of change from baseline over time will be provided for vital 
signs and descriptive statistics will be tabulated for ECOG PS.  ECG findings over time 
will be summarized. 
Study drug administration will be summarized by duration and cumulative dose.  In 
addition, treatment exposure will be summarized including the number of doses received, 
dose intensity, and the percentage of planned dose. 
Subgroup analyses will be performed to evaluate the safety profile within the subgroups 
of patients including by sex, age (< 65 vs. ≥ 65 years), and race (non-Asian vs. Asian). 
An IDMC will review the safety data collected during the conduct of the study.  Safety 
monitoring will be performed periodically.  Further details will be outlined in the IDMC 
Charter. 
6.6 
PHARMACOKINETIC ANALYSES 
Standard NCA may be conducted for PK data collected from patients participating in 
serial/intensive PK collections for relevant analytes, as data allow, as appropriate, and if 
needed.  PK parameters, including but not limited to AUC, maximum concentration 
(Cmax), and time to maximum concentration (Tmax), will be calculated on the basis of the 
available data as appropriate and where data allow.  Additional PK parameters may be 
calculated as deemed appropriate. 
Individual and mean plasma concentrations at each sampling timepoint and/or PK 
parameters for alectinib and metabolite(s) will be listed, as appropriate. 
Summary statistics (e.g., means, standard deviation, coefficient of variation %, 
geometric means, medians and ranges) for plasma concentrations and/or PK 


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parameters for alectinib and metabolite(s) will be presented by treatment and nominal 
collection times (plasma concentrations only), as appropriate.  Additional plots or 
summary statistics may be constructed or calculated, as appropriate. 
Results of PK and/or any PK/pharmacodynamic analyses may be reported outside the 
clinical study report. 
Nonlinear mixed-effects modeling (with software NONMEM) (Beal et al. 1999) will be 
used to analyze the sparse and/or serial/intensive plasma concentration-time data for 
alectinib.  The PK data from this study may be pooled with data from other studies.  
Population and individual PK parameters will be estimated and the influence of various 
covariates (such as age, gender, and body weight) on these parameters will be 
investigated. 
Exploratory analyses will be conducted to investigate the relationship between alectinib 
PK exposure and efficacy/safety parameters. 
Details of the mixed-effects modeling and exploratory analyses will be reported in a 
document separate from the clinical study report. 
6.7 
PATIENT-REPORTED OUTCOME ANALYSES 
The following PRO endpoints will be analyzed and PRO data will be presented 
separately from adverse event data. 
6.7.1 
Time to Deterioration of Patient-Reported Lung Cancer 
Symptoms 
TTD from baseline will be assessed at every study visit (Week 4, Week 8, and then after 
every 4 weeks) until disease progression and during post-progression on treatment in 
case of isolated, asymptomatic CNS progression; at post-treatment Visit (4 weeks after 
permanent treatment discontinuation); and at subsequent 8-weekly survival follow-up 
visits for 6 months, for the following lung cancer symptoms: cough (Question 31 on the 
QLQ-LC13), dyspnea single item (Question 8 on the QLQ-C30), dyspnea multi-item 
subscale (Questions 33-35 on the QLQ-LC13), chest pain (Question 40 on the 
QLQ-LC13), arm/shoulder pain (Question 41 on the QLQ-LC13) and fatigue multi-item 
subscale (Questions 10, 12, and 18 on the QLQ-C30) for patients in each arm.  
Completion and compliance rates will be summarized at each timepoint by treatment 
arm with reasons for missing data.  TTD will be analyzed for the ITT population.  If a 
baseline or post-baseline PRO evaluation is not available, TTD will be censored at the 
date of randomization.  If they have not deteriorated, patients will be censored at the last 
time when they completed an assessment for cough, dyspnea (single item), dyspnea 
(subscale items), chest pain, arm/shoulder pain, and fatigue. 


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6.7.2 
Additional Patient-Reported Outcomes 
PROs of HRQoL, lung cancer−related symptoms, and health status will be measured 
using the EORTC QLQ-C30 and EORTC QLQ-LC13. 
Summary statistics (mean, standard deviation, median, and range) of linear transformed 
scores will be reported for all the items and subscales of the EORTC QLQ-C30 
questionnaire, and the QLQ-LC13 according to the EORTC scoring manual guidelines.  
Completion and compliance rates will be summarized at each timepoint by treatment 
arm with reasons for missing data.  Only patients with a baseline assessment and at 
least one post-treatment assessment will be included in the analyses. 
6.8 
EXPLORATORY ANALYSES 
The EQ-5D-3L is a generic PRO instrument that is used for across diseases and 
indications cost-effectiveness analyses.  This instrument quantifies the QoL of various 
health outcomes and is applicable to a wide range of health states.  Analyses of this 
outcome will be exploratory and will generate utility scores for use in economic models 
for reimbursement purposes only.  The PRO will be administered every 4 weeks until 
disease progression and during post-progression on treatment in case of isolated, 
asymptomatic CNS progression; at the post-treatment visit (4 weeks after permanent 
treatment discontinuation); and every follow-up visit (every 8 weeks) after post-treatment 
visit for 6 months (see Appendix 1).  
It has been reported that crizotinib therapy triggered rapid suppression of testosterone 
levels in men causing rapid-onset hypogonadism.  Whether reductions in testosterone 
reflect an effect of crizotinib on ALK or on some combination of the drug’s targets 
(i.e., c-MET) is unknown (Weickhardt et al. 2012, 2013).  Total testosterone, albumin, 
and sex hormone-binding globulin (SHBG) to calculate free testosterone (calculator: 
http://www.issam.ch/freetesto.htm) and FSH and LH levels in blood will be measured 
(see Appendix 1) in male patients enrolled in the study for exploratory analysis of an 
onset of hypogonadism.  The recommended time of day to have a blood sample taken 
for this test is between 7 a.m. and 10 a.m. 
The Abbott Vysis FISH test will be used as an exploratory assay, after patients have 
been enrolled in this study.  Results from these analyses will be used to quantify the 
degree of correlation between Vysis FISH and Ventana IHC for the detection of 
ALK-positive NSCLC.  The FPP will be a secondary analysis population for efficacy and 
safety.  This analysis population will be used to perform a supportive analysis of the 
study data based on the Vysis FISH assay rather than the Ventana IHC.  This 
population may be used for registration purposes in the unlikely event of registrational 
failure of the Ventana IHC companion diagnostic, in which case all analyses will be 
based on this population. 
Results of exploratory analyses on post-progression tumor samples to measure 
molecular mechanisms of resistance to ALK inhibitors and plasma samples to measure 


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ALK rearrangements in circulating tumor cells will be communicated outside the main 
study report. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC using eCRFs.  
Sites will be responsible for data entry into the EDC system.  In the event of discrepant 
data, the Sponsor will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data or other electronic 
data will be sent directly to the Sponsor, using the Sponsor’s standard procedures to 
handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
ePRO data will be collected through use of an electronic device provided by an ePRO 
vendor.  The device is designed for entry of data in a way that is attributable, secure, 
and accurate, in compliance with the FDA regulations for electronic records (21 CFR 
Part 11).  The ePRO device data are available for view access only via secure access to 
a web server.  Only identified and trained users may view the data, and their actions 
become part of the audit trail.  The Sponsor will have view access only.  System 
backups for data stored by the Sponsor and records retention for the study data will be 
consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 


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7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
Patients will use an ePRO device to capture PRO data.  The data will be transmitted via 
pre-specified transmission method (e.g., web or wireless) automatically after entry to a 
centralized database at the ePRO vendor.  The data can be reviewed by site staff via 
secure access to a web server. 
Once the study is complete, the ePRO data, audit trail, and trial and system 
documentation will be archived.  The investigator will receive patient data for the site in 
both human- and machine-readable formats on an archival-quality compact disc that 
must be kept with the study records as source data.  Acknowledgement of receipt of the 
compact disc is required.  In addition, the Sponsor will receive all patient data in a 
machine-readable format on a compact disc. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 


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7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a United States 
IND application will comply with FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the European Union or European Economic Area will comply 
with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 


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submission.  The final IRB/EC−approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient before his or her 
participation in the study.  The case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC−approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 


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8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  In 
addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 


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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, which includes an audit trail containing a complete record of all changes 
to data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
Steering Committee is established to provide the study Sponsor with recommendations 
related to any aspect of the trial, specifically study design, data interpretation, 
exploratory analyses, or alternate changes to the trial that may assist in patient accrual, 
data collection, analysis, and interpretation of the study results.  The Sponsor is 
ultimately responsible for all decisions regarding the study. 
The test for the study inclusion criteria of ALK-positive NSCLC will be performed at 
Sponsor’s designated central laboratories and assessed by Ventana IHC test. 
An IDMC will be established to monitor the progress of the study and ensure that the 
safety of patients enrolled in the study is not compromised.  Details of the composition, 
roles, and responsibilities, and processes of the IDMC are documented in a separate 
IDMC charter.  The IDMC will review safety data and can make recommendations to the 
Sponsor to stop or amend the study on the basis of safety findings.  The frequency of 
these reviews as well as the data to be reviewed will be agreed with the IDMC and 
outlined in the separate IDMC charter.  No stopping for early proof of efficacy will result 
from any of these regular safety reviews.  IDMC review meetings will be held in a blinded 
manner to the Sponsor. 


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An IRC will review the tumor assessments to determine the secondary endpoints of the 
overall disease PFS and time to CNS progression, both on the basis of RECIST v1.1.  In 
addition to the secondary endpoint of time to CNS progression together with C-ORR, 
C-DOR, and CNS progression rate at 6, 12, 18, and 24 months, an IRC will review the 
tumor assessments on the basis of RANO criteria. 
The independent review of MRI and CT scans will NOT determine either eligibility OR 
patient treatment.  All treatment decisions will be made by the investigator using local 
assessments. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing information on 
the trial to healthcare professionals and to the public, both at scientific congresses and in peer-
reviewed journals.  The Sponsor will comply with all requirements for publication of study 
results.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical trial results within 6 months after the 
availability of the respective clinical study report.  In addition, for all clinical trials in 
patients involving an IMP for which a marketing authorization application has been 
filed or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and 
statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 


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Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


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CA Cancer J Clin 2012;62:220−41. 
Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4–ALK fusion 
gene in non-small-cell lung cancer. Nature 2007;448:561−6. 
Takeuchi K, Choi YL, Soda M, et al. Multiplex reverse transcription-pcr screening for 
eml4-alk fusion transcripts. Clin Cancer Res 2008;14:6618−24. 


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U.S. Department of Health and Human Services. Guidance for industry: clinical trial 
endpoints for the approval of cancer drugs and biologics [resource on Internet]. 2007 
[cited 2014 Jan 20]. Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/ucm071590.pdf. 
Weickhardt A, Doebele R, Purcell W, et al. Symptomatic reduction in free testosterone 
levels secondary to crizotinib use in male cancer patients. Cancer 2013;119:2383−90. 
Weickhardt A, Rothman M, Salian-Mehta S, et al. Rapid-onset hypogonadism secondary 
to crizotinib use in men with metastatic nonsmall cell lung cancer. Cancer 
2012;118:5302−9. 
Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for 
high-grade gliomas: response assessment in Neuro-Oncology Working Group. J Clin 
Oncol 2010;28:1963−72. 
Wong DWS, Leung ELH, So KKT, et al. The EML4-ALK fusion gene is involved in 
various histologic types of lung cancers from nonsmokers with wild-type EGFR and 
KRAS. Cancer 2009;115:1723−33. 
XALKORI® U.S. Package Insert, Pfizer Inc. 2012 [cited 2014 Jan 20]. Available from: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202570s002lbl.pdf. 
 


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Appendix 1  
Schedule of Assessments 
Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) Until 
PD, Death, or 
Withdrawal 
from Study 
prior to PD 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation) 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D) 
Informed consent 
x 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
Pregnancy testa 
 
x 
To be repeated as necessary 
 
 
 
Physical 
examinationb 
x 
 
x 
x 
x 
x 
x 
 
 
Vital signs 
x 
 
x 
x 
x 
x 
x 
 
 
ECOG PS 
x 
 
x 
x 
x 
x 
x 
 
 
ECGc 
x 
 
xd 
x 
 
x 
 
 
 
Hematology, 
Coagulation 
x 
 
xd 
x 
x 
x 
x 
 
 
Biochemistry 
x 
 
xd 
x 
x 
x 
x 
 
 
Urinalysis 
x 
 
xd 
x 
x 
x 
x 
 
 


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Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
125 
Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) Until 
PD, Death, or 
Withdrawal 
from Study 
prior to PD 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation) 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D) 
Concomitant 
medications 
x 
 
x 
x 
x 
x 
x 
 
 
Mandatory tumor 
sample for ALK 
testinge 
x 
 
 
 
 
 
 
 
 
Optional tumor 
sample 
 
 
xf 
 
 
xg 
xg 
 
 
Blood sample for 
ALK fusion 
detection in 
circulating tumor 
cells (20 mL of 
blood) 
 
 
x 
 
 
xh 
xh 
 
 
Plasma for 
detection of ALK 
mutation status 
(20 mL of blood) 
 
 
x 
 
 
xi 
xi 
 
 


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Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
126 
Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) Until 
PD, Death, or 
Withdrawal 
from Study 
prior to PD 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation) 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D) 
Blood sample for 
pharmacogenomics 
research at pre-
dose (3 mL of 
blood) j 
 
 
x 
 
 
 
 
 
 
Tumor 
assessmentk 
xl 
 
xl 
 
x 
xm 
x 
xn 
 
MRI scan of the 
brain 
xl 
 
xl 
 
x 
xm 
x 
xn 
 
PK samples (2 mL 
blood)o 
 
 
x 
x 
x 
x 
 
 
 
PRO (EORTC 
QLQ-C30/LC13); 
EQ-5Dp 
 
 
x 
x 
x 
x 
x 
x 
xq 


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Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
127 
Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) Until 
PD, Death, or 
Withdrawal 
from Study 
prior to PD 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation) 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D) 
Total testosterone, 
albumin, and 
SHBG to calculate 
free testosterone, 
FSH, and LHr 
 
 
x 
x 
x 
x 
 
 
 
Adverse eventss 
x 
x 
x 
x 
x 
x 
x 
x 
 
Subsequent 
therapy for NSCLC 
 
 
 
 
 
 
x 
x 
xq 
Drug dispensing 
and accountabilityt 
 
 
x 
x 
x 
x 
x 
x (accountability 
only) 
 
Blood Sample for 
Roche Clinical 
Repository (10 mL) 
 
 
x 
 
 
 
 
 
 
ALK = anaplastic lymphoma kinase; ALP = alkaline phosphatase;  CT = computed tomography; CTC = circulating tumor cells; CTCAE = Common 
Terminology Criteria for Adverse Events; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30 = European 
Organization for the Research and Treatment of Cancer Quality of Life Questionnaire−Core; EQ-5D = EuroQoL 5 Dimension; 


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Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
128 
FSH = follicle-stimulating hormone; LH = luteinizing hormone; MRI = magnetic resonance imaging; NCI = National Cancer Institute; 
NSCLC = non−small cell lung cancer; PD = progressive disease; PK = pharmacokinetic; PRO = patient-reported outcome; ULN = upper limit of normal. 
Notes: First dose of study drug to be taken as soon as patient has been randomized and appropriate drug has been provided–within ≤ 24 hours.  
Post-baseline assessments are to be performed within ± 1 week for the first two 4 weekly and subsequent 8 weekly assessments. 
a Urine or serum, to be repeated as necessary. 
b Including an ophthalmologic examination if clinically indicated. 
c At screening, Visit 0 (baseline), Visit 1 (Week 4), Visit 4 (Week 24), Visit 8 (Week 56), last treatment visit, and as clinically indicated throughout 
the study. 
d Screening laboratory assessment done within 3 days can be counted as the baseline assessment. 
e Preferably blocks fixed in neutral buffered formalin; if blocks are not available, a minimum of 10 to 15 unstained 5-µm slides are required.  Tumor 
ALK status will be assessed by central laboratory before randomization. 
f Optional tumor sample could be taken from the tumor block obtained at screening. 
g At the time of disease progression from progressive lesions. 
h Mandatory blood sample (20 mL) for CTCs should match in time to tumor progression (CNS progression and/or systemic disease progression) at 
discretion of the investigator. 
i Blood sample (20 mL) to obtain plasma for exploratory biomarkers will be collected at Visit 0 (baseline), during the study every second visit (i.e., 
every 16 weeks) until disease progression and during post-progression on treatment in case of isolated, asymptomatic CNS progression. 
j This sample is required in all patients in alectinib arm, and in those patients in the crizotinib arm who wish to participate in optional genomics 
sequencing. 
k Tumor assessment consists at minimum of a CT/MRI scan of chest and abdomen (for imaging of liver and adrenal glands).  Patients who are 
known to have bone metastasis or who display clinical or laboratory signs (e.g., serum ALP >1.5 × ULN) of bone metastasis should undergo 
radionuclide bone scan.  Post-baseline assessments are to be performed within ±1 week for the 8 weekly assessments.  If there is suspicion of 
disease progression on the basis of clinical or laboratory findings, a tumor assessment should be performed as soon as possible before the next 
scheduled evaluation. 
l Screening tumor assessment done within 14 days will be counted as the baseline assessment. 
m Tumor assessment can be performed whenever clinically indicated.  Brain assessment scans should be performed at every systemic imaging 
tumor assessment.  Tumor assessment should continue until disease progression if a patient discontinues treatment prior to PD, regardless of 
whether they subsequently receive non-study, anti-cancer therapy (a use of subsequent non-study, anti-cancer therapy prior to disease 
progression would be considered a protocol violation).  


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Schedule of Assessments (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
129 
n If treatment was permanently discontinued due to disease progression. 
o Pre-dose PK (2 mL) sampling for all patients on alectinib treatment will be performed at each visit during the treatment period and at the final 
study visit.  The pre-dose PK samples should be taken immediately before (within 2 hours) intake of study medication at all study visits. Remind 
the patient not to take a daily dose at home on the day of scheduled study visit.  For a subset of patients on alectinib treatment (10%−15%, at 
least n = 20) participating in serial/intensive PK sample collection, additional PK will be collected on Visits 0 (baseline) and 1 (Week 4) at 
pre-dose (within 2 hours before intake of study medication), 1, 2, 4, 6, 8, 10, and 12 hours post-dose. 
p PRO questionnaires are to be completed every 4 weeks until disease progression and during post-progression on treatment in case of isolated, 
asymptomatic CNS progression; at the post-treatment visit (4 weeks after permanent treatment discontinuation); and every follow up visit (every 
8 weeks) after post-treatment visit for 6 months..  Further guidelines on PRO questionnaire administration will be provided in the study manual. 
q Performed every 8 weeks after post-treatment visit during the first 6 months and then every 12 weeks or performed as appropriate.  The PRO 
assessments should be performed during the first 6 months. 
r Male patients only, using institutional standard assay. The recommended time of day to have a blood sample taken for this test is between 7 a.m. 
and 10 a.m.  Free testosterone calculator: http://www.issam.ch/freetesto.htm. 
s Graded according to NCI CTCAE (version 4.0).  Serious adverse events collection must start from first study-specific procedure. 
t For details on drug dispensing and accountability, see Section 4.3.3. 
 


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Appendix 2  
Schedule of Alectinib Pharmacokinetic Assessments 
Visit 
Timepoint 
Visit 0 (baseline) 
Pre-dose (within 2 hours before intake of alectinib)
Visit 1 (Week 4) 
Pre-dose (within 2 hours before intake of alectinib)
Visit 2 (Week 8) 
Pre-dose (within 2 hours before intake of alectinib)
All subsequent visits (every 
8 weeks) until PD or 
death/withdrawal from study prior to 
PD 
Pre-dose (within 2 hours before intake of alectinib)
Visit 0 (baseline) and Visit 1 
(Week 4)a 
Pre-dose (within 2 hours before intake of 
alectinib), 1, 2, 4, 6, 8, 10, and 12b hours post-
dose 
PD = progressive disease; PK = Pharmacokinetic 
a For patients participating in the serial/intensive PK sample collection only. 
b A time window of ± 1 hour may be considered for the 12-hour PK sample only 


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Appendix 3  
List of Substrates, Inhibitors, and Inducers of Drug-Metabolizing 
Enzymes and Transporters 
This representative list is not intended to be an exhaustive list.  Each patient’s 
concomitant medications should be carefully considered by the investigator with regard 
to the risk-benefit for the particular patient and appropriate monitoring, including any 
concomitant medication, dose adjustment, or therapeutic alternatives, which should be 
determined by the investigator caring for the patient. 
CYP3A Inducers 
CYP3A Potent Inhibitors 
avasimibe, aminoglutethimide, barbiturates, 
carbamazepine, dexamethasone, efavirenz, 
ethosuximide, garlic supplements, 
glucocorticoids, glutethimide, griseofulvin, 
modafinil, nafcillin, nevirapine, oxcarbazepine, 
phenobarbital, phenytoin, pioglitazone, 
primidone, rifabutin, rifampin, rifapentine, St. 
John’s wort, troglitazone 
aprepitant, atazanavir, boceprevir, 
ciprofloxacin, clarithromycin, conivaptan, 
diltiazem, erythromycin, fluconazole, grapefruit 
juice, indinavir, itraconazole, ketoconazole, 
lopinavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, troleandomycin, verapamil, 
voriconazole 
 
P-gp 
Substrates 
Inhibitors 
Inducers 
aliskiren, ambrisentan, 
colchicine, dabigatran, 
digoxin, everolimus, 
fexofenadine, imatinib, 
lapatinib, maraviroc, nilotinib, 
posaconazole, pravastatin, 
ranolazine, saxagliptin, 
sirolimus, sitagliptin, talinolol, 
tolvaptan, topotecan 
amiodarone, azithromycin, 
captopril, carvedilol, 
clarithromycin, conivaptan, 
cyclosporine, diltiazem, 
erythromycin, felodipine, 
itraconazole, ketoconazole, 
lopinavir, quercetin, quinidine, 
ranolazine, verapamil 
avasimibe, carbmazepine, 
phenytoin, rifampin, St John’s 
wort, tipranavir 
Dual UGT1A1/CYP3A 
Substrates 
Inhibitors 
Inducers 
buprenorphine, raltegravir 
atazanavir 
rifampin 
Sensitive CYP3A and 2C8 substrates 
alfentanil, aprepitant, budesonide, buspirone, conivaptan, darifenacin, darunavir, dasatinib, 
dronedarone, eletriptan, eplerenone, everolimus, felodipine, indinavir, fluticasone, lopinavir, 
lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, quetiapine, saquinavir, sildenafil, 
simvastatin, sirolimus, tolvaptan, tipranavir, triazolam, ticagrelor, vardenafil, astemizole, 
cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus, terfenadine, repaglinide, paclitaxol 
 


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Appendix 3  
List of Substrates, Inhibitors, and Inducers of Drug-Metabolizing 
Enzymes and Transporters (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
 
132 
This information in this appendix is adapted from Levien and Baker 20031, Zhang 20102, 
and FDA Guidance on Drug-Drug Interactions. 
Also see: 
• 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dr
ugInteractionsLabeling/ucm080499.htm  
• 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx  
Potent inhibitors of CYP3A are those considered to be “strong CYP3A inhibitors” 
previously shown to result in a ≥ 5-fold increase in the AUC of a concomitantly 
administered CYP3A substrate.  These are based on the available published literature 
and, thus, are not considered exhaustive or inclusive.  See FDA Guidance on Drug-Drug 
Interactions for further detail. 
                                            
1 Levien TL, and Baker DE Cytochrome PͶͷͲ Drug )nteractions. Therapeutic Research Center 
Pharmacist’s Letter/Prescriber’s Letter [resource on the )nternet]. ʹͲͲ͵. Available from: 
www.pharmacistsletter.com and www.prescribersletter.com. 
2 Zhang L. Transporter Mediated Drug‐Drug )nteractions. FDA. Clinical Pharmacology Advisory 
Committee Meeting Topic Ͷ: Transporter‐Mediated Drug‐Drug )nteractions Atlanta, GA, March ͳ͹, 
ʹͲͳͲ. 


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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1: Excerpt from Original Publication 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1,1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2 
MEASURABILITY OF TUMOR AT BASELINE 
DEFINITIONS 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below. 
Measurable tumor lesions 
Tumor lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 
• 
10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater than 
5 mm) 
• 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
• 
20 mm by chest X-ray 
Malignant lymph nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
≥ 15 mm in the short axis when assessed by CT scan (CT scan slice thickness is 
recommended to be no greater than 5 mm).  At baseline and follow-up, only the short 
axis will be measured and followed.  See also notes below on “Baseline Documentation 
of Target and Non-Target Lesions” for information on lymph node measurement. 
Non-Measurable tumor lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 
                                            
1  Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors:  
revised REC)ST guideline ȋVersion ͳ.ͳȌ. Eur J Cancer ʹͲͲͻ;Ͷͷ:ʹʹͺ–Ͷ͹. 
2  For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made. 


Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
134 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone lesions 
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions.  However, these techniques 
can be used to confirm the presence or disappearance of bone lesions. 
Lytic bone lesions or mixed lytic−blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques, such as CT or MRI, can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
Blastic bone lesions are non-measurable. 
Cystic lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
TARGET LESIONS: SPECIFICATIONS BY METHODS OF MEASUREMENTS  
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
Method of assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 
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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
135 
Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested. 
Chest X-Ray 
Chest CT is preferred over chest X-Ray, particularly when progression is an important 
endpoint, because CT is more sensitive than X-Ray, particularly in identifying new 
lesions.  However, lesions on chest X-Ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 
CT, MRI 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  This guideline has defined measurability of lesions on CT 
scan on the basis of the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable.  
If, prior to enrollment, it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease and should be 
optimized to allow for comparison with the prior studies if possible.  Each case should be 
discussed with the radiologist to determine if the substitution of these other approaches 
is possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of non-target disease or new lesions because the same lesion may 
appear to have a different size using a new modality. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. 
Endoscopy, laparoscopy, tumor markers, cytology, histology 
The utilization of these techniques for objective tumor evaluation cannot generally be 
advised. 
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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
136 
TUMOR RESPONSE EVALUATION 
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least one 
measurable lesion, as detailed above. 
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions, up to a 
maximum of five lesions total and a maximum of two lesions per organ, representative of 
all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be recorded as non-measurable lesions (even if the size is > 10 mm by CT scan).   
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but, in addition, the lesions 
should lend themselves to reproducible repeated measurements.  It may be the case 
that, on occasion, the largest lesion does not lend itself to reproducible measurement, in 
which circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT this is 
almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or 
coronal).  The smaller of these measures is the short axis.  For example, an abdominal 
node that is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node.  In this example, 20 mm should be recorded as the 
node measurement.  All other pathological nodes (those with short axis ≥ 10 mm but 
< 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
< 10 mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
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Response Evaluation Criteria in Solid Tumors (RECIST) 
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into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
All other lesions or sites of disease, including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression”. 
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). 
RESPONSE CRITERIA 
Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
• 
CR:  Disappearance of all target lesions 
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm. 
• 
PR:  At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum of diameters. 
• 
PD:  At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (nadir), including baseline. 
In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered progression. 
• 
SD:  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum on study. 
Special notes on the assessment of target lesions 
Lymph nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to < 10 mm on study.  This means that when 
lymph nodes are included as target lesions, the sum of lesions may not be zero even if 
CR criteria are met, since a normal lymph node is defined as having a short axis of 
< 10 mm. 
Target lesions that become too small to measure 
During the study, all lesions (nodal and non-nodal) recorded at baseline should have 
their actual measurements recorded at each subsequent evaluation, even when very 
small (e.g., 2 mm).  However, sometimes lesions or lymph nodes that are recorded as 
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Version 1.1: Excerpt from Original Publication (cont.) 
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138 
target lesions at baseline become so faint on the CT scan that the radiologist may not 
feel comfortable assigning an exact measure and may report them as being too small to 
measure.  When this occurs, it is important that a value be recorded on the CRF, as 
follows:   
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
If the lesion is believed to be present and is faintly seen but is too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should be 
ticked.  (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such as 
in the retroperitoneum; however, if a lymph node is believed to be present and is faintly 
seen but is too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well and BML should also be ticked). 
To reiterate:  if the radiologist is able to provide an actual measure, this 
measurement should be recorded, even if it is below 5 mm, and, in that case, BML 
should not be ticked. 
Lesions that split or coalesce on treatment 
When non-nodal lesions fragment, the longest diameters of the fragmented portions 
should be added together to calculate the target lesion sum.  Similarly, as lesions 
coalesce, a plane between them may be maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion.  If the lesions have truly coalesced 
such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximum longest diameter for the coalesced lesion. 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  Whereas some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the protocol. 
• 
CR:  Disappearance of all non-target lesions 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• 
Non-CR/Non-PD:  Persistence of one or more non-target lesions 
• 
PD:  Unequivocal progression of existing non-target lesions 
The appearance of one or more new lesions is also considered progression. 
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Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
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Protocol BO28984, Version 2 
139 
Special notes on assessment of progression of non-target disease 
When the patient also has measurable disease 
In this setting, to achieve unequivocal progression on the basis of the non-target 
disease, there must be an overall level of substantial worsening in non-target disease in 
a magnitude that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy.  A modest increase 
in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or PR of target disease will 
therefore be extremely rare. 
When the patient has only non-measurable disease 
This circumstance arises in some Phase III trials when it is not a criterion of study entry 
to have measurable disease.  The same general concepts apply here as noted above; 
however, in this instance, there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden.  Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly 
non-measurable), a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden on the 
basis of the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease, that is, an 
increase in tumor burden representing an additional 73% increase in volume (which is 
equivalent to a 20% increase in diameter in a measurable lesion).  Examples include an 
increase in a pleural effusion from “trace” to “large” or an increase in lymphangitic 
disease from localized to widespread.  Examples may be described in protocols as 
“sufficient to require a change in therapy”.  If unequivocal progression is seen, the 
patient should be considered to have had overall PD at that point.  Though it would be 
ideal to have objective criteria to apply to non-measurable disease, the very nature of 
that disease makes it impossible to do so; therefore, the increase must be substantial. 
New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(e.g., some “new” bone lesions may be simply healing or flare of preexisting lesions).  
This is particularly important when the patient’s baseline lesions show PR or CR (e.g., 
necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, 
which it is not). 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
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Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
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Protocol BO28984, Version 2 
140 
If a new lesion is equivocal (e.g., because of its small size) continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan. 
EVALUATION OF RESPONSE 
Timepoint response (overall response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used. 
Table 1 
Timepoint Response: Patients with Target Lesions (with or 
without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD
 = 
stable disease. 
 


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Protocol BO28984, Version 2 
141 
Table 2 
Timepoint Response: Patients with Non-Target Lesions Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised. 
 
Missing assessments and not-evaluable designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned timepoint response.  This would be most likely 
to happen in the case of PD (e.g., if a patient had a baseline sum of 50 mm with three 
measured lesions and during the study only two lesions were assessed, but those gave 
a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution 
of the missing lesion).  
If one or more target lesions were not assessed either because the scan was not done 
or because the scan could not be assessed due to poor image quality or obstructed 
view, the response for target lesions should be “unable to assess” since the patient is 
not evaluable.  Similarly, if one or more non-target lesions are not assessed, 
the response for non-target lesions should be “unable to assess”, except where there is 
clear progression.  Overall response would be “unable to assess” if either the target 
response or the non-target response is “unable to assess”, except where this is clear 
evidence of progression, as this equates with the case being not evaluable at that 
timepoint. 


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Response Evaluation Criteria in Solid Tumors (RECIST) 
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142 
Table 3 
Best Overall Response When Confirmation Is Required 
Overall Response at First 
Timepoint 
Overall Response at 
Subsequent Timepoint 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR a 
CR 
SD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
CR 
PD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
CR 
NE 
SD, provided minimum 
duration for SD was met; 
otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
PR 
NE 
SD, provided minimum 
duration for SD was met; 
otherwise, NE 
NE 
NE 
NE 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even 
disease meeting PR criteria relative to baseline, qualifies as PD at that point (since disease 
must have reappeared after CR).  Best response would depend on whether the minimum 
duration for SD was met.  However, sometimes CR may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR, at the 
first timepoint.  Under these circumstances, the original CR should be changed to PR and the 
best response is PR. 
 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (< 10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
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Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
143 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Table 1 to Table 3. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes, or necrosis in existing lesions), treatment may continue until the 
next scheduled assessment.  If at the next scheduled assessment, progression is 
confirmed, the date of progression should be the earlier date when progression was 
suspected. 
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or non-target lesion.


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Appendix 5  
Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework or 
office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about > 50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair > 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair 
5 
Dead 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires 
 


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Appendix 6 
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
146 
 


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Appendix 6 
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
147 
 


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Appendix 6 
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
148 
 


Appendix 6 
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
149 
 
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Appendix 6 
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
150 
 
 


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Appendix 7  
Modification of Diet in Renal Disease (MDRD) Formula 
The estimating glomerular filtration rate (eGFR) will be calculated on the basis of the 
following formula: 
eGFR = 175 × SCRT -1.154 × AGE -0.203 [× 0.742 if female] [× 1.212 if African 
American] (conventional units) 
Reference: Miller WG. Estimating glomerular filtration rate. Clin Chem Lab Med 
2009;47(9):1017-9.


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Appendix 8  
Anaplastic Lymphoma Kinase (ALK) Immunohistochemistry 
Overview 
The VENTANA anti-ALK (D5F3) Rabbit Monoclonal Primary Antibody (VENTANA 
anti-ALK [D5F3]) IHC assay will be used to determine anaplastic lymphoma kinase (ALK) 
IHC status and to select patients with positive ALK for enrollment in Study BO28984.  
The anti-ALK (D5F3) rabbit monoclonal antibody IHC assay is currently being developed 
by Ventana Medical Systems as a companion diagnostic to Roche’s ALK inhibitor, 
alectinib.  For Study BO28984, the VENTANA anti-ALK (D5F3) assay will be used for 
investigational purposes only. 
VENTANA anti-ALK (D5F3) is intended for laboratory use in the detection of the ALK 
protein in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) 
tissue stained with using a VENTANA automated slide stainer.  It is indicated as an aid 
in identifying patients eligible for treatment with alectinib. 
Device Description 
The VENTANA anti-ALK (D5F3) IHC assay is an automated IHC staining assay system 
comprising a pre-diluted, ready to-use anti-ALK (D5F3) rabbit monoclonal primary 
antibody, the BenchMark® automated slide staining platform, OptiView DAB detection kit, 
OptiView Amplification kit, Rabbit Monoclonal Negative Control Ig, and VENTANA 
anti-ALK 2-in-1 cell line control slides or other appropriate system run control. 
Scoring System 
The IHC scoring system evaluates specific VENTANA anti-ALK (D5F3) staining in 
NSCLC tumor cells by the presence of a strong, granular, cytoplasmic staining pattern.  
Pathologists must rely on the Negative Reagent Control (NRC) slides to distinguish 
non-specific staining from specific ALK positivity.  Samples must be assessed for 
morphological damage and the presence of viable tumor versus necrosis.  Light, 
granular, cytoplasmic stippling in alveolar macrophages can occur on anti-ALK (D5F3) 
and/or NRC slides as an artifact of the detection system.  This staining artifact should be 
noted on the Slide Evaluation Form comment field but should NOT be interpreted as 
ALK-positive staining.  Some background staining has also been observed on normal 
mucosa in NSCLC specimens, as well as in necrotic tumor areas; this staining also 
should not be interpreted as ALK-positive staining.  Case slide sets failing to show 
specific staining of the case tissue with VENTANA anti-ALK (D5F3) cannot be 
considered ALK-positive.  Refer to VENTANA ALK Scoring Interpretation Guide for non-
small cell lung carcinoma (NSCLC) for additional information. 
 


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Appendix 9  
Drug Metabolism Enzymes, Transporters (DMET), and Liver Injury Polymorphisms 
ABCB1 
CHST13 
CYP3A5 
HNMT 
SLC22A3 
UGT1A4 
ADRB3 
HSP90AA1 
STAT6 
ABCB11 
CHST2 
CYP3A7 
MAOA 
SLC22A4 
UGT1A5 
ALG10B 
IGF1 
TNF 
ABCB4 
CHST3 
CYP46A1 
MAOB 
SLC22A5 
UGT1A6 
APOA1 
IGF2 
TNFRSF1B 
ABCB7 
CHST4 
CYP4A11 
MAT1A 
SLC22A6 
UGT1A7 
APOC3 
IL10 
TXNIP 
ABCC1 
CHST5 
CYP4B1 
METTL1 
SLC22A7 
UGT1A8 
ARHGAP24 
IL22 
UBC 
ABCC2 
CHST6 
CYP4F11 
NAT1 
SLC22A8 
UGT1A9 
ATF3 
IL4 
UCP1 
ABCC3 
CHST7 
CYP4F12 
NAT2 
SLC25A27 
UGT2A1 
ATIC 
IL4R 
VDR 
ABCC4 
CHST8 
CYP4F2 
NNMT 
SLC28A1 
UGT2B11 
BIRC2 
IL6 
 
ABCC5 
CHST9 
CYP4F3 
NQO1 
SLC28A2 
UGT2B15 
BIRC3 
IL8 
 
ABCC6 
COMT 
CYP4F8 
NR1I2 
SLC28A3 
UGT2B17 
C3orf38 
INSR 
 
ABCC8 
CROT 
CYP4Z1 
NR1I3 
SLC29A1 
UGT2B28 
CALCA 
IRS1 
 
ABCC9 
CYP11A1 
CYP51A1 
NR3C1 
SLC29A2 
UGT2B4 
CASP9 
IRS2 
 
ABCG1 
CYP11B1 
CYP7A1 
ORM1 
SLC5A6 
UGT2B7 
CD33 
IRS4 
 
ABCG2 
CYP11B2 
CYP7B1 
ORM2 
SLC6A6 
UGT8 
CD36 
ITPA 
 
ABP1 
CYP17A1 
CYP8B1 
PGAP3 
SLC7A5 
VKORC1 
CD44 
JAK1 
 
ADH1A 
CYP19A1 
DCK 
PNMT 
SLC7A7 
XDH 
CDK4 
JUN 
 
ADH1B 
CYP1A1 
DPYD 
PON1 
SLC7A8 
 
CDK6 
KCNIP4 
 
ADH1C 
CYP1A2 
EPHX1 
PON2 
SLCO1A2 
 
CEBPB 
KRT18 
 
ADH4 
CYP1B1 
EPHX2 
PON3 
SLCO1B1 
 
CEP44 
KRT8 
 
ADH5 
CYP20A1 
FAAH 
POR 
SLCO1B3 
 
CES1 
LEP 
 
ADH6 
CYP21A2 
FMO1 
PPARD 
SLCO2B1 
 
CTLA4 
LEPR 
 
ADH7 
CYP24A1 
FMO2 
PPARG 
SLCO3A1 
 
CYP3A 
LMX1A 
 
AHR 
CYP26A1 
FMO3 
PPP1R9A 
SLCO4A1 
 
EGFR 
LPL 
 
153


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Appendix 9  
Drug Metabolism Enzymes, Transporters (DMET), and Liver Injury Polymorphisms (cont.)  
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 2 
 
AKAP9 
CYP26C1 
FMO4 
PRSS53 
SLCO5A1 
 
ETNK2 
MCTP2 
 
ALB 
CYP27A1 
FMO5 
PTGIS 
SPG7 
 
FASLG 
MT-CO2 
 
ALDH1A1 
CYP27B1 
FMO6 
QPRT 
SPN 
 
FMOD 
MTHFR 
 
ALDH2 
CYP2A13 
G6PD 
RALBP1 
SULT1A1 
 
FOS 
NFE2L2 
 
ALDH3A1 
CYP2A6 
GSTA1 
RPL13 
SULT1A2 
 
FPGS 
NOS2 
 
ALDH3A2 
CYP2A7 
GSTA2 
RXRA 
SULT1A3 
 
GGH 
NOS3 
 
AOX1 
CYP2B6 
GSTA3 
SERPINA7 
SULT1B1 
 
GPNMB 
OR5H2 
 
APOA2 
CYP2B7P1 
GSTA4 
SLC10A1 
SULT1C2 
 
GPT 
PARD3B 
 
ARNT 
CYP2C18 
GSTA5 
SLC10A2 
SULT1C4 
 
GPX1 
PRKCZ 
 
ARSA 
CYP2C19 
GSTM1 
SLC13A1 
SULT1E1 
 
GPX3 
RASGRP1 
 
ATP7A 
CYP2C8 
GSTM2 
SLC15A1 
SULT2A1 
 
GPX4 
RB1 
 
ATP7B 
CYP2C9 
GSTM3 
SLC15A2 
SULT2B1 
 
GYS1 
RDH5 
 
CA5P 
CYP2D6 
GSTM4 
SLC16A1 
SULT4A1 
 
GYS2 
RIPK1 
 
CBR1 
CYP2E1 
GSTM5 
SLC19A1 
TBXAS1 
 
HCP5 
SOCS3 
 
CBR3 
CYP2F1 
GSTO1 
SLC22A1 
TPMT 
 
HGF 
SOD1 
 
CDA 
CYP2J2 
GSTP1 
SLC22A11 
TPSG1 
 
HLA-A 
SOD2 
 
CES2 
CYP2S1 
GSTT1 
SLC22A12 
TYMS 
 
HLA-B 
SPP1 
 
CHST1 
CYP39A1 
GSTT2 
SLC22A13 
UGT1A1 
 
HLA-DQA1 
SQSTM1 
 
CHST10 
CYP3A4 
GSTZ1 
SLC22A14 
UGT1A10 
 
HLA-DQB1 
ST6GAL1 
 
CHST11 
CYP3A43 
HMGCR 
SLC22A2 
UGT1A3 
 
HLA-DRB1 
STAT1 
 
 
 
 
 
154


Clinical Study Report: RO5424802 - F. Hoffmann-La Roche Ltd
Protocol BO28984     Report Number 1078196
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Title
10-Feb-2014 23:21:31
Date and Time (UTC)
Company Signatory
Approver's Name
FINAL PROTOCOL APPROVAL 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 1 
PROTOCOL 
TITLE: 
RANDOMIZED, MULTICENTER, PHASE III, 
OPEN-LABEL STUDY OF ALECTINIB VERSUS 
CRIZOTINIB IN TREATMENT-NAÏVE ANAPLASTIC 
LYMPHOMA KINASE−POSITIVE ADVANCED 
NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: BO28984 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
2013-004133-33 
IND NUMBER: 
111723 
TEST PRODUCT: 
Alectinib (RO5424802) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
See electronic date stamp below 


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TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................... 9 
PROTOCOL SYNOPSIS .................................................................................... 10 
1. 
BACKGROUND .......................................................................................... 21 
1.1 
Background on Anaplastic Lymphoma 
Kinase−Positive Non−Small Cell Lung Cancer...................... 21 
1.2 
Background on Alectinib........................................................ 23 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 28 
2. 
OBJECTIVES.............................................................................................. 30 
2.1 
Efficacy Objectives ................................................................ 30 
2.2 
Safety Objectives................................................................... 31 
2.3 
Pharmacokinetic Objectives .................................................. 31 
2.4 
Patient-Reported Outcome Objectives .................................. 31 
2.5 
Exploratory Objectives........................................................... 31 
3. 
STUDY DESIGN ......................................................................................... 31 
3.1 
Description of Study .............................................................. 31 
3.2 
End of Study.......................................................................... 33 
3.3 
Rationale for Study Design.................................................... 34 
3.3.1 
Rationale for Alectinib Dosage .............................................. 34 
3.3.2 
Rationale for Patient Population ............................................ 35 
3.3.3 
Rationale for Control Group................................................... 35 
3.3.4 
Rationale for Open-Label Design .......................................... 36 
3.3.5 
Rationale for Primary Endpoint Selection .............................. 37 
3.3.6 
Rationale for Secondary Endpoint of Time to 
CNS Progression................................................................... 38 
3.3.7 
Rationale for PK Sample Collection Schedule....................... 39 
3.3.8 
Rationale for Biomarker Assessments................................... 39 
3.3.9 
Rationale for PRO Assessments ........................................... 40 
3.4 
Outcome Measures ............................................................... 41 
3.4.1 
Efficacy Outcome Measures.................................................. 41 
3.4.2 
Safety Outcome Measures .................................................... 42 


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3.4.3 
Pharmacokinetic Outcome Measures.................................... 42 
3.4.4 
Patient-Reported Outcome Measures ................................... 42 
3.4.5 
Exploratory Outcome Measures ............................................ 43 
4. 
MATERIALS AND METHODS .................................................................... 43 
4.1 
Patients.................................................................................. 43 
4.1.1 
Inclusion Criteria.................................................................... 43 
4.1.2 
Exclusion Criteria................................................................... 44 
4.2 
Method of Treatment Assignment and Blinding..................... 46 
4.3 
Study Treatment.................................................................... 46 
4.3.1 
Formulation, Packaging, and Handling.................................. 46 
4.3.1.1 
Alectinib................................................................................. 46 
4.3.1.2 
Crizotinib................................................................................ 47 
4.3.2 
Dosage, Administration, and Compliance.............................. 47 
4.3.2.1 
Alectinib................................................................................. 47 
4.3.2.2 
Crizotinib................................................................................ 47 
4.3.3 
Investigational Medicinal Product Accountability ................... 48 
4.3.4 
Post-Trial Access to Alectinib ................................................ 48 
4.4 
Concomitant Therapy ............................................................ 48 
4.4.1 
Permitted Therapy ................................................................. 48 
4.4.2 
Prohibited Therapy ................................................................ 50 
4.4.3 
Prohibited Food ..................................................................... 51 
4.5 
Study Assessments ............................................................... 51 
4.5.1 
Informed Consent Forms and Screening Log........................ 51 
4.5.2 
Medical History and Demographic Data ................................ 51 
4.5.3 
Corticosteroid Use for CNS Metastases ................................ 51 
4.5.4 
Physical Examinations........................................................... 52 
4.5.5 
Vital Signs.............................................................................. 52 
4.5.6 
ECOG Performance Status ................................................... 52 
4.5.7 
Tumor and Response Evaluations......................................... 52 
4.5.8 
Laboratory, Biomarker, and Other Biological 
Sample .................................................................................. 54 
4.5.8.1 
Laboratory Assessments ....................................................... 54 
4.5.8.2 
Pre-Treatment Tumor Samples (Mandatory)......................... 54 


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4.5.8.3 
Pre- and Fresh Post-Treatment Tumor Biopsies 
(Optional)............................................................................... 55 
4.5.8.4 
Blood and Plasma Samples (Mandatory) .............................. 55 
4.5.8.5 
Samples for Pharmacokinetic Assessments.......................... 57 
4.5.9 
Electrocardiograms................................................................ 57 
4.5.10 
Patient-Reported Outcomes .................................................. 58 
4.5.11 
Samples for Roche Clinical Repository.................................. 58 
4.5.11.1 
Overview of the Roche Clinical Repository............................ 58 
4.5.11.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 59 
4.5.11.3 
Sample Collection.................................................................. 59 
4.5.11.4 
Confidentiality........................................................................ 59 
4.5.11.5 
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 60 
4.5.11.6 
Withdrawal from the Roche Clinical Repository..................... 60 
4.5.11.7 
Monitoring and Oversight....................................................... 61 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 61 
4.6.1 
Patient Discontinuation.......................................................... 61 
4.6.2 
Study Treatment Discontinuation........................................... 61 
4.6.3 
Study and Site Discontinuation.............................................. 62 
5. 
ASSESSMENT OF SAFETY....................................................................... 62 
5.1 
Safety Plan ............................................................................ 62 
5.1.1 
Adverse Events Collection..................................................... 62 
5.1.2 
Adverse Events Relating to ALK Inhibitors and/or 
the Tyrosine Kinase Inhibitor Class and Alectinib 
Data....................................................................................... 63 
5.1.2.1 
Interstitial Lung Disease ........................................................ 63 
5.1.2.2 
Hepatobiliary Laboratory Test Elevations .............................. 63 
5.1.2.3 
Hematologic Abnormalities.................................................... 63 
5.1.2.4 
Gastrointestinal Disorders ..................................................... 64 
5.1.2.5 
Skin Disorders ....................................................................... 64 
5.1.2.6 
Vision Disorders .................................................................... 64 
5.1.2.7 
Edema ................................................................................... 65 


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5.1.2.8 
Cardiovascular Effects (QT Interval Prolongation)................. 65 
5.1.2.9 
Abnormal Renal Function ...................................................... 65 
5.1.2.10 
Muscular Adverse Events and CPK Elevations ..................... 65 
5.1.3 
Management of Specific Adverse Events with 
Alectinib................................................................................. 66 
5.1.4 
Safety of Crizotinib and Management of Adverse 
Events.................................................................................... 70 
5.2 
Safety Parameters and Definitions ........................................ 72 
5.2.1 
Adverse Events ..................................................................... 72 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 73 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 73 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 74 
5.3.1 
Adverse Event Reporting Period ........................................... 74 
5.3.2 
Eliciting Adverse Event Information ....................................... 74 
5.3.3 
Assessment of Severity of Adverse Events ........................... 75 
5.3.4 
Assessment of Causality of Adverse Events ......................... 75 
5.3.5 
Procedures for Recording Adverse Events............................ 76 
5.3.5.1 
Diagnosis Versus Signs and Symptoms................................ 76 
5.3.5.2 
Adverse Events that are Secondary to Other 
Events.................................................................................... 76 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 76 
5.3.5.4 
Abnormal Laboratory Values ................................................. 77 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 78 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 78 
5.3.5.7 
Deaths ................................................................................... 78 
5.3.5.8 
Preexisting Medical Conditions.............................................. 79 
5.3.5.9 
Lack of Efficacy or Worsening of Non-Small Cell 
Lung Cancer.......................................................................... 79 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 79 
5.3.5.11 
Adverse Events Associated with an Overdose ...................... 80 
5.3.5.12 
Patient-Reported Outcome Data ........................................... 80 


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5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 80 
5.4.1 
Emergency Medical Contacts................................................ 81 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 81 
5.4.2.1 
Events That Occur Prior to Study Drug Initiation ................... 81 
5.4.2.2 
Events That Occur After Study Drug Initiation ....................... 81 
5.4.3 
Reporting Requirements for Pregnancies.............................. 82 
5.4.3.1 
Pregnancies in Female Patients............................................ 82 
5.4.3.2 
Pregnancies in Female Partners of Male Patients................. 82 
5.4.3.3 
Abortions ............................................................................... 83 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 83 
5.5 
Follow-Up of Patients After Adverse Events .......................... 83 
5.5.1 
Investigator Follow-Up........................................................... 83 
5.5.2 
Sponsor Follow-Up ................................................................ 83 
5.6 
Post-Study Adverse Events.................................................... 84 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 84 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 84 
6.1 
Determination of Sample Size ............................................... 85 
6.2 
Summaries of Conduct of Study............................................ 87 
6.3 
Summaries of Treatment Group Comparability ..................... 87 
6.4 
Efficacy Analyses .................................................................. 87 
6.4.1 
Primary Efficacy Endpoint...................................................... 87 
6.4.2 
Secondary Efficacy Endpoints............................................... 88 
6.4.2.1 
Sensitivity Analyses............................................................... 90 
6.4.2.2 
Subgroup Analyses ............................................................... 90 
6.5 
Safety Analyses..................................................................... 90 
6.6 
Pharmacokinetic Analyses..................................................... 91 
6.7 
Patient-Reported Outcome Analyses .................................... 92 
6.7.1 
Time to Deterioration of Patient-Reported Lung 
Cancer Symptoms................................................................. 92 


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6.7.2 
Additional Patient-Reported Outcomes ................................. 93 
6.8 
Exploratory Analyses............................................................. 93 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 94 
7.1 
Data Quality Assurance......................................................... 94 
7.2 
Electronic Case Report Forms............................................... 94 
7.3 
Electronic Patient-Reported Outcome Data........................... 95 
7.4 
Source Data Documentation.................................................. 95 
7.5 
Use of Computerized Systems .............................................. 96 
7.6 
Retention of Records............................................................. 96 
8. 
ETHICAL CONSIDERATIONS.................................................................... 96 
8.1 
Compliance With Laws and Regulations ............................... 96 
8.2 
Informed Consent .................................................................. 96 
8.3 
Institutional Review Board or Ethics Committee.................... 98 
8.4 
Confidentiality........................................................................ 98 
8.5 
Financial Disclosure .............................................................. 98 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 99 
9.1 
Study Documentation ............................................................ 99 
9.2 
Protocol Violations................................................................. 99 
9.3 
Site Inspections ..................................................................... 99 
9.4 
Administrative Structure......................................................... 99 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 100 
9.6 
Protocol Amendments ......................................................... 100 
10. REFERENCES ......................................................................................... 101 
 
 
 
 
 


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LIST OF TABLES 
Table 1 
Overall Response Rates and Time to Response in Patients 
in Part 2 of Study AF-001JP........................................................ 25 
Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib ...................................................................................... 66 
Table 3 
Crizotinib Dose Modification⎯Hematologic Toxicities 
(Except Lymphopenia) ................................................................ 71 
Table 4 
Crizotinib Dose Modification⎯Non-Hematologic Toxicities......... 71 
Table 5 
Adverse Event Severity Grading Scale ....................................... 75 
 
 
LIST OF FIGURES 
Figure 1 
Change in Size of Target Lesions as Assessed by the 
Independent Review Committee in Part 2 of Study AF-001JP 
Using RECIST v1.1 (Data Cutoff Date: 18 April 2013)................ 24 
Figure 2 
Duration of Dosing by Cohort in Patients in Part 1 of 
Study NP28761/AF-002JG (Data Cutoff Date: 
12 September 2013) ................................................................... 26 
Figure 3 
Best Percent Change in Size of Target Lesions from 
Baseline as Assessed by the Investigator in Patients in 
Part 1 of Study NP28761/AF-002JG (Data Cutoff Date: 
12 September 2013) ................................................................... 27 
Figure 4 
Summary of Study Design .......................................................... 33 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 106 
Appendix 2 
Schedule of Alectinib Pharmacokinetic Assessments............... 112 
Appendix 3 
List of Substrates, Inhibitors, and Inducers of Drug-
Metabolizing Enzymes and Transporters.................................. 113 
Appendix 4 
Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1: Excerpt from Original Publication.......................... 115 
Appendix 5 
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 126 
Appendix 6 
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires .......... 127 
Appendix 7 
Modification of Diet in Renal Disease (MDRD) Formula ........... 133 
Appendix 8 
Anaplastic Lymphoma Kinase (ALK) Immunohistochemistry.... 134 
Appendix 9 
Drug Metabolism Enzymes, Transporters (DMET), and Liver 
Injury Polymorphisms................................................................ 135 


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PROTOCOL ACCEPTANCE FORM 
TITLE: 
RANDOMIZED, MULTICENTER, PHASE III, 
OPEN-LABEL STUDY OF ALECTINIB VERSUS 
CRIZOTINIB IN TREATMENT-NAÏVE ANAPLASTIC 
LYMPHOMA KINASE−POSITIVE ADVANCED 
NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: BO28984 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
2013-004133-33 
IND NUMBER: 
111723 
TEST PRODUCT: 
Alectinib (RO5424802) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return a copy of the form to your local study monitor.  Please retain the original 
for your study files 


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PROTOCOL SYNOPSIS 
TITLE: 
RANDOMIZED, MULTICENTER, PHASE III, OPEN-LABEL STUDY 
OF ALECTINIB VERSUS CRIZOTINIB IN TREATMENT-NAÏVE 
ANAPLASTIC LYMPHOMA KINASE−POSITIVE ADVANCED 
NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: 
BO28984 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
2013-004133-33 
IND NUMBER: 
111723 
TEST PRODUCT: 
Alectinib (RO5424802) 
PHASE: 
Phase III 
INDICATION: 
Anaplastic lymphoma kinase−positive (ALK-positive) non−small cell 
lung cancer (NSCLC) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Efficacy Objectives 
The primary efficacy objective for this study is as follows: 
• 
To evaluate and compare the efficacy of alectinib compared to crizotinib in patients with 
treatment-naïve anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung 
cancer (NSCLC), as measured by investigator-assessed progression-free survival (PFS) 
The secondary efficacy objectives for this study are as follows: 
• 
To evaluate and compare the Objective Response Rate (ORR) and Duration of Response 
(DOR) 
• 
To evaluate and compare the time to progression in the CNS on the basis of Independent 
Review Committee (IRC) review of radiographs by Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 and Revised Assessment in Neuro Oncology (RANO) criteria, as 
well as: 
To evaluate CNS objective response rate (C-ORR) in patients with CNS metastases 
who have measurable disease in the CNS at baseline  
To assess CNS duration of response (C-DOR) in patients who have a CNS Objective 
Response  
To assess CNS progression rates (C-PR) at 6, 12, 18, and 24 months on the basis of 
cumulative incidence  
• 
To evaluate and compare the PFS assessment by the IRC 
• 
To evaluate and compare the overall survival (OS) 
Safety Objective 
The safety objective for this study is as follows: 
• 
To evaluate the safety and tolerability of alectinib compared to crizotinib 
Pharmacokinetic Objective 
The secondary pharmacokinetic (PK) objective for this study is as follows: 
• 
To characterize the pharmacokinetics of alectinib and metabolite(s) 


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Patient-Reported Outcome Objectives 
The secondary patient-reported outcome (PRO) objectives for this study are as follows: 
• 
To evaluate and compare time to deterioration (TTD) in patient-reported lung cancer 
symptoms of cough, dyspnea (single item and multi-item subscales), chest pain, 
arm/shoulder pain, and fatigue as measured by the European Organization for the 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire − Core 
(QLQ-C30) and the supplemental lung cancer module (QLQ-LC13) as well as a composite 
of three symptoms (cough, dyspnea, chest pain). 
• 
To evaluate and compare PROs of health-related quality of life (HRQoL), patient functioning, 
and side effects of treatment as measured by the EORTC QLQ-C30 and EORTC 
QLQ-LC13. 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To evaluate and compare patient's health status as assessed by the EuroQoL 5 Dimension 
(EQ-5D-3L) questionnaire to generate utility scores for use in economic models for 
reimbursement. 
• 
To evaluate and compare an onset of hypogonadism in adult men by measuring total 
testosterone, albumin and sex hormone-binding globulin (SHBG) to calculate free 
testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in 
blood. 
• 
To evaluate and compare efficacy and safety in patients with treatment-naïve ALK-positive 
NSCLC as assessed by the FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott). 
• 
To investigate molecular mechanisms of resistance to ALK inhibitors. 
• 
To investigate detection of ALK mutations in plasma and circulating tumor cells. 
Study Design 
Description of Study 
This is a randomized, active controlled, multicenter Phase III open-label study in patients with 
treatment-naïve ALK-positive advanced NSCLC.  All patients are required to provide 
pretreatment tumor tissue to confirm the presence of ALK rearrangement (by 
immunohistochemistry [IHC] test).  Patients will be randomized 1:1 into one of the two treatment 
arms to receive either alectinib or crizotinib. 
This study will comprise approximately 180 centers, in around 30 countries worldwide. 
Central randomization will be performed via an interactive voice or web-based response system 
(IxRS) using the following stratification factors:  Eastern Cooperative Oncology Group 
Performance Status (ECOG PS) (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at 
baseline (yes vs. no).  An IxRS manual containing relevant information will be provided to each 
study site. 
The experimental arm will receive alectinib at 600 mg orally twice daily (BID), taken with food.  
The control arm will receive crizotinib at 250 mg orally BID, taken with or without food. 
Patients will be treated until disease progression, unacceptable toxicity, withdrawal of consent, 
or death.  After progression (as per RECIST v1.1), patients should discontinue the study 
medication. After disease progression, patients will be treated at the discretion of the 
investigator according to local practice.  Information regarding the nature and the duration of 
subsequent therapies will be collected. 
In case of isolated asymptomatic CNS progression (e.g., new CNS oligometastases) a local 
therapy can be given (e.g., stereotactic radiotherapy or surgery) followed by continuation of 
either alectinib (in alectinib arm) or crizotinib (in crizotinib arm) until systemic disease 
progression and/or symptomatic CNS progression.  The decision to continue the treatment 
beyond isolated, asymptomatic CNS progression is at the investigator’s discretion for patients 
who can continue to benefit from respective treatment. 
Patients who discontinue treatment prior to disease progression (e.g., due to unacceptable 
toxicity or withdrawal of consent) will continue to be followed until disease progression and for 


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OS regardless of whether they subsequently receive non-study anti-cancer therapy.  Data for 
subsequent therapy will be collected for the analysis of OS. 
Number of Patients 
Approximately 286 patients will be randomly assigned in a 1:1 allocation ratio to the two 
treatment arms via a block stratified randomization procedure and over a planned recruitment 
period of 25 months. 
Randomization will guard against systematic selection bias and should ensure the comparability 
of treatment groups.  To assist balance in important prognostic factors, randomization will be 
stratified by ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at baseline 
(yes vs. no). 
Target Population  
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not 
amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive 
as assessed by the Ventana IHC test.  Sufficient tumor tissue to perform ALK IHC and ALK 
FISH is required.  Both tests will be performed at designated central laboratories. 
• 
Age ≥ 18 years old. 
• 
Life expectancy of at least 12 weeks. 
• 
ECOG PS of 0-2. 
• 
Patients had no prior systemic treatment for advanced or recurrent (Stage IIIB not 
amenable for multimodality treatment) or metastatic (Stage IV) NSCLC. 
• 
Adequate hematologic function: 
Platelet count ≥ 100 × 109/L 
ANC ≥ 1500 cells/μL 
Hemoglobin ≥ 9.0 g/dL 
• 
Adequate renal function: 
Calculated creatinine clearance at least 45 mL/min 
• 
Patients must have recovered from effects of any major surgery or significant traumatic 
injury at least 28 days before the first dose of study treatment. 
• 
Measurable disease (by RECIST v1.1) prior to the administration of study treatment. 
• 
Prior brain or leptomeningeal metastases allowed if asymptomatic and diagnosed 
incidentally at study baseline.  If patients have neurological symptoms or signs due to CNS 
metastasis, patients need to complete whole brain radiation or gamma knife irradiation 
treatment at least 14 days before enrollment and be clinically stable. 
• 
For all females of childbearing potential, a negative pregnancy test must be obtained within 
3 days before starting study treatment. 
• 
For women who are not postmenopausal ( ≥ 12 months of non-therapy-induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus):  agreement to remain abstinent or 
use single or combined contraceptive methods that result in a failure rate of  < 1% per year 
during the treatment period and for at least 3 months after the last dose of study drug.  
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  Examples of 
non-hormonal contraceptive methods with a failure rate of < 1% per year include tubal 
ligation, male sterilization, hormonal implants, established, proper use of combined oral or 
injected hormonal contraceptives, and certain intrauterine devices.  Alternatively, two 
methods (e.g., two barrier methods such as a condom and a cervical cap) may be 
combined to achieve a failure rate < 1% per year.  Barrier methods must always be 
supplemented with the use of a spermicide.  


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• 
For men:  agreement to remain abstinent or use a condom plus an additional contraceptive 
method that together result in a failure rate of  < 1% per year during the treatment period 
and for at least 3 months after the last dose of study drug.  Abstinence is only acceptable if 
it is in line with the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.   
• 
Able and willing to provide written informed consent prior to performing any study related 
procedures and to comply with the study protocol, including patients must be willing and 
able to use the electronic patient-reported outcome device. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients with a previous malignancy within the past 3 years are excluded (other than 
curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by 
endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered 
to have no impact in PFS and OS for the current NSCLC). 
• 
Any GI disorder that may affect absorption of oral medications, such as mal-absorption 
syndrome or status post-major bowel resection. 
• 
Liver disease characterized by: 
ALT or AST > 3 × ULN (≥ 5 × ULN for patients with concurrent liver metastasis) 
confirmed on two consecutive measurements 
OR 
Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or other 
conditions of decompensated liver disease such as coagulopathy, hepatic 
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices 
OR 
Acute viral or active autoimmune, alcoholic, or other types of hepatitis 
• 
National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) 
Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding 
alopecia), which have not shown improvement and are strictly considered to interfere with 
current study medication. 
• 
History of organ transplant. 
• 
Co-administration of anti-cancer therapies other than those administered in this study. 
• 
Patients with baseline QTc > 470 ms or patients with symptomatic bradycardia  < 45 beats 
per minute. 
• 
Administration of strong/potent cytochrome P4503A inhibitors or inducers within 14 days 
prior to the first dose of study treatment and while on treatment with alectinib or crizotinib 
except for oral corticosteroids up to 20 mg of prednisolone equivalent per day  
• 
Administration of agents with potential QT interval prolonging effects within 14 days prior to 
the first administration of study drug and while on treatment.  
• 
History of hypersensitivity to any of the additives in the alectinib drug formulation (lactose 
monohydrate, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose, 
sodium lauryl sulfate [SLS], magnesium stearate). 
• 
History of hypersensitivity to any of the additives in the crizotinib drug formulation (silica, 
colloidal anhydrous cellulose, microcrystalline calcium hydrogen phosphate, anhydrous 
sodium starch glycolate, magnesium stearate). 
• 
Pregnant or lactating women. 
• 
Known HIV positivity or AIDS-related illness. 


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• 
Any clinically significant concomitant disease or condition that could interfere with, or for 
which the treatment might interfere with, the conduct of the study or the absorption of oral 
medications or that would, in the opinion of the Principal Investigator, pose an unacceptable 
risk to the patient in this study. 
• 
Any psychological, familial, sociological, or geographical condition potentially hampering 
compliance with the study protocol requirements and/or follow-up procedures; those 
conditions should be discussed with the patient before trial entry. 
Length of Study 
The time from first patient screened to end of study, defined below, will be approximately 
43 months. 
End of Study 
This study is event-driven, with a recruitment period of approximately 25 months.  The required 
number of events for the final analysis of the primary endpoint is expected approximately 
31 months after the first patient has been enrolled.  Patients are to be treated until disease 
progression, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.  
Follow-up for survival will continue until the survival follow-up analysis or the Sponsor decides to 
end the trial, whichever occurs first.  The study will formally end once the survival follow-up 
analysis is complete. 
A survival follow-up analysis will be performed once approximately 50% of patients 
(i.e., 143 patients) have died, which is estimated to occur approximately 42 months after the first 
patient has been enrolled. 
Outcome Measures 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
• 
PFS, which is defined as the time from randomization to the first documented disease 
progression, as determined by the investigators (primary endpoint) or IRC (secondary 
endpoint) using RECIST v1.1 or death from any cause, whichever occurs first.  Patients 
without an event will be censored at the last tumor assessment either during follow-up or 
during study treatment.  Patients with no post-baseline assessments will be censored at the 
date of randomization. 
• 
ORR, which is defined as the percentage of patients who attain complete response (CR) or 
partial response (PR); response, as determined by the investigators using RECIST v1.1.  
Patients without any assessments will be regarded as non-responders. 
• 
Time to CNS progression, which is defined as the time from randomization to the first 
occurrence of disease progression in the CNS as determined by IRC using RECIST v1.1 
and RANO (separate assessments and analyses), as well as C-ORR in patients with CNS 
metastases who have measurable disease in the CNS at baseline, C-DOR in patients who 
have a CNS Objective Response, and C-PR at 6, 12, 18, and 24 months. 
• 
DOR, which is defined as the time from when response (CR or PR) was first documented to 
first documented disease progression or death (whichever occurs first).  This will only be 
calculated for patients who have a best overall response of CR or PR.  Patients who do not 
progress or die after they have had a response are censored at the date of their last tumor 
measurement. 
• 
OS, which is defined as the time from randomization to death from any cause.  Patients 
without an event will be censored at the last date known to be alive.  Patients without any 
follow-up information will be censored at the date of randomization. 
Safety Outcome Measures 
The secondary safety outcome measures for this study are as follows: 
• 
Serious and non-serious adverse events 
• 
Safety laboratory tests values 
• 
Vital signs (blood pressure, heart rate), ECG 
• 
Physical examination 


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Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Sparse (pre-dose) PK samples for measurement of alectinib and its major metabolite(s) will 
be collected in all study patients receiving alectinib treatment 
• 
Serial/intensive PK sampling will be collected in a subset of consenting patients enrolled to 
receive alectinib treatment (approximately 10%−15%, at least approximately n = 20) 
• 
PK parameters will be determined as appropriate and where data allow: 
The pharmacokinetics of alectinib (and metabolite[s], if appropriate) will be described, 
and the between-patient variability will be estimated using a population PK approach.  
The potential influence of covariates that contribute significantly to the between-patient 
differences in PK parameters of alectinib will also be explored and quantified. 
Non-compartmental analysis may be conducted in patients undergoing serial/intensive 
PK sample collection, as appropriate and where data allow. 
Patient-Reported Outcome Measures 
The PRO measures for this study are as follows: 
• 
EORTC QLQ-C30 and the EORTC QLQ-LC13 to determine the impact of alectinib 
compared with crizotinib as measured by TTD in patient-reported lung cancer symptoms 
(e.g., cough, dyspnea [single item and multi-item scales], pain in chest, pain in 
arm/shoulder, fatigue). 
• 
The EORTC QLQ-C30 and EORTC QLQ-LC13 to measure PROs of HRQoL, patient 
functioning, and side effects of therapy compared between patients treated with alectinib 
and those treated with crizotinib. 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
EQ-5D-3L to generate utility scores for use in economic models for reimbursement. 
• 
Total testosterone, albumin and SHBG to calculate free testosterone level, FSH, and LH, in 
blood to measure an onset of hypogonadism in adult men. 
• 
The FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) to evaluate and compare 
efficacy and safety in patients with treatment-naïve NSCLC that is ALK-positive by FISH 
test. 
• 
Post progression tumor mutation status to study molecular mechanisms of resistance to 
ALK inhibitors. 
• 
ALK mutation status in plasma DNA to monitor efficacy and disease progression. 
• 
ALK fusion status in circulating tumor cells in blood. 
Investigational Medicinal Products 
Test Product 
Alectinib comes in a capsule dosage form containing the following active ingredient: 
[Chemical name] 9-Ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-6, 
11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride 
Each capsule contains 150 mg of alectinib (as free base) along with lactose monohydrate, 
carmellose calcium, hydroxypropyl cellulose, SLS, and magnesium stearate. 
Alectinib capsules should be stored in accordance with the storage instructions on the label. 
Alectinib capsules should be administered orally BID with food (within 30 minutes after a meal, 
in the morning and evening). 
Comparator 
Crizotinib comes in a hard capsule dosage form.  Each capsule contains 250 mg or 200 mg 
crizotinib.  Crizotinib hard capsules should be stored in accordance with the storage instructions 
on the label.  Crizotinib capsules should be administered orally BID. 
For further details, see the local prescribing information for crizotinib (Xalkori®). 


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Non-Investigational Medicinal Products 
Standard-of-care therapy administered to all patients in addition to test product or comparator. 
Statistical Methods 
Primary Analysis 
PFS is defined as the time from date of randomization to the date of first documented disease 
progression or death, whichever occurs first.  The primary endpoint of PFS will be determined 
on the basis of investigator assessment of progression using RECIST v1.1.  Patients who have 
not experienced disease progression or death at the time of analysis will be censored at the last 
tumor assessment date either during study treatment or during follow-up.  Patients with no post-
baseline tumor assessment will be censored at the date of randomization. 
Patients who discontinue treatment prior to disease progression (e.g., due to toxicity) will 
continue on study and will be followed until disease progression and for OS regardless of 
whether they subsequently receive anti-cancer therapy. 
The treatment comparison of PFS will be based on a stratified log-rank test at the 5% level of 
significance (two-sided).  The stratification factors are the randomization stratification factors:  
ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at baseline (yes vs. no), 
as recorded on the eCRF.  Results from an unstratified log-rank test will also be presented. 
The Kaplan-Meier method will be used to estimate the median PFS for each treatment arm with 
95% confidence limits, and a Kaplan-Meier curve will be constructed to provide a visual 
description of the difference between the treatment arms.  A stratified Cox proportional 
regression model will be used including treatment in order to provide an estimate of the 
treatment effect expressed as a hazard ratio (HR) (alectinib vs. crizotinib), as well as a 95% CI. 
The difference between the two treatment groups will be assessed and tested for the following 
hypothesis:  the survival distribution function (SDF) of PFS of the alectinib treatment group is 
the same as for the crizotinib treatment group versus the alternative that the two distributions 
are different:  
H0:  SDF (alectinib) = SDF (crizotinib) 
versus 
H1:  SDF (alectinib) ≠ SDF (crizotinib) 
where SDF denotes the survival distribution function of the parameter PFS. 
Determination of Sample Size   
The focus of this clinical trial is hypothesis testing, and the primary endpoint of PFS was used to 
determine the sample size of the study. 
At the time of writing the protocol, there are no Phase III data on crizotinib in the first line setting 
in ALK-positive patients.  The median PFS for crizotinib administered as second line therapy 
from the global randomized Phase III PROFILE 1007 study was 7.7 months (95% CI: 6.0%, 
8.8%).  From the Phase II single arm study of patients who had received ≥ 1 line of 
chemotherapy (with 85% patients having received ≥ 2 prior chemotherapy regimens), the 
median PFS was 8.5 months (95% CI: 6.2%, 9.9%). 
A median PFS of 9.8 months for the crizotinib arm has been assumed.  An HR of 0.65 for 
alectinib versus crizotinib (i.e., an increase from 9.8 months median PFS to 15.1 months) will be 
targeted.  In this study, 286 patients will be enrolled in a 1:1 randomization allocation.  
Enrollment will take approximately 25 months on the basis of an assumption of non-linear 
recruitment as follows: 
• 
Month 1:  1 patients per month 
• 
Month 2:  2 patients per month 
• 
Month 3:  4 patients per month 
• 
Month 4:  6 patients per month 
• 
Month 5:  8 patients per month 
• 
Month 6:  10 patients per month 
• 
Month 7:  12 patients per month 
• 
Months 8−12:  13 patients per month 


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• 
Months 13−14:  14 patients per month 
• 
Month 15 onwards:  15 patients per month 
A total of 169 PFS events are required to achieve 80% power at a two-sided alpha level of 5%.  
This level of enrollment is estimated to occur approximately 31 months after the first patient has 
been enrolled. 
Interim Analyses 
No interim analysis for efficacy or futility is planned. 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
AUC 
area under the concentration−time curve 
BID 
twice daily 
Cmax 
maximum concentration 
C-DOR 
CNS duration of response 
C-ORR 
CNS objective response rate 
C-PR 
CNS progression rate 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DOT 
duration of treatment 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EML4 
echinoderm microtubule-associated protein-like 4 
EORTC  
European Organization for the Research and Treatment of Cancer  
ePRO 
electronic patient-reported outcome 
EQ-5D-3L 
EuroQoL 5 Dimension 
FDA 
U.S. Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FPP 
FISH Positive Population 
FSH 
follicle-stimulating hormone 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
HRQoL 
health-related quality of life 


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Abbreviation 
Definition 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITT 
intent-to-treat 
IxRS 
interactive voice or web-based response system 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
LH 
luteinizing hormone 
MET 
mesenchymal-epithelial transition factor 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCA 
non-compartmental analysis 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
not evaluable 
NSCLC 
non−small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
P-gp 
P-glycoprotein 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PRO 
patient-reported outcome 
QLQ-C30 
Quality of Life Questionnaire−Core 
QLQ-LC13 
Quality of Life Questionnaire lung cancer module 
RANO 
Revised Assessment in Neuro Oncology 
RCR 
Roche Clinical Repository 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROS1 
c-ros oncogene 1 
SAE 
serious adverse event 
SAP 
Safety Analysis Population 


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Abbreviation 
Definition 
SD 
stable disease 
SDF 
survival distribution function 
SLS 
sodium lauryl sulfate 
TKI 
tyrosine kinase inhibitor 
TTD 
time to deterioration 
UGT 
uridine 5'-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 


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1. 
BACKGROUND 
1.1 
BACKGROUND ON ANAPLASTIC LYMPHOMA 
KINASE−POSITIVE NON−SMALL CELL LUNG CANCER 
Non−small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality 
worldwide.  Lung cancer was estimated to cause 160,340 deaths in the United States 
in 2012, accounting for 28% of all cancer-related deaths according to the report from the 
American Lung Association (Lung Cancer Fact Sheet).  There is an annual incidence of 
310,000 cases of NSCLC in men in the Europe with a mortality of 276,000 deaths 
(GLOBOCAN 2008).  Among women in the Europe, there is an annual incidence of 
107,000 cases and a mortality of 91,000 deaths.  In total, there are 417,000 cases of 
NSCLC and 367,000 deaths in Europe each year, which represents a major health 
problem.  Survival rates for lung cancer tend to be much lower than other common 
cancers because of its late diagnosis and limited effective therapy in the advanced stage.  
The expected 5-year survival rate for all patients in whom lung cancer is diagnosed is 
16.3% compared with 65.2% for colon cancer, 90.0% for breast cancer, and 99.9% for 
prostate cancer (Siegel et al. 2012).  Conventional anti-cancer therapies are far from 
satisfactory, and there is an unmet medical need for the development of new therapies 
for NSCLC. 
Recent progress in the identification of genetic mutations or chromosomal 
rearrangements in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral 
oncogene homolog (KRAS), mesenchymal-epithelial transition factor (MET), and other 
genes has provided new opportunities to use targeted therapeutic agents for the 
treatment of NSCLC, when the tumor is identified as having these mutations 
(Katayama et al. 2011; Doebele et al. 2012). 
Approximately 5% of NSCLC cases have been shown to harbor the echinoderm 
microtubule-associated protein-like 4 (EML4)−anaplastic lymphoma kinase (ALK) fusion 
gene as a result of a chromosomal inversion at 2p21 and 2p23 (Choi et al. 2010; 
Ou et al. 2012).  The formation of the resulting ALK fusion protein results in activation 
and dysregulation of the gene’s expression and signaling, which can contribute to 
increased cell proliferation and survival in tumors expressing these genes.  This is 
further supported by reports that the TFG and KIF5B genes can also serve as ALK 
fusion partners in some NSCLC patients.  Expression of these ALK fusion genes in 
mouse 3T3 fibroblasts causes their transformation and enhanced proliferation.  ALK 
gene alterations are generally in a mutually exclusive relationship with mutations in 
EGFR or KRAS (Soda et al. 2007; Inamura et al. 2008; Inamura et al. 2009; 
Wong et al. 2009), although EGFR mutations may develop as a resistance mechanism 
after treatment with crizotinib (Doebele et al. 2012).  Inhibition of ALK activity in Ba/F3 
cells transfected with the EML4-ALK fusion protein resulted in inhibition of cell growth 
(Ou et al. 2012), whereas a small molecule inhibitor of ALK demonstrated anti-tumor 
efficacy in two xenograft models in athymic mice, namely, the H3122 NSCLC and 
Karpas299 anaplastic large cell lymphoma models harboring the EML4-ALK and 


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nucleophosmin-ALK fusion proteins, respectively.  Hence, ALK appears to be a suitable 
therapeutic target for NSCLC with ALK gene rearrangements. 
Wild-type ALK is hardly expressed at all in most normal human tissues, being expressed 
at higher levels in a few limited types of tissue such as developing and mature nervous 
system tissue (glial cells, neurons, endothelial cells, and pericytes) (Pulford et al. 1997).  
By contrast, an aberrant ALK with constitutively active kinase results from the formation 
of the EML4-ALK fusion gene by chromosomal translocation. 
Currently, the only approved treatment for ALK-positive NSCLC is crizotinib (Xalkori®, 
Pfizer, Inc.), an inhibitor of receptor tyrosine kinases including ALK, hepatocyte growth 
factor receptor (HGFR, c-Met), recepteur d’origine nantais (RON), and c-ros oncogene 1 
(ROS1) (Sahu et al. 2013).  
Crizotinib was first granted accelerated approval by the U.S. Food and Drug 
Administration (FDA) for the treatment of patients with locally advanced or metastatic 
NSCLC that is positive for ALK as detected by an FDA-approved test in August 2011. 
The approval was based on two single-arm trials.  The primary endpoint of both trials 
was ORR as assessed by the investigator.  In one study, the ORR was 50% 
(95% CI: 42%, 59%) with a median response duration of 42 weeks, and, in other study, 
the ORR was 61% (95% CI: 52%, 70%) with a median response duration of 48 weeks 
(Camidge et al. 2012; Kim et al. 2012).  In November 2013, the FDA granted regular 
approval for crizotinib on the basis of demonstrating superior PFS and ORR for crizotinib 
compared with chemotherapy in patients with ALK-positive NSCLC whose disease 
progressed after platinum-based doublet chemotherapy (PROFILE 1007 study).  An 
open-label active-controlled multinational randomized trial enrolled 347 patients with 
ALK-positive metastatic NSCLC.  Patients were required to have disease progression 
following platinum-based chemotherapy.  The trial demonstrated significantly prolonged 
PFS with crizotinib treatment compared with chemotherapy (HR = 0.49 [95% CI: 0.37, 
0.64], p < 0.0001).  Median PFS was 7.7 months for patients treated with crizotinib and 
3.0 months for patients treated with chemotherapy.  The ORR was significantly higher 
for patients treated with crizotinib (65% vs. 20%), with median response durations of 
7.4 months for patients treated with crizotinib and 5.6 months for patients treated with 
chemotherapy.  No difference in overall survival (OS) was noted between the two groups 
(HR = 1.02 [95% CI: 0.68%, 1.54%]) in a planned interim analysis (Shaw et al. 2013).  
Common adverse reactions in clinical trials with crizotinib, occurring at an incidence of 
25% or higher, included visual disorders, nausea, diarrhea, vomiting, constipation, 
edema, elevated transaminases, and fatigue (National Cancer Institute 2013).  These 
results showed that an ALK inhibitor is effective in patients with NSCLC harboring ALK 
fusion genes.  Crizotinib has subsequently been approved in other countries, such as 
Japan, Korea, Canada, and Switzerland.  In the European Union, crizotinib was 
conditionally approved in October 2012 for the treatment of adults with previously treated 
ALK positive NSCLC. 


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Although substantial benefit has been observed with crizotinib therapy, relapse remains 
the norm.  Studies with patients who had progression with crizotinib treatment reveal two 
main reasons for treatment failure: the development of resistance because of secondary 
(e.g., gatekeeper) mutations (predominantly in ALK or occasionally in other genes, such 
as EGFR, cKIT, or KRAS) (Katayama et al. 2011; Doebele et al. 2012; Kim et al. 2013) 
and CNS relapse (crizotinib has impaired control of brain metastases in comparison to 
other sites of systemic disease).  The CNS is the primary site of initial treatment failure in 
46% of patients with ALK-positive NSCLC treated with crizotinib (Costa et al. 2011; 
Chun et al. 2012; Weickhardt et al. 2012).  Significant morbidity is associated with brain 
metastases as a function of brain involvement, and because of treatment (corticosteroids, 
surgery, and radiation) required for disease control. 
A new generation of ALK inhibitors will have the potential to overcome these two major 
limitations of crizotinib treatment to offer patients a better chance of prolonged remission 
and minimize the development of CNS metastases and the attendant comorbidity. 
1.2 
BACKGROUND ON ALECTINIB 
Alectinib (also RO5424802 or CH5424802) is a newly developed small molecule, highly 
selective, and potent oral next-generation ALK inhibitor with a benzo[b]carbazole 
scaffold.  In enzyme inhibition assays performed in vitro, this compound has been shown 
to selectively inhibit ALK.  The compound also shows high antitumor activity both in vitro 
and in vivo against tumor cell lines with some type of ALK gene alteration, including 
NSCLC and anaplastic large cell lymphoma lines harboring an ALK translocation and a 
neuroblastoma line harboring amplified ALK gene. 
Nonclinical pharmacology studies showed that alectinib is efficacious in a model of 
tumors expressing an ALK fusion bearing the L1196M mutation, which is associated with 
resistance to crizotinib, and alectinib is effective in mouse NCI H2228 NSCLC xenografts 
that are already maximally suppressed by crizotinib.  Alectinib also prolongs survival in 
an intracerebral NCI H2228 implantation model, and it reduces tumor growth in an 
intracranial model monitored using bioluminescence. 
The clinical development program for alectinib, to date, comprises three ongoing 
Phase I/II studies in patients with ALK-positive NSCLC.  The ongoing Phase I/II studies 
are as follows:  Study AF-001JP, which is being conducted in Japan; Study 
NP28761/AF-002JG, which is being conducted in North America; and Study NP28673, 
which is being conducted globally. 
The first-in-human study AF-001JP is an open-label Phase I/II study being conducted in 
Japan.  This study is assessing the pharmacokinetics, safety, and efficacy of alectinib in 
patients with ALK-positive NSCLC who are crizotinib-naïve and have disease 
progression after at least one line of chemotherapy.  This study has completed 
enrollment, but it is still ongoing.  A total of 70 patients were included (24 patients in the 
Phase I portion and 46 patients in the Phase II portion of the study).  In the Phase I 


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portion of the study, at the data cutoff date of 31 July 2012, 24 patients were treated at 
doses of 20−300 mg twice daily (BID).  No dose-limiting toxicities (DLTs) or adverse 
events of Grade 4 were noted up to the highest dose; thus, 300 mg BID was evaluated 
in the Phase II portion of the study without further escalating the dose.  In the Phase II 
portion of the study, 46 patients were treated with the highest evaluated dose of 300 mg 
BID, of whom 43 achieved an objective response (93.5%; 95% CI: 82.1%, 98.6%) and 
7 patients had a complete response (CR) on the basis of an independent radiological 
review in the 12-month follow-up analysis (data cutoff for response data: 18 April 2013).  
The median duration of treatment (DOT) in the study has not been achieved at that date 
because 86% of patients were still on treatment in the study, but the projected median 
DOT is more than 14 months as data mature. 
Figure 1 shows the waterfall plot of the best change from baseline in the size of target 
lesions by an independent radiological review.  Table 1 shows the objective response 
rate (ORR) by time interval.  The majority (86%) of patients had a time to response of 
within 6 weeks after administration of the first dose. 
Figure 1 Change in Size of Target Lesions as Assessed by the 
Independent Review Committee in Part 2 of Study AF-001JP 
Using RECIST v1.1 (Data Cutoff Date: 18 April 2013) 
 


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Two of 7 patients who were assessed as having a CR had lymph nodes as the target 
lesions.  Per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), 
the percent change from baseline for patients with CR can be less than 100% when 
lymph nodes are identified as the target lesions.  Therefore, they were assessed as 
having CR, although their tumor change from baseline was less than 100%. 
Table 1 
Overall Response Rates and Time to Response in Patients 
in Part 2 of Study AF-001JP 
Response (Data Cutoff Date: 18 April 2013) 
IRC Assessment (N = 46) 
Complete response 
7 
Partial response 
36 
Stable disease 
1 
Progressive disease 
0 
Not evaluable 
2 
Total response 
43 
Overall response rate (95% CI) 
93.5% (82.1%, 98.6%) 
Time to Response 
IRC Assessment (N = 43) 
0 to ≤ 3 weeks 
22 (51%) 
> 3 to ≤ 6 weeks 
15 (35%) 
> 6 to ≤ 9 weeks 
3 (7%) 
> 9 weeks 
3 (7%) 
IRC = Independent Review Committee. 
 
In Study NP28761/AF-002JG (crizotinib-failed ALK-positive NSCLC patients), the 
Phase I portion has completed enrollment.  Two ‘bridging’ cohorts of patients receiving 
alectinib using the 150-mg capsule at 600 and 900 mg BID were included in 
Study NP28761/AF-002JG to transition/facilitate the planned formulation for the Phase II 
trials.  A total of 47 patients were enrolled in Phase I (Part 1).  There does not appear to 
be any substantial difference in pharmacokinetics between the two formulations 
(20/40-mg capsule and the 150-mg capsule) at the 600-mg dose on the basis of 
available data. 
The radiological imaging analysis performed in 44 evaluable patients who had a baseline 
scan and at least one follow-up scan (data cutoff date: 12 September 2013) has shown 
that 2 of 7 patients in the 300-mg BID dosage cohort, 5 of 7 patients in the 460-mg BID 
dosage cohort, 4 of 10 patients in the 600-mg BID dosage cohort, and 4 of 13 patients 
(including 1 patient with CR) in the 900-mg BID dosage cohort have achieved a 
confirmed partial response (PR), as assessed by the investigator.  Three of 10 patients 
in the 600-mg BID dosage cohort, 2 of 7 patients in the 760-mg BID dosage cohort, and 
4 of 13 patients in the 900-mg BID dosage cohort have achieved a PR, as assessed by 
the investigator, which is still to be confirmed.  Three patients (all in the 600-mg BID 






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both systemic disease and CNS progression).  No patient discontinued because of CNS 
progression alone. 
In addition, 2 patients with leptomeningeal carcinomatosis received benefit from alectinib 
treatment.  One patient with leptomeningeal spread in Study NP28761/AF-002JG 
achieved PR after 6 weeks of treatment.  Another patient with leptomeningeal 
carcinomatosis but without systemic lesions was treated under a single-patient 
Investigational New Drug (IND) application because of ineligibility to enter either of the 
two Phase II alectinib studies (because of the high intake of dexamethasone for 
symptom control).  After 6 weeks of treatment, this patient achieved CR as 
demonstrated by complete disappearance of gadolinium enhancement on magnetic 
resonance imaging (MRI) and disappearance of positive CSF cytology.  This patient has 
been able to reduce corticosteroids to physiological replacement dose only. 
See the Alectinib Investigator's Brochure for additional details on nonclinical and clinical 
studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Over the past 10 years, the treatment of NSCLC has become increasingly focused on 
guiding treatment based on the presence or absence of an actionable mutation.  
Numerous oncogenes have now been identified in NSCLC, including mutations in the 
genes coding for EGFR, KRAS, phosphoinositide-3-kinase, catalytic, α polypeptide, and 
human EGFR 2 (Pao and Girard 2011).  As described in previous sections, a 
translocation in the gene encoding the receptor tyrosine kinase ALK, leading to the 
expression of ALK fusion proteins, was identified as an oncogenic driver in a subset of 
patients with NSCLC (Soda et al. 2007).  ALK rearrangements are found in 
approximately 4.6% of unselected patients with NSCLC (Koivunen et al. 2008; 
Takeuchi et al. 2008; Boland et al. 2009; Wong et al. 2009; Bang 2011; Kim et al. 2011; 
Paik et al. 2011; Cardarella et al. 2012; Dai et al. 2012; Fukui et al. 2012;). 
Crizotinib is the only first-generation ALK inhibitor that is currently approved and has 
been registered in multiple countries worldwide for the treatment of ALK-positive NSCLC.  
Crizotinib is an oral small-molecule multitargeted tyrosine kinase inhibitor (TKI) targeting 
ALK, MET, RON, and ROS1 tyrosine kinases (Sahu et al. 2013, Shaw et al. 2013).  The 
clinical studies reported at present demonstrate that median PFS with crizotinib ranged 
from 7.7−9.7 months (Camidge et al. 2012, Kim et al. 2013, Shaw et al. 2013), while 
published clinical evidence on crizotinib’s efficacy in ALK-positive NSCLC first line 
treatment setting is still limited. 
Although substantial benefit has been observed with crizotinib therapy, relapse 
eventually occurs.  Two main reasons for this are the development of resistance 
because of secondary (e.g., gatekeeper) mutations or CNS relapse 
(Katayama et al. 2011; Doebele et al. 2012; Kim et al. 2013).  This could be due to the 
fact that crizotinib is a P-gp substrate and has a low penetration in the CNS.  Thus 


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ALK-positive NSCLC treated with crizotinib has impaired control of brain metises relative 
to other sites of systemic disease, with 46% of progressions in patients treated with 
crizotinib involving the CNS (Costa et al. 2011; Weickhardt et al. 2012).  The CNS 
becomes a sanctuary site for ALK-positive NSCLC treated with crizotinib⎯a physiologic 
and anatomic mechanism of drug resistance. 
Alectinib is a highly selective and potent, oral next generation ALK inhibitor.  Clinical 
data from the Phase II portion of the still ongoing Study AF-001JP, assessing alectinib in 
patients with ALK-positive NSCLC who are crizotinib-naïve and have disease 
progression after at least one line of chemotherapy, reported that the median treatment 
duration in the study has not been achieved as 86% of patients were still active on the 
study, but the projected median DOT is estimated to be at least 14 months as data 
mature (Inoue et al. 2013). 
Moreover, alectinib is lipophilic drug and not a P-glycoprotein (P-gp) substrate, thus, 
could penetrate through the blood-brain barrier and has the potential to reach higher 
concentration in brain as compared to substrates of the P-gp such as crizotinib.  This 
has been shown in the nonclinical setting on the basis of the prolongation of survival in a 
mouse model with implanted CNS lesions and in a tissue distribution study with a single 
oral dose of [14C]-alectinib at 1 mg/kg to albino rats (Ou et al. 2013).  Preliminary clinical 
data from the Phase I/II studies show consistent therapeutic efficacy of alectinib in brain 
metastases. 
The clinical efficacy data is compelling given the shown activity for a longer progression 
free interval with alectinib and improved activity in the CNS, thus delaying the impact of 
CNS metastases on neurologic function along with the morbidities associated with 
treatment like brain radiation, surgery and corticosteroid use required for disease control.  
The currently available clinical safety data is supportive for an acceptable safety and 
tolerability profile with alectinib.  Altogether, it would be important to compare alectinib to 
crizotinib as a therapeutic option for ALK-positive advanced NSCLC patients. 
In this proposed Phase III study, treatment-naïve patients with ALK-positive advanced 
NSCLC will be enrolled and will be randomized to receive either crizotinib or alectinib 
treatment.  The results of this study will determine whether alectinib treatment has 
superior efficacy compared to crizotinib. 
The first Phase I dose-escalation study of alectinib conducted only in Japan 
(Study AF001-JP), with a dose schedule of 20, 40, 80, 160, 240, and 300 mg BID orally, 
showed that alectinib was generally well tolerated without major toxicities.  Of the 
58 patients who received treatment with 300 mg BID alectinib in Study AF-001JP, 
27 experienced Grade 3 adverse events and 9 experienced serious adverse events.  No 
deaths were reported during this study and up to 28 days after treatment discontinuation.  
There were 5 adverse events leading to treatment discontinuation in Part 2 (brain edema, 
sclerosing cholangitis, interstitial lung disease [ILD], ALT increased, and tumor 


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hemorrhage).  Alectinib was well tolerated at all doses investigated in this study.  Its 
adverse event profile was consistent with the one known to be associated with TKIs.  In 
the Phase II Study NP28761/AF-002JG, alectinib was well tolerated, with no DLTs or 
treatment-related dose modifications up to 600 mg BID.  Two DLTs were reported at 
900 mg BID.  The recommended alectinib Phase II dosage of 600 mg BID was chosen 
as having the best balance between clinical safety, efficacy, and pharmacokinetic (PK) 
data as observed in the Phase I/II studies (see Section 3.3.1). 
On the basis of available preliminary data, the estimated benefits of alectinib treatment 
outweigh the risks, specifically: 
• 
Available nonclinical and clinical data demonstrate that alectinib is active in NSCLC 
in crizotinib-naïve patients as well as after progression on prior crizotinib therapy 
• 
Clinical safety data in humans up to 900 mg BID demonstrate that its safety profile 
is consistent to the one known to be associated with TKIs. 
Identified and potential risks associated with alectinib treatment will continue to be 
closely monitored throughout the clinical program.  Patient safety during the alectinib 
program is ensured by:  targeting the most appropriate patient population, stringent 
safety monitoring by the Sponsor and Independent Data Monitoring Committee (IDMC), 
and by protocol-specified study drug interruption criteria. 
2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The primary efficacy objective for this study is as follows: 
• 
To evaluate and compare the efficacy of alectinib compared to crizotinib in patients 
with treatment-naïve ALK-positive advanced NSCLC, as measured by 
investigator-assessed PFS 
 
The secondary efficacy objectives for this study are as follows: 
• 
To evaluate and compare the Objective Response Rate (ORR) and Duration of 
Response (DOR) 
• 
To evaluate and compare the time to progression in the CNS on the basis of IRC 
review of radiographs by RECIST v1.1 and Revised Assessment in Neuro Oncology 
(RANO) criteria, as well as: 
To evaluate CNS objective response rate (C-ORR) in patients with CNS 
metastases who have measurable disease in the CNS at baseline  
To assess CNS duration of response (C-DOR) in patients who have a CNS 
Objective Response  
To assess CNS progression rates (C-PR) at 6, 12, 18, and 24 months on the 
basis of cumulative incidence  
• 
To evaluate and compare the PFS assessment by the IRC 
• 
To evaluate and compare the OS 


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2.2 
SAFETY OBJECTIVES 
The secondary safety objective for this study is as follows: 
• 
To evaluate the safety and tolerability of alectinib compared to crizotinib 
 
2.3 
PHARMACOKINETIC OBJECTIVES 
The secondary PK objective for this study is as follows: 
• 
To characterize the pharmacokinetics of alectinib and metabolite(s) 
 
2.4 
PATIENT-REPORTED OUTCOME OBJECTIVES 
The secondary patient-reported outcome (PRO) objectives for this study are as follows: 
• 
To evaluate and compare time to deterioration (TTD) in patient-reported lung cancer 
symptoms of cough, dyspnea (single item and multi-item subscales), chest pain, 
arm/shoulder pain, and fatigue as measured by the European Organization for the 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire−Core 
(QLQ-C30) and the supplemental lung cancer module (QLQ-LC13) as well as a 
composite of three symptoms (cough, dyspnea, chest pain). 
• 
To evaluate and compare PROs of (HRQoL), patient functioning, and side effects of 
treatment as measured by the EORTC QLQ-C30 and EORTC QLQ-LC13. 
 
2.5 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To evaluate and compare patient’s health status as assessed by the EuroQoL 5 
Dimension (EQ-5D-3L) questionnaire to generate utility scores for use in economic 
models for reimbursement. 
• 
To evaluate and compare an onset of hypogonadism in adult men by measuring 
total testosterone, albumin and sex hormone-binding globulin (SHBG) to calculate 
free testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) 
levels in blood. 
• 
To evaluate and compare efficacy and safety in patients with treatment-naïve 
ALK-positive NSCLC as assessed by the FISH Vysis® ALK Break Apart FISH Probe 
Kit (Abbott). 
• 
To investigate molecular mechanisms of resistance to ALK inhibitors. 
• 
To investigate detection of ALK mutations in plasma and circulating tumor cells. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a randomized, active-controlled, multicenter Phase III open-label study in patients 
with treatment-naïve ALK-positive advanced NSCLC.  All patients are required to 
provide pretreatment tumor tissue to confirm the presence of ALK rearrangement (by 
immunohistochemistry [IHC] test).  Patients will be randomized 1:1 into one of the two 
treatment arms to receive either alectinib or crizotinib. 


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This study will comprise approximately 180 centers, in around 30 countries worldwide. 
The primary endpoint of the study is investigator-assessed PFS. 
Central randomization will be performed via an interactive voice or web-based response 
system (IxRS) using the following stratification factors:  Eastern Cooperative Oncology 
Group Performance Status (ECOG PS) (0/1 vs. 2), race (Asian vs. non-Asian), and CNS 
metastases at baseline (yes vs. no).  An IxRS manual containing relevant information 
will be provided to each study site. 
The experimental arm will receive alectinib at 600 mg orally BID, taken with food.  The 
control arm will receive crizotinib at 250 mg orally BID, taken with or without food. 
Patients will be treated until disease progression, unacceptable toxicity, withdrawal of 
consent, or death.  After progression (as per RECIST v1.1), patients should discontinue 
the study medication.  After disease progression, patients will be treated at the discretion 
of the investigator according to local practice.  Information regarding the nature and the 
duration of subsequent therapies will be collected. 
In case of isolated asymptomatic CNS progression (e.g., new CNS oligometastases), 
local therapy can be given (e.g., stereotactic radiotherapy or surgery) followed by 
continuation of either alectinib (in alectinib arm) or crizotinib (in crizotinib arm) until 
systemic disease progression and/or symptomatic CNS progression.  The decision to 
continue the treatment beyond isolated, asymptomatic CNS progression is at the 
investigator’s discretion for patients who can continue to benefit from their respective 
treatment. 
Patients who discontinue treatment prior to disease progression (e.g., due to 
unacceptable toxicity or withdrawal of consent) will continue to be followed until disease 
progression and for OS regardless of whether they subsequently receive non-study 
anti-cancer therapy.  Data for subsequent therapy will be collected for the analysis of OS. 
Approximately 286 patients (143 per treatment arm) will be enrolled into the study over a 
planned competitive recruitment period of 25 months.  Patients inappropriately 
randomized into the study will not be replaced.  The final analysis evaluating the primary 
endpoint of investigator-assessed PFS will occur when approximately 169 patients have 
progressed or died which is expected to occur approximately 31 months after the first 
patient has been enrolled.  Data collection will continue for each patient until death or 
study closure, whichever occurs first. 
An IDMC will be established to monitor the progress of the study and ensure that the 
safety of patients enrolled in the study is not compromised as outlined in Section 9.4. 
A summary of the study design is shown in Figure 4. 




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3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Alectinib Dosage 
Selection of the alectinib dose for the study is based on the clinical safety, efficacy, and 
PK data observed in the Phase I/II studies, AF-001JP and NP28761/AF-002JG, and the 
supportive nonclinical data for alectinib. 
The first-in-human study, AF-001JP evaluated escalating doses of alectinib in an 
accelerated titration scheme to rapidly identify the maximum tolerated dose (MTD).  All 
doses, including the highest evaluated dose in the study, 300 mg BID, were well 
tolerated with no DLTs observed at any dose.  The highest tested dose, 300 mg BID, 
was further evaluated in the Phase II portion of the study and demonstrated robust 
efficacy and good safety with an ORR by IRC of 93.5% (43/46 patients; 95% CI: 82.1%, 
98.6%). 
With no MTD determined in Study AF-001JP, dose escalation progressed in the United 
States Study NP28761/AF-002JG using a modified 3 + 3 design, where 3 patients were 
assessed for DLT evaluation whereas additional patients were enrolled for PK evaluation.  
The starting dose in Study NP28761/AF-002JG was the highest dosage evaluated in 
Study AF-001JP, 300 mg BID.  Following multiple dosages of alectinib at 300 mg BID in 
Study NP28761/AF-002JG, median alectinib exposure (area under the concentration 
time curve [AUC] from 0 to 10 hours) appeared to be approximately two-fold lower 
compared with that in patients from Study AF-001JP, which demonstrated the robust 
efficacy and safety.  Dose escalation progressed with evaluation of higher doses of 
alectinib up to 900 mg BID. 
In Study NP28761/AF-002JG, no DLTs were observed in the dose escalation cohorts, 
up to dose-level of 900 mg BID.  However, 2 patients in the subsequent 900 mg BID 
bridging cohort experienced a DLT; 1 patient had Grade 3 headache and 1 patient had 
Grade 3 neutropenia, and both patients continued study treatment at a reduced dosage 
of 600 mg BID.  Overall, alectinib was well tolerated in the study population.   
Importantly, administration of 600 mg BID provides systemic exposures that meet or 
exceed exposures achieved in patients receiving 300 mg BID in Study AF-001JP, 
demonstrating its robust efficacy and safety in crizotinib-naïve patients.  Further, in 
Study NP28761/AF-002JG, the 600-mg BID regimen has demonstrated promising 
activity in crizotinib-resistant patients, including activity in patients with CNS metastases 
while being tolerated by patients.  On the basis of available preclinical data, 
administration of alectinib 600 mg BID provides systemic exposures within the expected 
range (on the basis of regression of available data) for tumor regression observed in 
mouse xenograft models. 
Thus, on the basis of nonclinical and clinical data, a dosing regimen of 600 mg BID of 
alectinib has been chosen as the optimal therapeutic dose level with the best balance 
between efficacy and safety. 


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Alectinib 600 mg should be administered orally BID with food (within 30 minutes after a 
meal, in the morning and evening). 
3.3.2 
Rationale for Patient Population 
The study population will comprise patients with non-resectable, locally advanced and 
metastatic NSCLC who have been shown to be ALK-positive by IHC test performed at 
central laboratories specially designated for the study.  Patients should not have 
received any prior treatment for advanced NSCLC (treatment-naïve). 
Both experimental (alectinib) and control (crizotinib) treatments are ALK-targeted 
therapies.  The clinical practice guidelines recommend targeted treatment for patients 
with metastatic, oncogene-driven disease as first-line systemic therapy (i.e., 
EGFR-inhibitors for EGFR-positive NSCLC and ALK-inhibitors for ALK-positive NSCLC) 
(NCCN 2014).  
To be eligible for the study, determination of ALK positivity will be performed centrally by 
the IHC assay (see Appendix 8) that is being developed by Ventana Medical Systems as 
a companion diagnostic to alectinib.  IHC may replace fluorescence in situ hybridization 
(FISH)-based identification of ALK rearrangement as the standard companion diagnostic 
in the future.  IHC is faster, easier to perform in local laboratories, and requires less 
equipment compared with the FISH assay.  In addition, IHC has high concordance with 
FISH and a lower false-negative rate (Kim et al. 2011). 
3.3.3 
Rationale for Control Group 
Targeted therapy (including ALK-targeted therapy) is likely to have a greater antitumor 
effect than standard chemotherapy, offering patients a higher response rate and longer 
durability of response with less toxicity compared with any potential chemotherapy 
options (Mok et al. 2009; Rosell et al. 2012; Sequist et al. 2013; Shaw et al. 2013). 
Crizotinib (Xalkori) is an oral small-molecule multi-targeted TKI targeting ALK, MET, 
RON, and ROS1 tyrosine kinases (Sahu et al. 2013, Shaw et al. 2013).  It is the only 
first-generation ALK inhibitor that has been approved in multiple countries worldwide for 
the treatment of ALK-positive NSCLC. 
In the United States, in November 2013, crizotinib has been granted a regular approval 
for ALK-positive NSCLC setting, regardless of treatment line (XALKORI® U.S. Package 
Insert), whereas in Europe, crizotinib is currently approved conditionally for patients with 
previously treated ALK-positive NSCLC (Crizotinib SmPC). 
The NCCN guidelines recommend crizotinib as first-line therapy for patients with 
advanced ALK-positive NSCLC (NCCN 2014). 
There are no publicly available Phase III data yet for crizotinib in the first-line setting.  
The randomized Phase III PROFILE 1014 study, which began in January 2011, is 


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currently being conducted to assess the efficacy of crizotinib versus standard 
platinum-based chemotherapy (pemetrexed plus cisplatin or carboplatin) as first-line 
treatment for patients with ALK-positive, non-squamous NSCLC.  The estimated primary 
completion date of this study is November 2013 (ClinicalTrials.gov), with data expected 
to be reported in 2014.  If PROFILE 1014 reported data will drastically differ from 
previously reported information, the study assumptions might be reevaluated. 
Crizotinib will be dosed as per standard dose recommendations from prescribing 
information—patients in the crizotinib arm will receive crizotinib at 250 mg orally BID with 
or without food until disease progression, unacceptable toxicity, withdrawal of consent, 
or death.  See Section 5.1.4 for criteria for dosing interruption and/or dose reduction for 
treatment with crizotinib.  
3.3.4 
Rationale for Open-Label Design 
An open-label study design is more appropriate for patients enrolled in this particular trial 
for a number of reasons defined below, and with the ultimate goal to ensure patient 
compliance as much as possible. 
For a blinded study design, all enrolled patients would be required to take five large 
capsules twice per day.  This high pill count results from the difference in capsule size 
between crizotinib (size 0) and alectinib (size 1).  Each dose would comprise one 250 
mg capsule of crizotinib or matching placebo and four 150 mg capsules of alectinib or 
matching placebo.  In order to blind, crizotinib capsules must be over-encapsulated. That 
furthermore increase the size of a capsule – from size 0 to size 00 (double zero). Size 00 
is usually the largest capsule size used orally for humans. For some patients size 00 
capsules are too large to swallow.  This high pill count of large capsules is considered to 
be a significant burden to patients and increases the risk of non-compliance. 
Additionally, a blinded study would increase the complexity of standard dose reductions.  
Dose interruption or dose reduction may be required on the basis of individual safety and 
tolerability.  The standard dose reductions for crizotinib would be 200 mg BID (different 
capsule, size 1), followed by 250 mg QD.  Dose reductions for alectinib would occur in 
150 mg steps.  In a double blind study, these multiple step dose reductions introduce a 
high level of complexity and potential for error. 
In order to avoid a significant burden to patients with high pill count, increased risk of 
non-compliance, and complexity of standard dose reductions, adequate steps have been 
taken to ensure the validity of the data in an open-label study design.  These include 
performing a supportive analysis of efficacy on the basis of determining progression by 
an IRC, performing sensitivity analyses to demonstrate the robustness of the primary 
endpoint, defining progression using established response evaluation criteria 
(RECIST v1.1), performing tumor assessment at the same frequency in both arms and 
adhering to protocol-defined schedules, and finalizing before trial start the strategy for 
the final analysis of the primary endpoint, including predefined methods for handling 


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missing data and censoring rules.  Efficacy analyses will only be performed at the pre-
specified analysis timepoints in the protocol (final analysis once 169 PFS events have 
occurred and survival follow-up analysis at 143 events). 
3.3.5 
Rationale for Primary Endpoint Selection 
The investigator-assessed PFS (which will be supported by IRC-assessed PFS analysis, 
one of the secondary endpoints of the study) is the primary endpoint for this trial. 
PFS, as an endpoint, can reflect tumor growth and can be assessed before the 
determination of a survival benefit, and its determination is not generally confounded by 
subsequent therapies.  Whether an improvement in PFS represents a direct clinical 
benefit or a surrogate for clinical benefit depends on the magnitude of the effect and the 
risk-benefit of the new treatment compared to available therapies (Guidance for 
Industry 2007; European Medicines Agency 2012).  A PFS HR of 0.65 will be targeted, 
which constitutes a clinically meaningful benefit in this patient population as it will delay 
the use of platinum-based chemotherapy and will potentially reduce the frequency of 
CNS relapse and the morbidity associated with treating CNS metastases. 
The assumed median PFS of patients in the alectinib treatment arm is 15.1 months, and 
an OS of more than 30 months is expected, which equates to a post-progression 
survival of at least 15 months.  Patients with ALK-positive NSCLC treated with crizotinib 
in the second-line setting had a median PFS of 7.7 months and an interim median OS of 
20.3 months (Shaw et al. 2013), which equated to a post-progression survival of 
12.6 months.  This lengthy post-progression survival provides an opportunity for 
subsequent treatment with other ALK inhibitors, several additional lines of chemotherapy, 
or participation in additional clinical trials. 
Patients in both study arms who experience disease progression on study treatment will 
likely be treated with other subsequent treatment options, including ALK inhibitors.  
The availability of crizotinib on the market, as well as the likely availability of other 
next-generation ALK TKIs, and the availability of other investigational agents in clinical 
trials offer potential treatment options to patients in the study who will eventually have 
disease progression.  Subsequent therapies frequently confound the detection of an OS 
benefit, particularly in a setting with a long post-progression survival, such as 
ALK-positive NSCLC.  This has been observed in trials for EGFR TKIs, in which strong 
PFS benefits were observed without evidence of OS benefit (Rosell et al. 2009; 
Fukuoka et al. 2011). 
The long post-progression survival and the confounding effects of subsequent lines of 
therapy indicate that it would be difficult to detect an OS benefit in this setting.  
Nevertheless, OS is one of the study’s secondary endpoints.  The crossover from the 
crizotinib arm to alectinib will not be allowed in this study, with the aim of preserving the 
trial’s ability to potentially demonstrate some degree of treatment benefit of alectinib in 


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OS.  However, the study will not be powered to demonstrate any statistically significant 
difference in the secondary endpoint of OS. 
To ensure the validity of the PFS as the primary endpoint, a number of measures have 
been implemented: full IRC assessment to support the analysis of the primary endpoint, 
a substantial target magnitude of benefit (target HR = 0.65) and study assessments that 
will allow a robust evaluation of risk-benefit (standard RECIST criteria to define 
progression with fixed assessment intervals that are identical in both treatment arms and 
a robust definition of PFS and prospectively defined methods to assess, quantify, and 
analyze PFS, including censoring methods and sensitivity analyses). 
3.3.6 
Rationale for Secondary Endpoint of Time to CNS Progression 
Lung cancer is the most common type of cancer to spread to the brain, with at least 40% 
of people with lung cancer developing brain metastases at some point during their 
disease.  ALK-positive NSCLC has a propensity to metastasize to the brain, and 
crizotinib has impaired control of brain metastases in comparison to other sites of 
systemic disease (Chun et al. 2012). 
Delaying or preventing the development of CNS metastases would provide patients with 
clinically meaningful benefit by avoiding consequences of neurological deficits from brain 
metastasis or by delaying/preventing long-term side effects associated with steroid use 
and brain irradiation. 
Preliminary evidence of CNS benefit with alectinib has been observed in patients in the 
two ongoing Phase II studies.  See Section 1.2 and Alectinib Investigator's Brochure for 
additional details. 
Time to CNS progression is defined as the time from randomization until radiographic 
evidence of CNS progression is documented.  The aim of the pre-specified analysis will 
be to evaluate whether alectinib significantly delays or prevents the development of CNS 
metastases. 
Randomization of the Phase III study will be stratified by the presence or absence of 
CNS metastasis at baseline. 
Imaging analysis by consistently used uniform image acquisition technique (MRI scans) 
will be performed routinely at baseline and at subsequent follow-up assessments along 
with every systemic imaging tumor assessment or whenever clinically indicated (i.e., 
clinical suspicion of CNS metastasis) in order to achieve an accurate determination of 
time to CNS progression.  This ensures that early brain metastatic lesions are detected 
and that assessment bias between the two arms is avoided by having regularly 
scheduled scans. 


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An independent central radiological review will be performed for all patients and the 
analysis of time to CNS progression, or response will be based on the data from the 
independent review.  The review will be based on the standard RECIST v1.1 criteria to 
assess the CNS lesions, and a second independent review on the basis of the RANO 
criteria, which are typically used to assess brain tumors (Wen et al. 2010), will be 
performed.  The assessment will be performed independently from the overall disease 
progression assessment. 
3.3.7 
Rationale for PK Sample Collection Schedule 
To date, the pharmacokinetics of alectinib have been characterized in 
chemotherapy-failed, crizotinib-naïve patients with NSCLC in Study AF-001JP and in 
patients who have failed chemotherapy and crizotinib treatment in Study NP28761/AF-
002JG and Study NP28673.  In order to better understand the pharmacokinetics of 
alectinib and to further support the development of a robust population PK model for 
alectinib in order to better understand, identify, and characterize variables which lead to 
changes in exposure, characterization of alectinib pharmacokinetics will be done in this 
study.  This study will include PK assessment of alectinib in ALK inhibitor treatment-
naïve patients with ALK-positive advanced NSCLC by collecting trough samples from all 
patients receiving alectinib.  Serial/intensive PK samples will be collected from a subset 
of patients (10%−15% [at least n = 20] of patients receiving alectinib) to facilitate the PK 
assessment.  The data that will be collected from this study will enable more robust 
understanding of alectinib pharmacokinetics in the global crizotinib-naïve population 
including investigation and potential identification of sources of variability influencing 
alectinib pharmacokinetics and/or response to alectinib therapy.  Results from PK data 
collection in this study and analyses of PK data could help support optimal use of 
alectinib therapy. 
3.3.8 
Rationale for Biomarker Assessments 
There are several molecular mechanisms of resistance to crizotinib reported in the 
literature: increased copy number of ALK gene, increased expression of ALK mRNA, 
secondary mutations in ALK (e.g., gatekeeper mutation), and changes (e.g., increased 
copy number, increased phosphorylation, or point mutations) in escape genes like EGFR, 
cKIT, or KRAS (Katayama et al. 2011; Doebele et al. 2012; Kim et al. 2013).  In order to 
investigate molecular mechanisms of resistance to ALK inhibitors and ALK mutation 
status, tumor samples will be collected before treatment and at the time of disease 
progression with the goal of sequencing nucleic acids.  Two types of approaches will be 
used: 1) targeted sequencing of a panel of genes known to be involved in cancer and 2) 
unbiased genomic sequencing.  
ALK rearrangements can be monitored in circulating tumor cells in blood (Ilie et al. 2012; 
Pailler et al. 2013).  Intact tumor cells are released into the circulation; hence, using 
specific surface markers, it is possible to selectively separate them from the remaining 
cells in the blood.  This allows downstream analysis like IHC or FISH, and in rare 


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occasions, there is enough material to perform reverse transcription–polymerase chain 
reaction or sequencing to detect mutant mRNA.  The presence of ALK rearrangements 
will be investigated in circulating tumor cells before treatment and at the end of study.  
This information will be used to investigate the use of blood as a surrogate of tumor for 
diagnostic purposes and to monitor the presence of ALK rearrangements in circulating 
tumor cells in the blood before and after treatment. 
Mutations in cancer genes appearing from drug resistance can be monitored in 
circulating nucleic acids in plasma (Forshew et al. 2012).  Tumor nucleic acids are shed 
into circulation in amounts that allow direct amplification by polymerase chain reaction 
and sequencing.  Plasma samples will be collected before treatment and at certain 
timepoints during treatment, to monitor mutations in ALK and other genes involved in 
resistance to ALK inhibitors.  Information from mutated genes in the tumor will be 
correlated with mutations in plasma DNA. 
Determination of ALK positivity will be initially performed by IHC (see Appendix 8).  In 
addition, the Abbott Vysis FISH test will be used as an exploratory assay, after patients 
have been enrolled in this study.  Results from these analyses will be used to quantify 
the degree of correlation between FISH and IHC for the detection of ALK-positive 
NSCLC.  For exploratory purposes, other methods to determine ALK positivity 
(e.g., reverse transcription-polymerase chain reaction) may also be used. 
3.3.9 
Rationale for PRO Assessments 
In the treatment of lung cancer, it is important to both increase survival and palliate 
symptoms because disease symptoms have negative impacts on HRQoL 
(Hyde and Hyde 1974; Hopwood and Stephens 1995; Sarna et al. 2008).  This is 
especially true for trials that use PFS as a primary endpoint, where it is important to 
translate the delay in disease progression into an endpoint that is meaningful to patients. 
Pain (chest; arm/shoulder), dyspnea, cough, and fatigue have been regarded as the 
most frequent and clinically relevant disease-related symptoms experienced by patients 
with NSCLC.  The BR.21 study (erlotinib vs. chemotherapy in second- or third-line 
NSCLC) demonstrated that longer TTD in the pain, dyspnea, and cough scales of the 
EORTC QLQ-C30 and QLQ-LC13 was consistent with superior PFS, OS, and 
quality-of-life benefits in the erlotinib arm as compared with the placebo arm 
(Aaronson et al. 1993; Bergman et al. 1994; Bezjak et al. 2006).  Additionally, patients in 
the crizotinib PROFILE 1005 trial reported clinically significant (10 points) improvements 
in the pain, cough, dyspnea, and fatigue symptom scales seen as early as 2 weeks on 
treatment (Crinò et al. 2011). 
The EORTC QLQ-C30 and QLQ-LC13 were used in the Phase III PROFILE 1007 study 
(second-line crizotinib vs. chemotherapy).  The study reported significantly greater 
overall reduction from baseline in the symptoms of alopecia, cough, dyspnea, fatigue, 
chest pain, arm or shoulder pain, and pain in other parts of the body with crizotinib than 


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with chemotherapy (p < 0.001 for all comparisons, without adjustment for multiple testing).  
Patients treated with crizotinib also had a significantly greater delay in the worsening of 
symptoms.  There was also a significantly greater overall improvement from baseline in 
the global quality of life among patients who received crizotinib treatment than among 
those who received chemotherapy (p < 0.001).  In all domains measuring functioning, 
except for the domain measuring cognitive functioning, there was a significantly greater 
overall improvement from baseline among patients in the crizotinib group than among 
patients in the chemotherapy group (Shaw et al. 2013). 
Therefore, to assess the quality of life of patients in this trial, PRO data will be collected 
from patients enrolled in this study using the validated questionnaires EORTC QLQ-C30 
and QLQ-LC13. 
3.4 
OUTCOME MEASURES 
3.4.1 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
• 
PFS, which is defined as the time from randomization to the first documented 
disease progression, as determined by the investigators (primary endpoint) or IRC 
(secondary endpoint) using RECIST v1.1 or death from any cause, whichever 
occurs first.  Patients without an event will be censored at the last tumor 
assessment either during follow-up or during study treatment.  Patients with no 
post-baseline assessments will be censored at the date of randomization. 
• 
ORR, which is defined as the percentage of patients who attain CR or PR; response, 
as determined by the investigators using RECIST v1.1.  Patients without any 
assessments will be regarded as non-responders. 
• 
Time to CNS progression, which is defined as the time from randomization to the 
first occurrence of disease progression in the CNS as determined by IRC using 
RECIST v1.1 and RANO (separate assessments and analyses), as well as C-ORR 
in patients with CNS metastases who have measurable disease in the CNS at 
baseline, C-DOR in patients who have a CNS Objective Response, and C-PR at 6, 
12, 18, and 24 months. 
• 
DOR, which is defined as the time from when response (CR or PR) was first 
documented to first documented disease progression or death (whichever occurs 
first).  This will only be calculated for patients who have a best overall response of 
CR or PR.  Patients who do not progress or die after they have had a response are 
censored at the date of their last tumor measurement. 
• 
OS, which is defined as the time from randomization to death from any cause.  
Patients without an event will be censored at the last date known to be alive.  
Patients without any follow-up information will be censored at the date of 
randomization. 
 


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3.4.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Serious and non-serious adverse events 
• 
Safety laboratory tests values 
• 
Vital signs (blood pressure, heart rate), ECG 
• 
Physical examination 
 
3.4.3 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Sparse (pre-dose) PK samples for measurement of alectinib and its major 
metabolite(s) will be collected in all study patients receiving alectinib treatment.  See 
Appendix 1 and Appendix 2 for PK sampling times. 
• 
Serial/intensive PK sampling will be collected in a subset of consenting patients 
enrolled to receive alectinib treatment (approximately 10%−15%, at least 
approximately n = 20).  See Appendix 1 and Appendix 2 for PK sampling times. 
• 
PK parameters will be determined as appropriate and where data allow: 
The pharmacokinetics of alectinib (and metabolite[s], if appropriate) will be 
described, and the between-patient variability will be estimated using a 
population PK approach.  The potential influence of covariates that contribute 
significantly to the between-patient differences in PK parameters of alectinib will 
also be explored and quantified. 
Non-compartmental analysis (NCA) may be conducted in patients undergoing 
serial/intensive PK sample collection, as appropriate and where data allow. 
 
3.4.4 
Patient-Reported Outcome Measures 
The PRO measures included for this study are as follows and will be administered to 
patients every 4 weeks until disease progression and during post-progression on 
treatment in case of isolated, asymptomatic CNS progression; at the post-treatment visit 
(4 weeks after permanent treatment discontinuation); and every follow-up visit (every 8 
weeks) after post-treatment visit for 6 months: 
• 
The EORTC QLQ-C30 and EORTC QLQ-LC13 to determine the impact of alectinib 
compared with crizotinib as measured by TTD in patient-reported lung cancer 
symptoms (e.g., cough, dyspnea [single item and multi-item scales], pain in chest, 
pain in arm/shoulder, fatigue). 
• 
The EORTC QLQ-C30 and EORTC QLQ-LC13 to measure PROs of HRQoL, 
patient functioning, and side effects of therapy compared between patients treated 
with alectinib and those treated with crizotinib. 
 


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3.4.5 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
EQ-5D-3L to generate utility scores for use in economic models for reimbursement. 
• 
Total testosterone, albumin and SHBG to calculate free testosterone, FSH, and LH, 
in blood to measure an onset of hypogonadism in adult men. 
• 
The FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) to evaluate and compare 
efficacy and safety in patients with treatment-naïve NSCLC that is ALK-positive by 
FISH test. 
• 
Post-progression tumor mutation status to study molecular mechanisms of 
resistance to ALK inhibitors. 
• 
ALK mutation status in plasma DNA to monitor efficacy and disease progression. 
• 
ALK fusion status in circulating tumor cells in blood. 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Target population is patients with treatment-naïve ALK-positive non-resectable, locally 
advanced and metastatic NSCLC. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage 
IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that 
is ALK-positive as assessed by the Ventana IHC test.  Sufficient tumor tissue to 
perform ALK IHC and ALK FISH is required.  Both tests will be performed at 
designated central laboratories. 
• 
Age ≥ 18 years old. 
• 
Life expectancy of at least 12 weeks. 
• 
ECOG PS of 0−2. 
• 
Patients had no prior systemic treatment for advanced or recurrent (Stage IIIB not 
amenable for multimodality treatment) or metastatic (Stage IV) NSCLC. 
• 
Adequate hematologic function: 
Platelet count ≥ 100 × 109/L 
ANC ≥ 1500 cells/μL 
Hemoglobin ≥ 9.0 g/dL 
• 
Adequate renal function: 
Calculated creatinine clearance at least 45 mL/min 
• 
Patients must have recovered from effects of any major surgery or significant 
traumatic injury at least 28 days before the first dose of study treatment. 


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• 
Measurable disease (by RECIST v1.1) prior to the administration of study treatment. 
• 
Prior brain or leptomeningeal metastases allowed if asymptomatic and diagnosed 
incidentally at study baseline.  If patients have neurological symptoms or signs due 
to CNS metastasis, patients need to complete whole brain radiation or gamma knife 
irradiation treatment at least 14 days before enrollment and be clinically stable. 
• 
For all females of childbearing potential, a negative pregnancy test must be 
obtained within 3 days before starting study treatment. 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to 
remain abstinent or use single or combined contraceptive methods that result in a 
failure rate of < 1% per year during the treatment period and for at least 3 months 
after the last dose of study drug.  Abstinence is only acceptable if it is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.  Examples of non-hormonal contraceptive 
methods with a failure rate of < 1% per year include tubal ligation, male sterilization, 
hormonal implants, established, proper use of combined oral or injected hormonal 
contraceptives, and certain intrauterine devices.  Alternatively, two methods (e.g., 
two barrier methods such as a condom and a cervical cap) may be combined to 
achieve a failure rate of < 1% per year.  Barrier methods must always be 
supplemented with the use of a spermicide.  
• 
For men:  agreement to remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of < 1% per year during the 
treatment period and for at least 3 months after the last dose of study drug.  
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception.   
• 
Able and willing to provide written informed consent prior to performing any 
study-related procedures and to comply with the study protocol, including patients 
must be willing and able to use the electronic patient-reported outcome (ePRO) 
device. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients with a previous malignancy within the past 3 years are excluded (other than 
curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer 
by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is 
considered to have no impact in PFS and OS for the current NSCLC). 
• 
Any GI disorder that may affect absorption of oral medications, such as 
mal-absorption syndrome or status post-major bowel resection. 


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• 
Liver disease characterized by: 
ALT or AST > 3 × ULN (≥ 5 × ULN for patients with concurrent liver metastasis) 
confirmed on two consecutive measurements 
OR 
Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or 
other conditions of decompensated liver disease such as coagulopathy, hepatic 
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal 
varices 
OR 
Acute viral or active autoimmune, alcoholic, or other types of hepatitis 
• 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy 
(e.g. radiotherapy) (excluding alopecia), which have not shown improvement and 
are strictly considered to interfere with current study medication. 
• 
History of organ transplant. 
• 
Co-administration of anti-cancer therapies other than those administered in this 
study. 
• 
Patients with baseline QTc > 470 ms or patients with symptomatic bradycardia 
< 45 beats per minute. 
• 
Administration of strong/potent cytochrome P450 (CYP)3A inhibitors or inducers 
within 14 days prior to the first dose of study treatment and while on treatment with 
alectinib or crizotinib (see Appendix 3) except for oral corticosteroids up to 20 mg of 
prednisolone equivalent per day. 
• 
Administration of agents with potential QT interval prolonging effects within 14 days 
prior to the first administration of study drug and while on treatment.  (See 
Section 4.4.2 for further details.) 
• 
History of hypersensitivity to any of the additives in the alectinib drug formulation 
(lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, 
hydroxypropyl cellulose, sodium lauryl sulfate [SLS], magnesium stearate). 
• 
History of hypersensitivity to any of the additives in the crizotinib drug formulation 
(silica, colloidal anhydrous cellulose, microcrystalline calcium hydrogen phosphate, 
anhydrous sodium starch glycolate, magnesium stearate). 
• 
Pregnant or lactating women. 
• 
Known HIV positivity or AIDS-related illness. 
• 
Any clinically significant concomitant disease or condition that could interfere with, 
or for which the treatment might interfere with, the conduct of the study or the 
absorption of oral medications or that would, in the opinion of the Principal 
Investigator, pose an unacceptable risk to the patient in this study. 


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• 
Any psychological, familial, sociological, or geographical condition potentially 
hampering compliance with the study protocol requirements and/or follow-up 
procedures; those conditions should be discussed with the patient before trial entry. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label trial, for which the rationale is described in Section 3.3.4. 
Approximately 286 patients will be randomly assigned in a 1:1 allocation ratio to the two 
treatment arms via a block-stratified randomization procedure and over a planned 
recruitment period of 25 months. 
Randomization will guard against systematic selection bias and should ensure the 
comparability of treatment groups.  To assist balance in important prognostic factors, 
randomization will be stratified by ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and 
CNS metastases at baseline (yes vs. no). 
Central randomization and drug pack number allocations will be performed and 
managed by an IxRS.  Further details will be provided in an IxRS manual. 
The independent review of scans for the secondary endpoints of PFS on the basis of 
IRC and time to CNS progression will be performed in a blinded fashion. 
4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Alectinib 
Alectinib comes in a capsule dosage form containing the following active ingredient: 
[Chemical name] 9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-6,11-
dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride 
Each capsule contains 150 mg of alectinib (as free base) along with lactose 
monohydrate, carmellose calcium, hydroxypropyl cellulose, SLS, and magnesium 
stearate. 
Alectinib capsules should be stored in accordance with the storage instructions on the 
label. 
Alectinib capsules should be administered orally BID with food (within 30 minutes after a 
meal, in the morning and evening). 
The formulation contains SLS as a surfactant excipient.  This excipient is known to be 
associated potentially with GI adverse events such as nausea, vomiting, diarrhea, and 
abdominal pain. 
For further details, see the alectinib Investigator's Brochure. 


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4.3.1.2 
Crizotinib 
Crizotinib comes in a hard capsule dosage form.  Each capsule contains 250 mg or 
200 mg crizotinib.  Crizotinib hard capsules should be stored in accordance with the 
storage instructions on the label.  Crizotinib capsules should be administered orally BID. 
For further details, see the local prescribing information for crizotinib (XALKORI® U.S. 
Package Insert). 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Alectinib 
Alectinib 600 mg (four 150-mg capsules) should be administered orally BID with food 
(within 30 minutes after a meal, in the morning and evening). 
If a patient misses a dose, it can be taken within 4 hours of the scheduled time.  If the 
time is greater than 4 hours, or if the patient vomits the dose, the patient should wait until 
the next scheduled time and take the next scheduled dose.  Patients should not take 
two doses at the same time to make up for a missed dose. 
Guidelines for dosage modifications and treatment interruptions or discontinuation due to 
specified adverse events are provided in Section 5.1.3. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF. 
4.3.2.2 
Crizotinib 
Crizotinib 250 mg (one 250-mg capsule) should be administered orally BID with or 
without food (in the morning and evening). 
If a dose is missed, then it should be taken as soon as the patient remembers unless it is 
less than 6 hours until the next dose, in which case the patient should not take the 
missed dose.  Patients should not take 2 doses at the same time to make up for a 
missed dose. 
If dose reduction is necessary, then the dose of crizotinib should be reduced to 200 mg 
taken BID.  If further dose reduction is necessary, then the dose should be modified to 
250 mg taken once daily.  Guidelines for dosage modification and treatment interruption 
or discontinuation are provided in Section 5.1.4. 
Any overdose or incorrect administration of crizotinib should be noted on the crizotinib 
Administration eCRF.  Adverse events associated with an overdose or incorrect 
administration of crizotinib should be recorded on the Adverse Event eCRF. 


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4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(alectinib and crizotinib) will be provided by the Sponsor where required by local health 
authority regulations.  The study site will acknowledge receipt of IMPs and confirm the 
shipment condition and content.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Post-Trial Access to Alectinib 
The Sponsor does not intend to provide alectinib or other study interventions to patients 
after conclusion of the study or any earlier patient withdrawal, under this protocol. 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy 
Concomitant medication includes any medication (e.g., prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used 
by a patient from 28 days prior to screening to the study completion/discontinuation visit.  
All concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF. 
All therapy and/or medication administered to manage adverse events should be 
recorded on the Adverse Event eCRF. 
The medications and/or treatments below are permitted: 
• 
Anticoagulants and antithrombotic agents (i.e., coumadin-derived anticoagulants, 
unfractionated heparin or low-molecular heparins, aspirin (≤ 325 mg/day), and 
clopidogrel. 
• 
Systemic corticosteroid should be no more than oral 20 mg prednisone equivalent 
daily.  Inhalation corticosteroid is allowed.  Steroid equivalence converter could be 
found at: http://www.medcalc.com/steroid.html 
• 
Acetaminophen up to 2 g/day 
 
Caution should be exercised when the following are co-administered with alectinib: 
• 
For medications that are substrates of P-gp transporter or breast cancer resistance 
protein transporter, the investigator should use caution and monitoring when 
considering concomitant use of alectinib.  Alectinib has been shown to have 


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potential for inhibition of these transporters.  Substrates with a narrow therapeutic 
index (e.g., methotrexate, digoxin) should be avoided.  If co-administration cannot 
be avoided, it is recommended that drug levels and/or signs for toxicity are carefully 
monitored (see Appendix 3). 
• 
For medications that are inhibitors of P-gp transporter, the investigator should use 
caution and monitoring when considering concomitant use of alectinib.  The major 
metabolite of alectinib, M4, has been shown to be a substrate of this transporter.  
Strong inhibitors of P-gp should be avoided, if possible (see Appendix 3). 
• 
For medications that are metabolized by CYP3A and CYP2C8, the investigator 
should use caution and monitoring when considering concomitant use of alectinib.  
Alectinib has been shown to have potential for inhibition of CYP3A and CYP2C8, 
including potential time-dependent inhibition.  Sensitive CYP3A and CYP2C8 
substrates should be avoided.  If co-administration cannot be avoided, it is 
recommended that drug levels and/or signs for toxicity are carefully monitored 
(see Appendix 3). 
 
Caution should be exercised when the following are co-administered with crizotinib: 
• 
Crizotinib has been shown to be a moderate inhibitor of CYP3A.  Dose reduction 
maybe needed for co-administered drugs that are predominantly metabolized by 
CYP3A in patients receiving crizotinib.  Concurrent use of CYP3A substrates with 
narrow therapeutic indices should be avoided (see Appendix 3). 
• 
On the basis of an in vitro study, crizotinib is predicted to inhibit intestinal P-gp.  
Therefore, administration of crizotinib with medicinal products that are substrates of 
P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin) may increase their 
therapeutic effect and adverse reactions (see Appendix 3).  Close clinical 
surveillance is recommended when crizotinib is administered with these medicinal 
products. 
• 
Bradycardia has been reported during clinical studies; therefore, use crizotinib with 
caution owing to the risk of excessive bradycardia when used in combination with 
other bradycardic agents (e.g., non-dihydropyridine calcium channel blockers such 
as verapamil and diltiazem, beta-blockers, clonidine, guanfacine, digoxin, 
mefloquine, anticholinesterases, pilocarpine). 
• 
The aqueous solubility of crizotinib is pH dependent, with higher pH resulting in 
lower solubility.  Drugs that elevate the gastric pH (such as proton pump inhibitors, 
H2 blockers, or antacids) may decrease the solubility of crizotinib and subsequently 
reduce its bioavailability. 
• 
The inhibitory effect of crizotinib on uridine 5'-diphospho-glucuronosyltransferases 
(UGTs), notably UGT1A1, has not been established.  Therefore, caution should be 
exercised when crizotinib and substrates of UGTs, such as paracetamol or 
morphine, are combined. 


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• 
In vitro studies in human hepatocytes indicated that crizotinib may induce 
pregnane X receptor and constitutive androstane receptor–regulated enzymes 
(e.g., CYP3A4, CYP2B6, CYP2C8, CYP2C9, UGT1A1).  However, there was no 
observed induction in vivo when crizotinib was coadministered with the CYP3A 
probe substrate midazolam.  Caution should be exercised in administering crizotinib 
in combination with medicinal products that are predominantly metabolized by these 
enzymes.  Of note, the effectiveness of concomitant administration of oral 
contraceptives may be altered. 
• 
In vitro studies indicated that crizotinib is an inhibitor of CYP2B6.  Therefore, 
crizotinib may have the potential to increase plasma concentrations of 
coadministered drugs that are metabolized by CYP2B6 (e.g., bupropion, efavirenz). 
 
4.4.2 
Prohibited Therapy 
Use of the following therapies (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) is prohibited during the study and for at 
least 14 days prior to initiation of study treatment (either alectinib or crizotinib), unless 
otherwise specified below.  Exceptions to the below listed concomitant therapies 
restrictions (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, nutritional supplements) may be made if the rationale is discussed and 
documented between the investigator and the Sponsor’s Clinical Pharmacologist. 
• 
Potent inducers of CYP3A (e.g., rifampin, rifabutin, phenobarbital, phenytoin, 
carbamazepine, and St. John’s wort [Hypericum perforatum]) within 2 weeks or 
5 half-lives (whichever is longer) before the first dose of study drug treatment and 
while on treatment with study drugs (see Appendix 3). 
• 
Potent inhibitors of CYP3A (e.g., ketoconazole) within 2 weeks or 5 half-lives 
(whichever is longer) before the first dose of study drug treatment and while on 
treatment with study drug (see Appendix 3). 
• 
Any concomitant medications known to affect QT interval duration, including but not 
limited to the following drugs: amiodarone, cisapride, clarithromycin, methadone, 
and quinidine, within 2 weeks before the first dose of study drug treatment and while 
on treatment with study drugs and through the end of the study. 
• 
Systemic immunosuppressive drugs, cytotoxic or chemotherapeutic agents 
(other than study drug treatment), ergot derivatives, probenecid, and bile 
acid-binding resins while on study treatment. 
• 
Systemic chemotherapy. 
• 
Radiotherapy/radionuclide therapy except for palliative radiotherapy to bone lesions 
or for pain control.  If palliative radiation is indicated for bone metastases, palliative 
radiation may start within 24 hours of the last dose of alectinib, unless, in the 
judgment of the investigator, patient safety will require a longer washout period prior 
to palliative therapy.  Dosing of alectinib may resume with the resolution of any 
radiation toxicity to  ≤ Grade 1. 
• 
Additional investigational drug (except for during the follow-up period). 
 


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The above lists of medications are not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication 
as well as the Internet references provided below when determining whether a certain 
medication is metabolized by or strongly inhibits or induces CYP3A.  In addition, the 
investigator should contact the Medical Monitor if questions arise regarding medications 
not listed above. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM292362.pdf 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
 
4.4.3 
Prohibited Food 
Use of grapefruit or grapefruit juice should be avoided during the study and for at least 
14 days prior to the initiation of study treatment (either alectinib or crizotinib) because it 
is a potent CYP3A inhibitor and may increase plasma concentration of either alectinib or 
crizotinib. 
4.5 
STUDY ASSESSMENTS 
See Appendix 1 for the schedule of assessments performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 28 days prior 
to the screening visit. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Corticosteroid Use for CNS Metastases 
For patients with CNS metastases requiring corticosteroid use, the corticosteroid intake 
should be captured at all tumor assessment visits and compared to the corticosteroid 
intake at the time of the last disease assessment.  The changes will be recorded as 


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Increased, Unchanged, or Decreased.  Increases and decreases in corticosteroid intake 
should be clinically justified.  Increases in corticosteroid dose for reasons other than for 
CNS metastases control do not need to be taken into consideration when making this 
comparison.  As per Section 4.4.1 of the protocol, systemic corticosteroid use cannot 
exceed oral 20 mg of prednisone equivalent daily. 
4.5.4 
Physical Examinations 
A complete physical examination at screening and baseline should include an evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, GI, genitourinary, and neurological systems as well as 
height and weight.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
Note:  for patients with known CNS metastases, a neurological examination must be 
performed at each tumor assessment visit and compared to the neurological 
examination performed at the time of the last disease assessment.  Definition of clear 
neurological worsening is difficult to describe because progression in the CNS can 
present in numerous ways.  Accordingly, evaluation of neurological function at each 
disease assessment will be based purely on the investigator’s assessment of the 
patient’s neurological state compared to the neurological function at the time of the last 
disease assessment.  Neurological status will be recorded as Improved, Stable, or 
Worsened. 
4.5.5 
Vital Signs 
Vital signs will include measurements of respiratory rate, oxygen saturation, pulse rate, 
and systolic and diastolic blood pressure while the patient is in a seated position, and 
temperature. 
4.5.6 
ECOG Performance Status 
PS will be measured using the ECOG Performance Status Scale (see Appendix 5).  It is 
recommended, where possible, that a patient’s PS be assessed by the same person 
throughout the study. 
4.5.7 
Tumor and Response Evaluations 
Disease burden must be documented at screening and re-assessed at each subsequent 
tumor evaluation.  Response will be assessed by the investigator on the basis of physical 
examinations, computed tomography (CT) scans, and other modalities (e.g., MRI, brain 
scans), using RECIST v1.1 (see Appendix 4).  For assessing response in patients with 
measurable disease, the preferred radiologic tumor response assessment is CT scan 


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with intravenous contrast.  If intravenous contrast is contraindicated, a 
non-contrast-enhanced chest CT scan will be acceptable for chest lesions, and MRI can 
be used for non-chest lesions.  If contrast-enhanced MRI is contraindicated, then 
non-contrast-enhanced MRI will suffice.  Positron emission tomography (PET) scan, bone 
scan, and ultrasound cannot be used to measure lesion as per RECIST v1.1 
(see Appendix 4).   
The same radiographic procedure used to define measurable disease sites at screening 
must be used throughout the study (e.g., the same contrast protocol for CT scans).  
Assessments should be performed by the same evaluator to ensure internal consistency 
across visits. 
CT/MRI scans of chest and abdomen, and MRI scans of the brain should be performed 
for all patients as described in Schedule of Assessments (see Appendix 1) at screening 
then every 8 weeks subsequently until disease progression and during post-progression 
on treatment in case of isolated, asymptomatic CNS progression and at the 
post-treatment visit (4 weeks after permanent treatment discontinuation).  CT/MRI scans 
of the neck bone and pelvis should be included if clinically indicated.  At the investigator’s 
discretion, CT/MRI scans may be repeated at any time if PD is suspected. 
Note: Brain imaging should be performed using MRI with the following image acquisition 
requirements: 
• 
Minimum sequences required: 
Pre-contrast T1, T2/FLAIR 
Post-contrast T1, with two orthogonal planes (or a volume acquisition) 
recommended 
• 
Recommended slice thickness ≤ 5 mm with no gap 
 
Patients with known or suspected bone metastases should undergo radionuclide bone 
scan at screening.  Bone scan, PET scan, or plain films are not considered adequate 
imaging techniques to measure bone lesions and do not need to be repeated routinely 
but can be used to confirm the presence or disappearance of bone lesions.  Lytic bone 
lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be 
evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
measurable lesions of the soft tissue component and meets the definition of measurability 
and should be followed by cross-sectional imaging. 


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4.5.8 
Laboratory, Biomarker, and Other Biological Sample 
4.5.8.1 
Laboratory Assessments 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Hematology (hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
absolute differential count [neutrophils, eosinophils, lymphocytes, monocytes, 
basophils, other cells]) 
• 
Coagulation (PT [or INR], and aPTT) 
• 
Serum chemistry (sodium, potassium, chloride, bicarbonate, fasting glucose, BUN 
or urea, creatinine [including calculated eGFR using the Modification of Diet in 
Renal Disease formula, see Appendix 7]; CPK; gamma-glutamyl transferase (GGT); 
calcium; total and direct bilirubin; total protein; albumin; ALT; AST; alkaline 
phosphatase [ALP]; phosphorus; magnesium; thyroid-stimulating hormone; and total 
testosterone, albumin and SHBG to calculate free testosterone, FSH, and LH [for 
male patients only]) 
• 
Urinalysis: Urine samples will be collected according to the schedule of 
assessments (Appendix 1) (first morning urine sample for baseline and end of 
treatment visit, spot urine for rest of visits).  Urine albumin and creatinine will be 
measured in order to assess micro- and macroalbuminuria. 
• 
Pregnancy test.  All women who are not postmenopausal (≥ 12 months of 
non-therapy-induced amenorrhea) or surgically sterile will have a serum pregnancy 
test at screening, within 3 days of dosing.  Urine pregnancy tests will be performed 
anytime during the course of the study, as per investigator’s discretion.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
 
4.5.8.2 
Pre-Treatment Tumor Samples (Mandatory) 
Mandatory pre-treatment tumor samples will be collected to centrally examine ALK 
status by IHC (eligibility criteria) and FISH.  Tumor blocks (formalin-fixed, preferred 10% 
neutral-buffered formalin) are the preferred source, but if blocks are not available, 
unstained slides (ten to fifteen 5-µm slides cut less than 3 months before screening) are 
also accepted.  Remaining tumor blocks will be returned to the sites; slides will not be 
returned. 
For fresh tumor biopsies (guided by ultrasound or CT scan), acceptable methods include 
core biopsies for lung and liver lesions and bronchoscopic biopsies for lung lesions.  The 
minimum size for the biopsy needle recommended is 20G. 
Central ALK testing to determine or confirm patient ALK status will be performed at a 
Sponsor designated central laboratory.  After completion of ALK testing for enrollment 
with a pre-specified ALK test by IHC (Appendix 8), patient samples will also be centrally 
tested by FISH Vysis® ALK Break Apart FISH Probe Kit (Abbott) for possible companion 
diagnostic development.  Additionally, other ALK assays may be used for testing patient 
samples to establish performance characteristics of these assays for diagnostic 


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development.  Testing may be performed on all screened patients (screen-failed and 
enrolled).  These additional testing data will have no impact on eligibility, and testing will 
be performed only after eligibility is established for each patient.  In addition, local ALK 
test information, baseline demographic, and disease-related characteristic data for all 
screened patients may be collected in order to support potential registration of a 
companion diagnostic assay for alectinib. 
Pre-treatment tumor samples may be used, after proper informed consent is obtained, 
for genomic sequencing. 
For sample handling procedures, storage conditions and shipment instructions, see the 
laboratory manual. 
4.5.8.3 
Pre- and Fresh Post-Treatment Tumor Biopsies (Optional) 
Pre-treatment tumor samples (preferably formalin-fixed blocks but if not available a 
minimum of 10-15 unstained 5 µm slides) for ALK testing is a mandatory requirement for 
this study.  Optional additional pre-treatment tumor samples and fresh post-treatment 
tumor biopsy at disease progression or withdrawal from treatment (at the last treatment 
or post-progression visit) may be collected, with proper informed consent.  These 
samples will be used to help to understand molecular mechanisms of resistance to ALK 
inhibitors by genomic sequencing.  Remaining tumor blocks will be returned to the sites, 
slides will not be returned. 
These specimens will be destroyed within 5 years after the date of final closure of the 
clinical database.  Other residual tissue material (slides, extracts, etc.) will be destroyed 
within 5 years after the date of final closure of the clinical database. 
On the basis of continuous analysis of the data in this study and other studies, or on the 
basis of data from literature, collection of optional tumor biopsies with exploratory 
purposes may be stopped at any time if the data from the samples collected do not 
produce useful information. 
4.5.8.4 
Blood and Plasma Samples (Mandatory) 
Mandatory plasma samples will be obtained to determine: 
• 
Mutations status in ALK and other escape genes (e.g., EGFR, KRAS).  It will require 
20 mL of blood to be collected at baseline, treatment Visit 3 (Week 16), and 
subsequently at every second treatment visit (every 16 weeks) (see Appendix 1 for 
detailed information) until disease progression and during post-progression on 
treatment in case of isolated, asymptomatic CNS progression.  For sample handling 
procedures, storage conditions and shipment instructions, see the laboratory 
manual.  These samples will not be taken in countries where regulatory agency or 
Institutional Review Board (IRB) does not allow genetic testing. 
 


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Mandatory blood samples will be obtained to determine: 
• 
ALK mutations assessment in circulating tumor cells.  It will require 12 mL of blood 
sample to be collected (2 tubes of 6 mL each) at baseline and at disease 
progression (at the last treatment or post-progression visit). It should match in time 
to tumor progression (CNS and/or systemic disease progression). 
• 
All patients who are randomized in alectinib arm will also participate in retrospective 
pharmacogenomic research to understand inter-individual variability of safety and 
pharmacokinetics of alectinib.  For this purpose, a 3-mL blood sample will be drawn 
at baseline (see Sections 4.5.8.4.1and 4.5.8.5). 
• 
Patients in the crizotinib arm who opt-in to optional genomics sequencing will 
provide a 3-mL blood sample.  This 3-mL blood sample will be used as a source of 
healthy tissue.  This sample is required for all patients in the crizotinib arm who wish 
to participate in the optional genomic sequencing (see Section 4.5.8.4.1). 
 
For biomarkers, a total of 35 mL of blood will be collected at baseline (20 mL for plasma 
purification and determination of mutation status in ALK and other escape genes, 12 mL 
for ALK fusion detection in circulating tumor cells, and 3 mL for pharmacogenomics 
research), 20 mL of blood (for plasma purification and determination of mutation status 
in ALK and other escape genes) will be collected at Visit 3 (Week 16) and subsequently 
at every second visit (every 16 weeks), and 32 mL will be collected at disease 
progression (CNS and/or systemic disease progression) (20 mL for plasma purification 
for determination of mutation status in ALK and other escape genes and 12 mL for ALK 
fusion detection in circulating tumor cells). 
Details of sample handling procedures, sample storage and shipment will be described 
in a separate laboratory manual. 
On the basis of continuous analysis of the data in this study and other studies, or on the 
basis of data from literature, collection of plasma and circulating tumor cell samples with 
exploratory purposes may be stopped at any time if they are deemed not informative. 
4.5.8.4.1 
Samples for Pharmacogenomic Assessments 
One sample (approximately 3 mL of whole blood) will be collected from all patients on 
alectinib treatment.  Samples will be used for the evaluation of genetic polymorphisms of 
drug metabolic enzymes including, but not limited to, CYP2C9, CYP3A4/5, and UGT1A1, 
and transporters (e.g., organic anion transporter polypeptide 1B1) and for genetic 
variants that could contribute to potentially drug-related liver safety assessments 
(including but not limited to human leukocyte antigen, see Appendix 9 for more details). 
For sample handling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Only in circumstances where there is concern for collection of this 
genetic material for above evaluations can this assessment be considered not 
mandatory as part of study assessments in this study.  Results of any analyses from 
these samples will be reported outside the clinical study report. 


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4.5.8.5 
Samples for Pharmacokinetic Assessments 
PK samples will be collected in all patients on alectinib treatment, as indicated in 
Appendix 1 and Appendix 2 for the analysis of alectinib and its major metabolite(s) 
(RO5468924, RO5507197, and/or others, if applicable and if appropriate, and if assays 
are available).  Residual samples following PK analysis may be used to evaluate 
profiling for alectinib metabolite(s). 
All trough/pre-dose PK samples should be collected within 2 hours BEFORE the 
morning doses of study medications.  
Serial/intensive samples will be collected in a subset of patients (10%–15% [at least 
n = 20] of patients receiving alectinib) on Visit 0 (baseline, after the first dose) and Visit 1 
(Week 4) at the timepoints specified in Appendix 2. 
Plasma concentrations for alectinib and its metabolite(s), if applicable, will be measured 
by specific and validated liquid chromatography tandem mass spectrometry methods. 
For each sample, approximately 2 mL of venous blood will be collected for alectinib PK 
analysis at the timepoints specified in the PK schedule in Appendix 1 and Appendix 2. 
Patients who permanently discontinue from study drugs will also discontinue from all PK 
assessments.  The procedures for the collection, handling, storage, and shipping of 
plasma samples for the PK analysis are specified in the Laboratory Manual.  Actual 
sampling times will be recorded for each PK sample in the eCRF.  
These samples will be destroyed when the final Clinical Study Report is complete. 
On the basis of continuous analysis of the data in this study and other studies, any 
sample type collection may be stopped at any time if the data from the samples collected 
do not produce useful information or at the discretion of the Sponsor. 
4.5.9 
Electrocardiograms 
An ECG will be recorded at specified timepoints as outlined in the schedule of 
assessments (Appendix 1) at screening, Visit 0 (baseline), Visit 1 (Week 4), Visit 4 
(Week 24), Visit 8 (Week 56), and at the last treatment visit and as clinically indicated 
throughout the study.  All ECG recordings must be performed using a standard high-
quality, high-fidelity digital electrocardiograph machine equipped with computer-based 
interval measurements.  All ECGs are to be obtained prior to other procedures 
scheduled at that same time (e.g., vital sign measurements, blood draws, study drug 
administration) and should not be obtained within 3 hours after any meal.  
Circumstances that may induce changes in heart rate, including environmental 
distractions (e.g., television, radio, conversation), should be avoided during the pre-ECG 
resting period and during ECG recording. 


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Patients must have been in a supine or semi-supine position for at least 5 minutes prior 
to the recording being taken.  The same recording position (supine or semi-supine) and 
the same equipment should be used for each patient throughout the study.  The ECG 
printout must be (1) reviewed by a medically qualified member of the study team at the 
site, (2) annotated to indicate any clinical finding, and (3) dated and signed by this 
person and filed in the patient notes.  ECG parameters will be entered on the ECG 
eCRF.  The following parameters should be captured on the eCRF: heart rate, RR, PQ, 
QRS and QT duration, and QT interval corrected using Fridericia’s formula. 
If any ECG abnormality is associated with an adverse event, it must be recorded and 
managed as described in Section 5.  Management of QT interval prolongation should be 
done according to guidance provided in Section 5.1.3.  
If considered appropriate by the Sponsor, ECGs may be analyzed retrospectively at a 
central laboratory.  Guidance for abnormal ECG results (QT prolongation) is provided in 
Table 2. 
4.5.10 
Patient-Reported Outcomes 
PROs (EORTC QLQ-C30, QLQ-L13, and EQ-5D) will be collected to more fully 
characterize the clinical profile of alectinib.  The instruments will be translated as 
required in the local language.  To ensure instrument validity and that data standards 
meet health authority requirements, the PROs scheduled for administration during a 
clinic visit (EORTC QLQ-C30, QLQ-L13, and EQ-5D) should be completed prior to the 
performance of non-PRO assessments and the administration of study treatment. 
Patients will use an ePRO device to capture PRO data.  The ePRO device and/or 
instructions for completing the PRO questionnaires electronically will be provided by the 
investigator staff.  The data will be transmitted via pre-specified transmission method 
(e.g., web or wireless) automatically after entry to a centralized database at the ePRO 
vendor.  The data can be accessed by appropriate study personnel securely via the 
Internet. 
4.5.11 
Samples for Roche Clinical Repository 
4.5.11.1 
Overview of the Roche Clinical Repository 
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future. 


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Specimens for the RCR will be collected from patients who give specific consent to 
participate in optional research.  RCR specimens will be used to achieve the following 
objectives: 
• 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.11.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's IRB or Ethics Committee (EC) and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval for RCR sampling, 
this section of the protocol (Section 4.5.11) will not be applicable at that site. 
4.5.11.3 
Sample Collection 
For RCR purposes, 10 mL of blood will be collected.  For all samples, dates of consent 
and specimen collection should be recorded on the associated RCR page of the eCRF.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
The dynamic biomarker specimens will be patient to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below. 
4.5.11.4 
Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 


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monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
4.5.11.5 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether the patient has given consent to participate 
by completing the RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research. 
4.5.11.6 
Withdrawal from the Roche Clinical Repository 
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 


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instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study BO28984 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study BO28984. 
4.5.11.7 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients who withdraw consent for treatment should continue to be 
followed for tumor assessments until progression and for OS, provided they have not 
withdrawn consent for the study.  However, patients will not be followed for any reason 
after consent for the study has been withdrawn.  Patients who withdraw from the study 
will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Pregnancy 
• 
Inability to tolerate study medication on the basis of the investigator judgment 
See guidelines for managing adverse events and for comprehensive guidance on study 
drug discontinuation in Section 5.1.3. 


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Patients who discontinue study drug prematurely will be asked to return to the clinic for 
tumor assessments until progression as per study schedule (see Appendix 1). 
The primary reason for premature study drug discontinuation should be documented on 
the appropriate eCRF.  Patients who discontinue study drug prematurely will not be 
replaced. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
5.1.1 
Adverse Events Collection 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events (SAEs) caused by a protocol-mandated intervention should be 
reported (e.g., SAEs related to invasive procedures such as biopsies).  After the first 
dose of study treatment and up to the 4-week follow-up after the last dose of study 
treatment, all adverse events (AEs) regardless of seriousness, causality assessment, or 
actions taken reported by the investigator or designated medically qualified study site 
personnel will be collected as described below.  At each visit, the investigator or 
designated medically qualified study personnel will ask the patient if any untoward 
medical event occurred since the last visit.  It is the investigator’s responsibility to record 
all AEs in the source patient’s medical records. 
All serious and non-SAEs will be reported on the standard AE/SAE eCRF. 


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5.1.2 
Adverse Events Relating to ALK Inhibitors and/or the Tyrosine 
Kinase Inhibitor Class and Alectinib Data 
Events described in Section 5.1.2.1 through Section 5.1.2.10 will be closely monitored 
and represent selected AEs for this study. 
A more detailed safety profile of alectinib is provided in the alectinib Investigator's 
Brochure. 
5.1.2.1 
Interstitial Lung Disease 
TKIs, including ALK inhibitor crizotinib, have been associated with the occurrence of 
treatment-related ILD (including fatalities). 
See Section 5.1.3 for management and follow-up. 
5.1.2.2 
Hepatobiliary Laboratory Test Elevations 
Hepatobiliary findings were observed in both the rat and monkey 4- and 13-week toxicity 
studies with alectinib, and findings in the 13-week studies were similar to those of the 
4-week studies.  The findings were at or close to clinically relevant exposures.  
Hepatobiliary effects included increased hepatic ALP, direct bilirubin, GGT and liver 
weight, vacuolation/degeneration/necrosis of bile duct epithelium, inflammatory cell 
infiltration in Glisson’s sheath, enlargement/focal necrosis of hepatocytes, and 
enlargement of Kupffer cells. 
Abnormal hepatobiliary laboratory test values, such as increased ALT, AST, or bilirubin 
levels, have been observed after alectinib administration.  AST, ALT, and total bilirubin 
levels temporarily increased in the initial stages of treatment and then improved.  
In patients treated with other tyrosine kinase ALK inhibitor drugs, abnormal liver function 
tests and fatal cases of hepatic failure have been reported. 
See Section 5.1.3 for management and follow-up. 
5.1.2.3 
Hematologic Abnormalities 
Hematologic findings were observed in both the rat and monkey 4- and 13-week toxicity 
studies with alectinib, and findings in the 13-week studies were similar to those of the 
4-week studies.  Findings were at or close to clinically relevant exposures.  Hematologic 
adverse effects such as anemia, thrombocytopenia, bleeding, and neutropenia have 
been observed with most TKIs, including ALK inhibitor crizotinib. 
Hematologic abnormalities of neutropenia, leukopenia, thrombocytopenia, and anemia 
have been reported with alectinib administration.  Neutrophil counts generally decreased 
early and remained stable thereafter. 
See Section 5.1.3 for management and follow-up. 


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5.1.2.4 
Gastrointestinal Disorders 
GI disorders such as nausea, vomiting, constipation, and diarrhea have been reported 
with alectinib.  Similar GI disorders have been observed with other TKIs, including ALK 
inhibitor crizotinib. 
SLS (syn. sodium dodecyl sulfate)) is a surfactant excipient in the clinical formulation at 
a concentration of 50% (w/w SLS to active pharmaceutical ingredient).  This excipient is 
a known GI irritant and may be associated with GI AEs including nausea, vomiting, 
diarrhea, and abdominal pain.  Of note, GI tract toxicity as the safety determinant of SLS 
is not because of systemic toxicity, but a consequence of local irritation to the GI tract.  
In general, when mixed with diet, higher levels of SLS⎯a known GI tract mucosal 
irritant⎯are tolerated versus gavage administrations. 
See Section 5.1.3 for management and follow-up. 
5.1.2.5 
Skin Disorders 
Results of an in vitro phototoxicity study indicated that alectinib may have phototoxic 
potential. 
Skin rash has been reported with majority of TKIs including those targeting the ALK 
receptor (Hartmann et al. 2009). 
Cases of skin rash and photosensitivity have been reported with alectinib and were 
generally Grade 1 or 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.6 
Vision Disorders 
In the rat quantitative whole body autoradiography study, tissue radioactivity 
disappeared over time, following a time course comparable to that of plasma 
radioactivity, except for melanin-containing tissues such as uveal tract of eyes, which 
had much higher and more sustained exposure in pigmented rats.  This is consistent 
with what is commonly observed for lipophilic basic drugs. 
Vision disorders, including diplopia, photopsia, blurred vision, visual impairment, and 
vitreous floaters, have been reported with several TKIs, including ALK inhibitors 
(crizotinib) (Shaw et al. 2013). 
Vision disorders, such as dry eye, blepharitis, conjunctivitis, blurred vision, and vision 
impaired, have been reported with alectinib and were generally Grades 1 and 2. 
See Section 5.1.3 for management and follow-up. 


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5.1.2.7 
Edema 
Most TKIs, including ALK inhibitor crizotinib, have been associated with edema.  Events 
of edema have been reported with alectinib, mostly Grade 1 or 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.8 
Cardiovascular Effects (QT Interval Prolongation) 
QT interval prolongation appears to be an off-target class effect of some TKIs, including 
ALK inhibitor crizotinib (Shah et al. 2013; XALKORI® U.S. Package Insert).  Many TKIs 
have been associated with bradycardia and hypertension. 
In the in vitro study of the cardiovascular system, alectinib inhibited the hERG current 
(IC20: 58 ng/mL; IC50: 217 ng/mL).  Because plasma protein binding by alectinib is ≥ 99%, 
the plasma concentration of alectinib required to induce the same inhibition in vivo would 
be 100 or more times greater than the concentration required in vitro.  In the monkey 
telemetry study, there were no effects on the ECG, any of the other cardiovascular 
parameters or body temperature at doses up to 15 mg/kg (mean maximum 
concentration [Cmax]: 279 ng/mL). 
In a preliminary non- Good Laboratory Practice telemetry study in conscious cynomolgus 
monkeys, a slight hypotensive effect (approximately 10 mmHg) was seen when alectinib 
was administered at 20 and 60 mg/kg orally with no effects on ECG or heart rate.  The 
hypotensive effect of alectinib observed in monkeys was considered to likely be caused 
by vasodilatation induced by L-type Ca2+ channel inhibition. 
Events of bradycardia have been reported with alectinib. 
See Section 5.1.3 for management and follow-up. 
5.1.2.9 
Abnormal Renal Function 
In the 2-week non-human primate study at 60 mg/kg, an increase in creatinine was 
observed but no changes were observed in histopathology.  In all other non-human 
primate studies, no changes in creatinine were observed. 
Serum creatinine increases have been reported with alectinib treatment and were 
generally Grades 1 and 2. 
See Section 5.1.3 for management and follow-up. 
5.1.2.10 
Muscular Adverse Events and CPK Elevations 
Postmarketing experience with some TKIs includes reports of myopathy and 
rhabdomyolysis (Hohenegger 2012). 
Blood CPK increases, generally Grades 1 and 2, and muscular AEs have been reported 
with alectinib treatment. 


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See Section 5.1.3 for management and follow-up and Table 2  for guidelines for 
managing AEs. 
5.1.3 
Management of Specific Adverse Events with Alectinib 
Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib 
Event 
Action to Be Taken 
Interstitial lung disease 
• 
Patients should be monitored for pulmonary symptoms 
indicative of pneumonitis.  
• 
Study drug should be permanently discontinued in patients 
diagnosed with interstitial lung disease. 
Hepatobiliary AE and 
laboratory test elevations 
 
Liver test laboratory abnormalities are to be reported as AEs only if 
fulfilling the criteria listed in Section 5.3.5.4 and Section 5.3.5.6. 
• 
If ALT or AST  > 3 × baseline, repeat testing of ALT, AST, ALP, 
and total bilirubin within 48–72 hours, with inquiry about 
symptoms. 
• 
At any time during the study treatment, if symptoms compatible 
with liver injury are observed, liver enzymes should be 
measured as soon as possible.  
• 
Study drug treatment has to be permanently discontinued if 
any of the following occurs: 
First observation of ALT or AST  > 8 × ULN 
ALT or AST > 5 × ULN for more than 2 weeks 
First observation of ALT or AST > 3 × ULN and total 
bilirubin > 2 × ULN  
First observation of ALT or AST > 3 × ULN and the 
appearance of jaundice or signs of hepatic dysfunction or 
other symptoms (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or 
eosinophilia [> 5%]). 
• 
Following study drug discontinuation, weekly monitoring of 
laboratory values should continue until the abnormal values 
have normalized to pre-treatment levels and/or an adequate 
explanation of the abnormal value is found. 
• 
Resumption of study drug is not allowed in patients 
discontinuing because of any of the above criteria. 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
Hematologic abnormalities Hematologic laboratory abnormalities are to be reported as AEs 
only if fulfilling the criteria listed in Section 5.3.5.4. 
• 
In case of hematologic toxicity:  Grade 4 (neutropenia, 
thrombocytopenia):  
Give supportive treatment per treating physician. 
First episode:  Temporarily interrupt alectinib until ANC is 
above 1200/µL and platelets are above 75 K/µL.  Upon 
resumption, reduce alectinib dose by 150 mg (1 capsule) 
BID (450 mg BID). 
Second episode:  Reduce dose by another 150 mg 
(1 capsule) BID (300 mg BID).  
Third episode:  Permanently discontinue alectinib. 
• 
In case of hematologic toxicity:  Grade 3 (neutropenia, 
thrombocytopenia):  
Temporarily interrupt alectinib until ANC is above 1200/µL 
and platelets are above 75 K/µL. 
Give supportive treatment per treating physician. 
If improvement to Grade ≤ 2 does not occur within 
3 weeks, permanently discontinue alectinib. 
• 
In case of hematologic toxicity:  Grade 1 or 2 (neutropenia, 
thrombocytopenia) no action is required. 
Gastrointestinal tract AEs 
(e.g., nausea, vomiting, 
diarrhea) 
The events are expected to be minimized by taking the study drug 
with meal.  In case GI events occur, appropriate measures should 
be taken in accordance with local clinical practice guidelines.  If GI 
toxicities are observed and not tolerable, treatment with study drug 
should be temporarily interrupted until recovery to Grade 1 or lower.
Skin disorder AEs 
(e.g., phototoxicity, rash) 
Patients should be advised to avoid prolonged sun exposure while 
taking alectinib and for at least 5 days after study drug 
discontinuation.  Patients should also be advised to use a 
broad-spectrum sun screen and lip balm of at least SPF > 30 to help 
protect against potential sunburn 
Vision disorders 
Investigators should consider referring the patients for an 
ophthalmological evaluation according to local clinical practice 
guidelines, if vision disorders persist or worsen in severity, and to 
advise patients to exercise caution when driving or operating 
machinery due to the risk of developing a vision disorder. 
Edema 
Physical examinations will be performed routinely in clinical trials.  
In case edema events occur, appropriate measures should be taken 
in accordance with local clinical practice guidelines 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
QT prolongation 
• 
Grade 1 (450–480 ms):  no action required 
• 
Grade 2 (481–500 ms): 
First and second episodes:  Continue study medication 
and monitoring 
Third episode:  Decrease the current dose of alectinib by 
150 mg (1 capsule) BID (450 mg BID) 
• 
Grade 3 ( ≥ 501 ms on at least two separate ECGs): 
Temporarily interrupt alectinib and refer patient to a 
cardiologist 
First episode:  If improvement to Grade ≤ 1 or baseline, 
restart with a dose of alectinib decreased by 150 mg 
(1 capsule) BID (450 mg BID) 
Second episode:  If improvement to Grade ≤ 1 or baseline, 
restart with a dose of alectinib decreased by 150 mg 
(1 capsule) BID (300 mg BID) 
Third episode:  Permanently discontinue alectinib 
• 
Grade 4 (≥ 501 ms or > 60 ms change from baseline and 
Torsade de pointes or polymorphic ventricular tachycardia or 
signs/symptoms of serious arrhythmia): 
Discontinue alectinib permanently and admit patient into 
the hospital for monitoring 
Abnormal kidney function 
AEs 
Kidney function laboratory abnormalities are to be reported as AEs 
only if fulfilling the criteria listed in Section 5.3.5.4. 
• 
If, at any time during the study treatment, serum creatinine 
increases by ≥ 100% over the baseline visit value, the patient 
has to be carefully monitored.  All of the underlying factors that 
may have acutely impacted serum creatinine levels need to be 
evaluated and corrected (e.g., dehydration, recent exposure to 
contrast media, increased amount of cooked meat in diet, 
concomitant medications affecting renal function as 
appropriate, etc.). 
• 
Any serum creatinine value that is increased by  ≥ 100% over 
the baseline visit value requires repeat testing. 
If, at the repeat test, the serum creatinine value is still 
≥ 100% over the baseline visit value, the treatment with 
alectinib should be interrupted. 
• 
Alectinib treatment may be resumed with caution if the serum 
creatinine value has decreased to approximately the baseline 
visit value. 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
Muscular AEs and/or CPK 
elevations 
CPK laboratory abnormalities are to be reported as AEs only if 
fulfilling the criteria listed in Section 5.3.5.4. 
• 
Myopathy should be considered in any patient with diffuse 
myalgia, muscle tenderness or weakness, and/or marked 
elevations of CPK levels.  Patients should promptly report 
unexplained muscle pain, tenderness, or weakness, 
particularly if accompanied by malaise or fever.  CPK levels 
should be assessed in patients reporting these symptoms. 
• 
At the first occurrence of any of asymptomatic CPK values 
(> 10 × ULN, symptomatic CPK  > 5 × ULN, or in the presence of 
severe muscular symptoms with CPK > ULN but  ≤ 5 × ULN) at 
any time during the study treatment, the patient requires 
monitoring of the CPK values until they are normalized to 
pre-treatment levels or a reasonable explanation for the CPK 
elevation and the symptoms is established. 


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Table 2 
Guidelines for Management of Specific Adverse Events with 
Alectinib (cont.)  
Event 
Action to Be Taken 
Other AEs or laboratory 
abnormalities: 
• 
Grade 3 or 4: 
Temporarily interrupt alectinib for a maximum of 3 weeks. 
If improvement to Grade ≤ 1 or baseline does not occur 
within 3 weeks, permanently discontinue alectinib. 
First episode:  If improvement to Grade ≤ 1 or baseline 
within 21 days, decrease the current dose of alectinib by 
150 mg (1 capsule) BID (450 mg BID).  
Second episode:  If improvement to Grade ≤ 1 or baseline 
within 21 days, decrease the current dose of alectinib by 
another 150 mg (1 capsule) BID (300 mg BID). 
Third episode:  Permanently discontinue alectinib. 
• 
Grade 2 (except any symptoms and signs that can be 
corrected with supportive care): 
Temporarily interrupt alectinib and resume if recovering to 
Grade ≤ 1 or baseline if clinically indicated. 
First episode:  If improvement to Grade ≤ 1 or baseline 
within 10 days, continue same dose of alectinib.  If 
improvement occurs after 10 days, decrease the current 
dose of alectinib by 150 mg (1 capsule) BID when 
resuming treatment (450 mg BID). 
Second episode:  If improvement to Grade ≤ 1 or baseline 
within 10 days, decrease the current dose of alectinib by 
150 mg (1 capsule) BID (450 mg BID or 300 mg BID if 
after first episode dose was reduced to 450 mg BID).  If 
improvement occurs after 10 days, decrease the current 
dose of alectinib by 300 mg (2 capsules) when resuming 
treatment (300 mg BID or 150 mg BID if after first episode 
dose was reduced to 450 mg BID). 
Third episode:  Permanently discontinue alectinib. 
• 
Grade 1:  no action required 
ANC = absolute neutrophil count.  
Note:  Diarrhea, nausea, and vomiting should be handled with best supportive care first before 
considering dose modification.  Preexisting pleural effusion will not be considered as an adverse 
event. 
 
5.1.4 
Safety of Crizotinib and Management of Adverse Events  
Dosing interruption and/or dose reduction may be required on the basis of individual 
safety and tolerability.  If dose reduction is necessary, then the dose of crizotinib should 
be reduced to 200 mg taken BID.  If further dose reduction is necessary, then the dose 
should be modified to 250 mg taken once daily on the basis of individual safety and 
tolerability (XALKORI® U.S. Package Insert; Crizotinib SmPC).  Dose reduction 
guidelines for hematologic and non-hematologic toxicities are provided in Table 3 and 
Table 4. 


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Table 3 
Crizotinib Dose Modification⎯Hematologic Toxicities (Except 
Lymphopenia) 
CTCAEa Grade 
Crizotinib Treatment 
Grade 3 
Withhold until recovery to Grade ≤ 2, then resume at 
the same dose schedule 
Grade 4 
Withhold until recovery to Grade ≤ 2, then resume at 
200 mg twice dailyb 
a National Cancer Institute Common Terminology Criteria for Adverse Events 
b In case of second episode, dosing should be withheld until recovery to Grade ≤ 2, then dosing 
should be resumed at 250 mg once daily.  Crizotinib must be permanently discontinued in case 
of a third episode of Grade 4 hematologic toxicity. 
 
Table 4 
Crizotinib Dose Modification⎯Non-Hematologic Toxicities 
CTCAEa Grade 
Crizotinib Treatment 
Grade 3 or 4 ALT)or AST elevation with 
Grade ≤ 1 total bilirubin 
Withhold until recovery to Grade ≤ 1 or 
baseline, then resume at 200 mg BIDb 
Grade 2, 3, or 4 ALT or AST elevation with 
concurrent Grade 2, 3, or 4 total bilirubin 
elevation (in the absence of cholestasis or 
hemolysis) 
Permanently discontinue 
Any grade pneumonitisc 
Permanently discontinue 
Grade 3 QTc prolongation 
Withhold until recovery to Grade ≤ 1, then 
resume at 200 mg BIDb 
Grade 4 QTc prolongation 
Permanently discontinue 
Grade 2 bradycardia (symptomatic, medical 
intervention indicated)  
Grade 3 bradycardia (severe, medically 
significant, medical intervention indicated)  
Withhold until recovery to Grade ≤1, evaluate 
concomitant medications, then resume at 
200 mg BID 
Grade 4 bradycardia due to crizotinib 
(life-threatening consequences, urgent 
intervention indicated)  
Permanently discontinue.  
Grade 4 bradycardia associated with 
concomitant medications known to cause 
bradycardia or hypotension (life-threatening 
consequences, urgent intervention indicated)  
Withhold until recovery to Grade ≤1 and, if 
concomitant medications can be discontinued, 
resume at 250 mg once daily with frequent 
monitoring.  
a National Cancer Institute Common Terminology Criteria for Adverse Events. 
b In case of second episode, dosing should be withheld until recovery to Grade ≤ 1, then dosing 
should be resumed at 250 mg once daily.  Crizotinib must be permanently discontinued in case 
of third episode of Grade 3 or 4 non-hematologic toxicity. 
c Not attributable to NSCLC progression, other pulmonary disease, infection, or radiation effect.  
Crizotinib should be withheld if pneumonitis is suspected and must be permanently 
discontinued if treatment-related pneumonitis is diagnosed. 
 


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Gastrointestinal events were commonly reported with crizotinib in clinical trials.  Nausea, 
diarrhea, vomiting, and constipation were the most commonly reported gastrointestinal 
events and were primarily Grade 1 in severity.  Supportive care for gastrointestinal 
events may include standard antiemetic and/or antidiarrheal or laxative medicinal 
products (XALKORI® U.S. Package Insert; Crizotinib SmPC). 
See local prescribing information for further crizotinib safety information. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
non-SAEs of special interest; measurement of protocol-specified safety laboratory 
assessments; measurement of protocol-specified vital signs; and other protocol-
specified tests that are deemed critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical occurrence in a clinical investigation patient administered a pharmaceutical 
product, regardless of causal attribution.  An AE can therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition). 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as 
biopsies) 
 


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5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
An SAE is any AE that meets any of the following criteria: 
• 
Fatal (i.e., the AE actually causes or leads to death) 
• 
Life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death) 
This does not include any AE that had it occurred in a more severe form or was 
allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.9) 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an AE (e.g., rated as mild, moderate, or severe, or according to National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] criteria; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF. 
SAEs are required to be reported by the investigator to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2 for reporting 
instructions). 
5.2.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-SAEs of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  AEs of special interest for this study are the 
following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.6) 


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• 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings indicating an infection 
in a patient exposed to a medicinal product.  This term applies only when a 
contamination of the study drug is suspected. 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs (see Section 5.2.1 for definition) 
are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Sections 5.4−5.6.  For each AE recorded 
on the Adverse Event eCRF, the investigator will make an assessment of seriousness 
(see Section 5.2.2 for seriousness criteria), severity (see Section 5.3.3), and causality 
(see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on AEs at each patient contact.  All AEs, whether 
reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
SAEs caused by a protocol-mandated intervention (e.g., invasive procedures such as 
biopsies, discontinuation of medications) should be reported (see Section 5.4.2 for 
instructions for reporting SAEs). 
After initiation of study drug, all AEs, regardless of relationship to study drug, will be 
reported until 4 weeks after the last dose of study drug.  After this period, the investigator 
is not required to actively monitor patients for AEs; however, the Sponsor should be 
notified if the investigator becomes aware of any post-study SAEs or non-SAEs of 
special interest (see Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient evaluation timepoints.  Examples of non-directive questions 
include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 


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5.3.3 
Assessment of Severity of Adverse Events 
The AE severity grading scale for the NCI CTCAE (v4.0) will be used for assessing AE 
severity.  Table 5 will be used for assessing severity for AEs that are not specifically 
listed in the NCI CTCAE. 
Table 5 
Adverse Event Severity Grading Scale 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  On the basis of the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
AE is considered to be related to the study drug, indicating "yes" or "no" accordingly.  
The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 


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• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs on 
the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 
5.3.5.1 
Diagnosis Versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported AEs based on 
signs and symptoms should be nullified and replaced by one AE report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events that are Secondary to Other Events 
In general, AEs that are secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events.  A medically significant secondary AE that is separated in 
time from the initiating event should be recorded as an independent event on the 
Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation timepoints.  The initial severity (intensity) of the event will be recorded at the 


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time the event is first reported.  If a persistent AE becomes more severe, the most 
extreme intensity should also be recorded on the Adverse Event eCRF.  If the event 
becomes serious, it should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning that the event became serious; see Section 5.4.2 for reporting 
instructions).  The Adverse Event eCRF should be updated by changing the event from 
"non-serious" to "serious," providing the date that the event became serious, and 
completing all data fields related to SAEs. 
A recurrent AE is one that resolves between patient evaluation timepoints and 
subsequently recurs.  Each recurrence of an AE should be recorded as a separate event 
on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE.  A laboratory test result must be 
reported as an AE if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment  
Note: For oncology trials, certain abnormal values may not qualify as AEs. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5 times the ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the AE.  For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 


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5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported 
as an AE if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment 
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an AE the occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as an SAE or a non-SAE of special interest (see Section 5.4.2). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified AE reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of NSCLC should be recorded only on the Study 
Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and 


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immediately reported to the Sponsor (see Section 5.4.2).  An independent monitoring 
committee will monitor the frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. 
During survival follow-up, deaths attributed to progression of NSCLC should be recorded 
only on the Survival eCRF. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such 
events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., "more 
frequent headaches"). 
5.3.5.9 
Lack of Efficacy or Worsening of Non-Small Cell Lung Cancer 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs.  These data will be captured as 
efficacy assessment data only.  In most cases, the expected pattern of progression will 
be based on RECIST criteria v1.1 (Appendix 4).  In rare cases, the determination of 
clinical progression will be based on symptomatic deterioration.  However, every effort 
should be made to document progression using objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an AE. 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization (i.e., in-patient admission to a hospital) or 
prolonged hospitalization should be documented and reported as an SAE (per the 
definition of SAE in Section 5.2.2), except as outlined below. 


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The following hospitalization scenarios are not considered to be AEs: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an AE 
• 
Hospitalization due solely to progression of the underlying cancer 
 
5.3.5.11 
Adverse Events Associated with an Overdose 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an AE, but it may result in an AE.  All AEs associated with an overdose or incorrect 
administration of study drug should be recorded on the Adverse Event eCRF.  If the 
associated AE fulfills serious criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.3.5.12 
Patient-Reported Outcome Data 
AE reports will not be derived from PRO data by the Sponsor, and safety analyses will 
not be performed using PRO data.  However, if any PRO responses suggestive of a 
possible AE are identified during site review of the PRO data, the investigator will 
determine whether the criteria for an AE have been met and, if so, will report the event 
on the Adverse Event eCRF. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
SAEs 
• 
Non-SAEs of special interest 
• 
Pregnancies 
 


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The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting SAEs to the local 
health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor (Roche Medical Responsible) Contact Information 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk and 
Medical Monitor contact information will be distributed to all investigators (see "Protocol 
Administrative and Contact Information & List of Investigators Form "). 
This list can be generated using contact numbers found at the following link: 
http://gcpcenter.roche.com/synergy/portal/view/pdq-spi/gcpcenter/34-64711453. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
5.4.2.1 
Events That Occur Prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported.  A paper Serious 
Adverse Event Reporting Form and fax cover sheet should be completed and faxed to 
Roche Safety Risk Management or its designee immediately (i.e., no more than 24 
hours after learning of the event), using the fax numbers provided to investigators (see 
"Protocol Administrative and Contact Information & List of Investigators"). 
5.4.2.2 
Events That Occur After Study Drug Initiation 
After initiation of study drug, SAEs and non-SAEs of special interest will be reported until 
4 weeks after the last dose of study drug.  Investigators should record all case details 
that can be gathered immediately (i.e., within 24 hours after learning of the event) on the 
Adverse Event eCRF and submit the report via the electronic data capture (EDC) system.  
A report will be generated and sent to Roche Safety Risk Management by the EDC 
system. 


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In the event that the EDC system is unavailable, a paper Serious Adverse Event 
Reporting Form and fax cover sheet should be completed and faxed to Roche Safety 
Risk Management or its designee immediately (i.e., no more than 24 hours after learning 
of the event), using the fax numbers provided to investigators (see "Protocol 
Administrative and Contact Information & List of Investigators").  Once the EDC system 
is available, all information will need to be entered and submitted via the EDC system. 
Instructions for reporting post-study AEs are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 3 months after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Roche Safety Risk Management.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any SAEs associated 
with the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF. 
In the event that the EDC system is unavailable, a paper Clinical Trial Pregnancy 
Reporting Form and fax cover sheet should be completed and faxed to Roche Safety 
Risk Management or its designee immediately (i.e., no more than 24 hours after learning 
of the pregnancy), using the fax numbers provided to investigators (see "Protocol 
Administrative and Contact Information & List of Investigators").  Once the EDC system 
is available, all information will need to be entered and submitted via the EDC system. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
3 months after the last dose of study drug.  A Pregnancy Report eCRF should be 
completed by the investigator immediately (i.e., no more than 24 hours after learning of 
the pregnancy) and submitted via the EDC system.  Attempts should be made to collect 
and report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  The pregnant partner will need to sign an Authorization 
for Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy.  Once the authorization has been signed, the investigator will update the 
Pregnancy Report eCRF with additional information on the course and outcome of the 
pregnancy.  An investigator who is contacted by the male patient or his pregnant partner 
may provide information on the risks of the pregnancy and the possible effects on the 


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fetus, to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 
5.4.3.3 
Abortions 
Any abortion should be classified as an SAE (as the Sponsor considers abortions to be 
medically significant), recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as an SAE, recorded on the Adverse Event eCRF, and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or 
the patient withdraws consent.  Every effort should be made to follow all SAEs considered 
to be related to study drug or trial-related procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.5.2 
Sponsor Follow-Up 
For SAEs, non-SAEs of special interest, and pregnancies, the Sponsor or a designee 
may follow up by telephone, fax, electronic mail, and/or a monitoring visit to obtain 
additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 


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5.6 
POST-STUDY ADVERSE EVENTS 
At the time of study completion or study discontinuation, the investigator should instruct 
each patient to report to the investigator any subsequent AEs that the patient’s personal 
physician believes could be related to prior study drug treatment or study procedures. 
The investigator is not required to actively monitor patients for AEs after the end of the 
AE reporting period (defined as 4 weeks after the last dose of study drug).  However, the 
Sponsor should be notified if the investigator becomes aware of any death, other SAE, 
or non-SAE of special interest occurring after the end of the AE reporting period, 
regardless of causality.  The Sponsor should also be notified if the investigator becomes 
aware of the development of cancer or a congenital anomaly/birth defect in a 
subsequently conceived offspring of a female patient exposed to study drug or the 
female partner of a male patient exposed to study drug. 
The investigator should report these events directly to Roche Safety Risk Management 
via telephone or via fax machine using the Serious Adverse Event Reporting Form and 
fax cover sheet (see "Protocol Administrative and Contact Information & List of 
Investigators"). 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all SAEs and non-SAEs of special interest against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators, IRBs, ECs, and applicable health authorities based on 
applicable legislation. 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference documents: 
• 
Alectinib Investigator's Brochure 
• 
Local prescribing information for crizotinib 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The primary analysis population for efficacy is the intent-to-treat (ITT) population defined 
as all randomized patients.  Patients will be assigned to the treatment group to which 
they were randomized. 


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The primary analysis population for safety is the Safety Analysis Population (SAP) 
defined as all patients who received at least one dose of study medication.  Patients will 
be assigned to treatment groups as treated, and all patients who received any dose of 
alectinib will be included in the alectinib treatment arm. 
A secondary analysis population for efficacy and safety is the FISH Positive Population 
(FPP).  For efficacy, this is defined as all patients in the ITT population who were 
ALK-positive using the FISH assay.  Patients will be assigned to the treatment group to 
which they were randomized.  For safety, this is defined as all patients in the SAP who 
were ALK-positive using the FISH assay.  Patients will be assigned to treatment groups 
as treated.  This analysis population will be used to perform a supportive analysis of the 
study data based on the FISH assay rather than the IHC.  This population may be used 
for registration purposes in the unlikely event of registrational failure of the IHC 
companion diagnostic, in which case all analyses will be based on this population and 
the same prespecified testing strategy of secondary endpoints defined in Section 6.4.2 
will be applied. 
The final analysis of the primary endpoint of PFS will occur when 169 PFS events have 
occurred, on the basis of the investigators’ assessments.  On the basis of the 
assumptions outlined in Section 6.1, this is estimated to occur approximately 31 months 
after the first patient has been enrolled.  A survival follow-up analysis will be performed 
once approximately 50% of patients (i.e., 143 patients) have died, which is estimated to 
occur approximately 42 months after the first patient has been enrolled. 
Hypothesis tests will be two-sided unless otherwise indicated. 
The baseline value of any variable will be defined as the last available value recorded 
prior to the first administration of alectinib or crizotinib. 
Further details of all analyses will be provided in the Statistical Analysis Plan. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The focus of this clinical trial is hypothesis testing (Section 6.4.1), and the primary 
endpoint of PFS was used to determine the sample size of the study. 
At the time of writing the protocol, there are no Phase III data on crizotinib in the first-line 
setting in ALK-positive patients.  The median PFS for crizotinib administered as 
second-line therapy from the global randomized Phase III PROFILE 1007 study was 
7.7 months (95% CI: 6.0%, 8.8%).  From the Phase II single arm study of patients who 
had received ≥ 1 line of chemotherapy (with 85% patients having received ≥ 2 prior 
chemotherapy regimens), the median PFS was 8.5 months (95% CI: 6.2%, 9.9%). 


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A median PFS of 9.8 months for the crizotinib arm has been assumed.  An HR of 0.65 
for alectinib versus crizotinib (i.e., an increase from 9.8 months median PFS to 15.1 
months) will be targeted. 
In this study, 286 patients will be enrolled in a 1:1 randomization allocation.  Enrollment 
will take approximately 25 months on the basis of an assumption of non-linear 
recruitment as follows: 
• 
Month 1:  1 patients per month 
• 
Month 2:  2 patients per month 
• 
Month 3:  4 patients per month 
• 
Month 4:  6 patients per month 
• 
Month 5:  8 patients per month 
• 
Month 6:  10 patients per month 
• 
Month 7:  12 patients per month 
• 
Months 8−12:  13 patients per month 
• 
Months 13−14:  14 patients per month 
• 
Month 15 onwards:  15 patients per month 
A total of 169 PFS events are required to achieve 80% power at a two-sided alpha level 
of 5%.  This level of enrollment is estimated to occur approximately 31 months after the 
first patient has been enrolled. 
No interim analysis for efficacy or futility is planned. 
A survival follow-up analysis will be performed once approximately 50% of patients 
(i.e., 143 patients) have died.  The median OS in the crizotinib arm is assumed to be 
25 months, and the expected median OS in the alectinib treatment arm is 30 months, 
equating to an HR of 0.83.  On the basis of the sample size (N = 286), the trial will not be 
powered to demonstrate any statistically significant difference in OS of this magnitude.  
At the time of the final analysis of the primary endpoint of PFS, on the basis of the above 
assumptions, 94 OS events are expected to have occurred.  The survival follow-up 
analysis is expected to occur approximately 42 months after the first patient has been 
enrolled. 
A follow-up analysis will be performed based on the FPP.  This will occur once 169 PFS 
events have occurred in the FPP to ensure 80% power of the log-rank test assuming a 
hazard ratio of 0.65 in this sub-population.  Based on a potential discrepancy/technical 
failure rate of 10% between the IHC assay and the FISH assay, 257 patients would be 
eligible for the FPP analysis, which is estimated to occur approximately 33 months after 
the first patient has been enrolled (i.e., 2 months after the primary IHC analysis) based 
on the above assumptions. 


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6.2 
SUMMARIES OF CONDUCT OF STUDY 
Study enrollment, study treatment administration, reasons for discontinuation from study 
treatment, and reasons for study termination will be summarized by treatment arm for all 
randomized patients.  Violations of inclusion and exclusion criteria, on the basis of 
information captured on the eCRF, will be reported and summarized by treatment arm. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Summaries of treatment group comparability will be based on the ITT population. 
Demographic, baseline disease characteristics and lung cancer history will be 
summarized by treatment arm for all randomized patients, including the randomization 
stratification factors.  Descriptive baseline summaries of continuous data will present the 
group mean, standard deviation, median, minimum, and maximum.  Descriptive 
summaries of discrete data will present the category counts as frequency and 
percentages. 
Previous and concomitant cancer therapy will also be summarized, as well as 
anti-cancer subsequent therapy.  Previous and concurrent diseases and medications will 
also be summarized. 
6.4 
EFFICACY ANALYSES 
The primary population for all primary and secondary efficacy analyses will be the ITT 
population. 
6.4.1 
Primary Efficacy Endpoint 
PFS is defined as the time from date of randomization to the date of first documented 
disease progression or death, whichever occurs first.  The primary endpoint of PFS will 
be determined on the basis of investigator assessment of progression using 
RECIST v1.1.  Patients who have not experienced disease progression or death at the 
time of analysis will be censored at the last tumor assessment date either during study 
treatment or during follow-up.  Patients with no post-baseline tumor assessment will be 
censored at the date of randomization. 
Patients who discontinue treatment prior to disease progression (e.g., due to toxicity) will 
continue on study and will be followed until disease progression and for OS regardless 
of whether they subsequently receive anti-cancer therapy. 
The treatment comparison of PFS will be based on a stratified log-rank test at the 5% 
level of significance (two-sided).  The stratification factors are the randomization 
stratification factors:  ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS 
metastases at baseline (yes vs. no), as recorded on the eCRF.  Results from an 
unstratified log-rank test will also be presented. 


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The Kaplan-Meier method will be used to estimate the median PFS for each treatment 
arm with 95% confidence limits, and a Kaplan-Meier curve will be constructed to provide 
a visual description of the difference between the treatment arms.  A stratified Cox 
proportional regression model will be used including treatment in order to provide an 
estimate of the treatment effect expressed as an HR (alectinib vs. crizotinib), as well as 
a 95% CI. 
The difference between the two treatment groups will be assessed and tested for the 
following hypothesis:  the survival distribution function (SDF) of the alectinib treatment 
group is the same as for the crizotinib treatment group versus the alternative that the two 
distributions are different:  
H0:  SDF (alectinib) = SDF (crizotinib) 
versus 
H1:  SDF (alectinib) ≠ SDF (crizotinib) 
where SDF denotes the survival distribution function of the parameter PFS. 
6.4.2 
Secondary Efficacy Endpoints 
If the primary endpoint of PFS is statistically significant at a two-sided 5% significance 
level, the following secondary endpoints will be tested in the following sequential order, 
each at a two-sided 5% significance level: 
• 
PFS by IRC 
• 
Time to CNS progression 
• 
ORR 
• 
OS 
 
PFS by IRC 
An analysis of PFS on the basis of the IRC assessments will be performed using the 
same methodology as specified for PFS on the basis of investigator assessment. 
Time to CNS Progression 
Time to CNS progression is defined as the time from randomization until radiographic 
evidence of CNS progression.  An independent central radiological review will be 
performed for all patients, and the analysis of CNS progression or response will be on 
the basis of the data from the independent review.  All patients will be included in the 
analysis regardless of their baseline status of CNS metastases.  CNS progression is 
defined as progression due to newly developed CNS lesions and/or progression of 
preexisting baseline CNS lesions.  On the basis of RECIST v1.1, this is defined as a new 
post-baseline CNS/brain lesion(s) and/or an increase of ≥ 20% in the sum of longest 
diameters of the measurable baseline CNS lesions compared to nadir and/or 
unequivocal progression of non-measurable baseline CNS lesions. 


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In order to account for the competing risks inherent in such an analysis, HRs, including 
statistical inference on the basis of a two-sided log-rank test, to compare the risk of CNS 
progression between the alectinib and crizotinib treatment groups, will be computed on 
the basis of cause-specific hazard functions. 
The probability of CNS progression, non-CNS progression, and death will each be 
estimated using cumulative incidence functions. 
For descriptive purposes, estimates of the CNS progression rates over time with 
95% CIs on the basis of cumulative incidence functions will be presented.  A Gray’s test 
to compare the risk of CNS progression between alectinib and crizotinib will also be 
performed as a supportive analysis. 
An exploratory analysis of CNS Time to Progression on the basis of RANO criteria will 
also be performed on the basis of the IRC assessments. 
In the subgroup of patients with measurable CNS lesions at baseline, an exploratory 
analysis of C-ORR defined as the percentage of patients who achieve a best overall 
response of CR or PR (defined by RECIST v1.1 as a 30% decrease in the sum of 
longest diameters of measurable CNS lesions referencing baseline) will also be 
performed.  Duration of CNS response will be listed and may be analyzed if there are a 
sufficient number of CNS responses.  An exploratory analysis of these endpoints will 
also be performed on the basis of RANO criteria assessed by the IRC. 
Objective Response Rate 
ORR, on the basis of investigator assessment, is defined as the percentage of patients 
who attain a CR or PR.  Per RECIST v1.1, confirmation of objective response is not 
required for this secondary endpoint.  Patients without a post-baseline tumor 
assessment will be considered non-responders, as will patients with a best overall 
response of stable disease (SD), PD, or NE (not evaluable). 
An estimate of ORR and its two-sided 95% CI will be calculated using the 
Clopper-Pearson method for each treatment arm.  Response rates in the treatment 
groups will be compared using a stratified Mantel-Haenszel test on the basis of the 
randomization stratification factors.  The difference in ORR between the two treatment 
arms will be presented together with a two-sided 95% CI on the basis of a normal 
approximation to the binomial distribution. 
DOR 
For patients who have experienced an objective response (CR or PR) during the study 
as assessed by the investigator, DOR is defined as the duration from the first tumor 
assessment that supports the patient’s objective response (CR or PR, whichever is first 
recorded) to first documented disease progression or death due to any causes, 
whichever occurred first.  Patients who have not progressed or died at the time of 


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analysis will be censored at the last tumor assessment date.  Because the determination 
of DOR is based on a non-randomized subset of patients, formal hypothesis testing will 
not be performed.  DOR will be estimated using Kaplan-Meier methodology and a HR on 
the basis of a Cox proportional regression model will be calculated. 
Overall Survival 
OS is defined as the time from the date of randomization to the date of death due to any 
cause.  Patients who are not reported as having died at the time of analysis will be 
censored at the date when they were last known to be alive.  Patients who do not have 
post-baseline information will be censored at the date of randomization.  OS will be 
analyzed using the same methodology as specified for the primary endpoint.  A survival 
follow-up will be performed based on more mature data. 
6.4.2.1 
Sensitivity Analyses 
The following sensitivity analyses will be performed on the primary endpoint of PFS: 
• 
The effect of non−protocol-specified anti-cancer therapy prior to progression will be 
assessed by censoring patients at the last adequate tumor assessment prior to the 
start of non−protocol-specified anti-cancer therapy. 
• 
The effect of missing tumor assessments will be assessed if the number of missing 
assessments in either arm is > 5%.  For patients with progression determined 
following one or more missing tumor assessments, the progression will be 
backdated to the first missing tumor assessment. 
• 
The effect of loss to follow-up will be assessed depending on the number of patients 
who are lost to follow-up.  If > 5% of patients are lost to follow-up for PFS in either 
treatment arm, a “worst-case” analysis will be performed in which patients who are 
lost to follow-up will be considered to have progressed at the last date they were 
known to be progression-free. 
 
6.4.2.2 
Subgroup Analyses 
Subgroup analyses of PFS will be performed for patients with baseline CNS metastases 
and for patients without baseline CNS metastases.  In addition, a subgroup analysis of 
Time to CNS Progression will be performed, excluding patients who had pre-treatment 
radiation therapy for CNS lesions. 
All other subgroup analyses will be specified in the SAP. 
6.5 
SAFETY ANALYSES 
The primary population for all safety analyses will be the SAP as defined in Section 6. 
All safety parameters will be summarized in tables to evaluate and compare the safety 
profile of patients treated with alectinib versus crizotinib in terms of: 
• 
Adverse events including adverse events leading to dose modifications or 
interruptions, study drug withdrawal, and death  


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• 
Severe, serious, and selected adverse events 
• 
Deaths 
• 
Laboratory parameters and abnormalities 
• 
Vital signs 
• 
ECGs 
• 
ECOG PS 
Adverse events will be coded using MedDRA and summarized by mapped term and 
appropriate thesaurus level.  All adverse events and routine laboratory parameters will 
be assessed according to the NCI CTCAE v4.0 grading system.  For adverse events, the 
most extreme intensity will be used for reporting.  Adverse events will be described by 
individual listings and by body system, as well as by severity.  In tables showing the 
overall incidence of adverse events, patients who experienced the same event on more 
than one occasion are counted only once in the calculation of the event frequency. 
Laboratory values will be summarized by treatment arm including summary tables for the 
shifts in grades from baseline to the worst grade observed during treatment.  In order to 
evaluate and compare hypogonadism in the two treatment arms, testosterone levels in 
the blood will be summarized for males by treatment arm over time (for details, see 
Section 6.8). 
Descriptive summary tables of change from baseline over time will be provided for vital 
signs and descriptive statistics will be tabulated for ECOG PS.  ECG findings over time 
will be summarized. 
Study drug administration will be summarized by duration and cumulative dose.  In 
addition, treatment exposure will be summarized including the number of doses received, 
dose intensity, and the percentage of planned dose. 
Subgroup analyses will be performed to evaluate the safety profile within the subgroups 
of patients including by sex, age (< 65 vs. ≥ 65 years), and race (non-Asian vs. Asian). 
An IDMC will review the safety data collected during the conduct of the study.  Safety 
monitoring will be performed periodically.  Further details will be outlined in the IDMC 
Charter. 
6.6 
PHARMACOKINETIC ANALYSES 
Standard NCA may be conducted for PK data collected from patients participating in 
serial/intensive PK collections for relevant analytes, as data allow, as appropriate, and if 
needed.  PK parameters, including but not limited to AUC, maximum concentration 
(Cmax), and time to maximum concentration, will be calculated on the basis of the 
available data as appropriate and where data allow.  Additional PK parameters may be 
calculated as deemed appropriate. 


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Individual and mean plasma concentrations at each sampling timepoint and/or PK 
parameters for alectinib and metabolite(s) will be listed, as appropriate. 
Summary statistics (e.g., means, standard deviation, coefficient of variation %, 
geometric means, medians and ranges) for plasma concentrations and/or PK 
parameters for alectinib and metabolite(s) will be presented by treatment and nominal 
collection times (plasma concentrations only), as appropriate.  Additional plots or 
summary statistics may be constructed or calculated, as appropriate. 
Results of PK and/or any PK or PK/pharmacodynamic analyses may be reported outside 
the clinical study report. 
Nonlinear mixed-effects modeling (with software NONMEM) (Beal et al. 1999) will be 
used to analyze the sparse and/or serial/intensive plasma concentration-time data for 
alectinib.  The PK data from this study may be pooled with data from other studies.  
Population and individual PK parameters will be estimated and the influence of various 
covariates (such as age, gender, and body weight) on these parameters will be 
investigated. 
Exploratory analyses will be conducted to investigate the relationship between alectinib 
PK exposure and efficacy/safety parameters. 
Details of the mixed-effects modeling and exploratory analyses will be reported in a 
document separate from the clinical study report. 
6.7 
PATIENT-REPORTED OUTCOME ANALYSES 
The following PRO endpoints will be analyzed and PRO data will be presented 
separately from adverse event data. 
6.7.1 
Time to Deterioration of Patient-Reported Lung Cancer 
Symptoms 
TTD from baseline will be assessed at every study visit (Week 4, Week 8, and then after 
every 4 weeks) until disease progression and during post-progression on treatment in 
case of isolated, asymptomatic CNS progression; at post-treatment Visit (4 weeks after 
permanent treatment discontinuation); and at subsequent 8-weekly survival follow-up 
visits for 6 months, for the following lung cancer symptoms: cough (Question 31 on the 
QLQ-LC13), dyspnea single item (Question 8 on the QLQ-C30), dyspnea multi-item 
subscale (Questions 33-35 on the QLQ-LC13), chest pain (Question 40 on the 
QLQ-LC13), arm/shoulder pain (Question 41 on the QLQ-LC13) and fatigue multi-item 
subscale (Questions 10, 12, and 18 on the QLQ-C30) for patients in each arm.  
Completion and compliance rates will be summarized at each timepoint by treatment 
arm with reasons for missing data.  TTD will be analyzed for the ITT population.  If a 
baseline or post-baseline PRO evaluation is not available, TTD will be censored at the 
date of randomization. If they have not deteriorated, patients will be censored at the last 


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time when they completed an assessment for cough, dyspnea (single item), dyspnea 
(subscale items), chest pain, arm/shoulder pain, and fatigue. 
6.7.2 
Additional Patient-Reported Outcomes 
PROs of HRQoL, lung cancer−related symptoms, and health status will be measured 
using the EORTC QLQ-C30 and EORTC QLQ-LC13. 
Summary statistics (mean, standard deviation, median, and range) of linear transformed 
scores will be reported for all the items and subscales of the EORTC QLQ-C30 
questionnaire, and the QLQ-LC13 according to the EORTC scoring manual guidelines.  
Completion and compliance rates will be summarized at each timepoint by treatment 
arm with reasons for missing data.  Only patients with a baseline assessment and at 
least one post-treatment assessment will be included in the analyses. 
6.8 
EXPLORATORY ANALYSES 
The EQ-5D-3L is a generic PRO instrument that is used for across diseases and 
indications cost-effectiveness analyses.  This instrument quantifies the QoL of various 
health outcomes and is applicable to a wide range of health states.  Analyses of this 
outcome will be exploratory and will generate utility scores for use in economic models 
for reimbursement purposes only.  The PRO will be administered every 4 weeks until 
disease progression and during post-progression on treatment in case of isolated, 
asymptomatic CNS progression; at the post-treatment visit (4 weeks after permanent 
treatment discontinuation); and every follow-up visit (every 8 weeks) after post-treatment 
visit for 6 months (see Appendix 1).  
It has been reported that crizotinib therapy triggered rapid suppression of testosterone 
levels in men causing rapid-onset hypogonadism.  Whether reductions in testosterone 
reflect an effect of crizotinib on ALK or on some combination of the drug’s targets 
(i.e., c-MET) is unknown (Weickhardt et al. 2012; Weickhardt et al. 2013).  Total 
testosterone, albumin, and sex hormone-binding globulin (SHBG) to calculate free 
testosterone (calculator: http://www.issam.ch/freetesto.htm) and FSH and LH levels in 
blood will be measured (see Appendix 1) in male patients enrolled in the study for 
exploratory analysis of an onset of hypogonadism.  The recommended time of day to 
have a blood sample taken for this test is between 7 a.m. and 10 a.m. 
The Abbott Vysis FISH test will be used as an exploratory assay, after patients have 
been enrolled in this study.  Results from these analyses will be used to quantify the 
degree of correlation between FISH and IHC for the detection of ALK-positive NSCLC.  
The FPP will be a secondary analysis population for efficacy and safety.  This analysis 
population will be used to perform a supportive analysis of the study data based on the 
FISH assay rather than the IHC.  This population may be used for registration purposes 
in the unlikely event of registrational failure of the IHC companion diagnostic, in which 
case all analyses will be based on this population. 


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Results of exploratory analyses on post-progression tumor samples to measure 
molecular mechanisms of resistance to ALK inhibitors and plasma samples to measure 
ALK rearrangements in circulating tumor cells will be communicated outside the main 
study report. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC using eCRFs.  
Sites will be responsible for data entry into the EDC system.  In the event of discrepant 
data, the Sponsor will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data. Central laboratory data or other electronic 
data will be sent directly to the Sponsor, using the Sponsor’s standard procedures to 
handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
ePRO data will be collected through use of an electronic device provided by an ePRO 
vendor.  The device is designed for entry of data in a way that is attributable, secure, 
and accurate, in compliance with the FDA regulations for electronic records (21 CFR 
Part 11).  The ePRO device data are available for view access only via secure access to 
a web server.  Only identified and trained users may view the data, and their actions 
become part of the audit trail.  The Sponsor will have view access only.  System 
backups for data stored by the Sponsor and records retention for the study data will be 
consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 


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7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
Patients will use an ePRO device to capture PRO data.  The data will be transmitted via 
pre-specified transmission method (e.g., web or wireless) automatically after entry to a 
centralized database at the ePRO vendor.  The data can be reviewed by site staff via 
secure access to a web server. 
Once the study is complete, the ePRO data, audit trail, and trial and system 
documentation will be archived.  The investigator will receive patient data for the site in 
both human- and machine-readable formats on an archival-quality compact disc that 
must be kept with the study records as source data.  Acknowledgement of receipt of the 
compact disc is required. In addition, the Sponsor will receive all patient data in a 
machine-readable format on a compact disc. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 


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7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a United States 
IND application will comply with FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the European Union or European Economic Area will comply 
with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 


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submission.  The final IRB/EC−approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient before his or her 
participation in the study.  The case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC−approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 


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8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  In 
addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 


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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, which includes an audit trail containing a complete record of all changes 
to data. 
9.2 
PROTOCOL VIOLATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
Steering Committee is established to provide the study Sponsor with recommendations 
related to any aspect of the trial, specifically study design, data interpretation, 
exploratory analyses, or alternate changes to the trial that may assist in patient accrual, 
data collection, analysis, and interpretation of the study results.  The Sponsor is 
ultimately responsible for all decisions regarding the study. 
The test for the study inclusion criteria of ALK-positive NSCLC will be performed at 
Sponsor’s designated central laboratories and assessed by Ventana IHC test. 
An IDMC will be established to monitor the progress of the study and ensure that the 
safety of patients enrolled in the study is not compromised.  Details of the composition, 
roles, and responsibilities, and processes of the IDMC are documented in a separate 
IDMC charter.  The IDMC will review safety data and can make recommendations to the 
Sponsor to stop or amend the study on the basis of safety findings.  The frequency of 
these reviews as well as the data to be reviewed will be agreed with the IDMC and 
outlined in the separate IDMC charter.  No stopping for early proof of efficacy will result 
from any of these regular safety reviews.  IDMC review meetings will be held in a blinded 
manner to the Sponsor. 


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An IRC will review the tumor assessments to determine the secondary endpoints of the 
overall disease PFS and time to CNS progression, both on the basis of RECIST v1.1.  In 
addition to the secondary endpoint of time to CNS progression together with C-ORR, 
C-DOR, and CNS progression rate at 6, 12, 18, and 24 months, an IRC will review the 
tumor assessments on the basis of RANO criteria. 
The independent review of MRI and CT scans will NOT determine either eligibility OR 
patient treatment.  All treatment decisions will be made by the investigator using local 
assessments. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
prior to submission.  This allows the Sponsor to protect proprietary information and to 
provide comments based on information from other studies that may not yet be available 
to the investigator. 
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


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Appendix 1  
Schedule of Assessments 
Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) Until 
PD, Death, or 
Withdrawal 
from Study 
prior to PD 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation) 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D)  
Informed consent 
x 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
Pregnancy testa 
 
x 
To be repeated as necessary 
 
 
 
Physical 
examinationb 
x 
 
x 
x 
x 
x 
x 
 
 
Vital signs 
x 
 
x 
x 
x 
x 
x 
 
 
ECOG PS 
x 
 
x 
x 
x 
x 
x 
 
 
ECGc 
x 
 
xd 
x 
 
x 
 
 
 
Hematology, 
Coagulation 
x 
 
xd 
x 
x 
x 
x 
 
 
Biochemistry 
x 
 
xd 
x 
x 
x 
x 
 
 
Urinalysis 
x 
 
xd 
x 
x 
x 
x 
 
 


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Schedule of Assessments (cont.) 
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Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) Until 
PD, Death, or 
Withdrawal 
from Study 
prior to PD 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation) 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D)  
Concomitant 
medications 
x 
 
x 
x 
x 
x 
x 
 
 
Mandatory tumor 
sample for ALK 
testinge 
x 
 
 
 
 
 
 
 
 
Optional tumor 
sample 
 
 
xf 
 
 
xg 
xg 
 
 
Blood sample for 
ALK fusion 
detection in 
circulating tumor 
cells (12 mL of 
blood) 
 
 
x 
 
 
xh 
xh 
 
 
Plasma for 
detection of ALK 
mutation status 
(20 mL of blood) 
 
 
x 
 
 
xi 
xi 
 
 


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Schedule of Assessments (cont.) 
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Protocol BO28984, Version 1 
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Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) Until 
PD, Death, or 
Withdrawal 
from Study 
prior to PD 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation) 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D)  
Blood sample for 
pharmacogenomics 
research at pre-
dose (3 mL of 
blood) j 
 
 
x 
 
 
 
 
 
 
Tumor 
assessmentk 
xl 
 
xl 
 
x 
xm 
x 
xn 
 
MRI scan of the 
brain 
xl 
 
xl 
 
x 
xm 
x 
xn 
 
PK samples (2 mL 
blood)o 
 
 
x 
x 
x 
x 
 
 
 
PRO (EORTC 
QLQ-C30/LC13); 
EQ-5Dp 
 
 
x 
x 
x 
x 
x 
x 
xq 


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Schedule of Assessments (cont.) 
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Protocol BO28984, Version 1 
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Screening 
Treatment Period 
Assessment 
Days 
-28 
to 0 
Days 
-3 to 
0 
Visit 0 
(Baseline) 
Visit 1 
(Week 4) 
Visit 2 
(Week 8) 
All 
Subsequent 
Visits (Every 
8 weeks) Until 
PD, Death, or 
Withdrawal 
from Study 
prior to PD 
Post-Progression 
Visits on 
Treatment in 
Case of Isolated, 
Asymptomatic 
CNS Progression 
(Every 8 weeks) 
Until Systemic 
Progression 
and/or 
Symptomatic 
CNS Progression 
Post-Treatment 
Visit (4 weeks 
after Permanent 
Treatment 
Discontinuation) 
Subsequent 
Therapy for 
NSCLC; 
Survival 
follow-up and 
PRO 
(EORTC 
QLQ-C30/ 
LC13; 
EQ-5D)  
Total testosterone, 
albumin, and 
SHBG to calculate 
free testosterone, 
FSH, and LHr 
 
 
x 
x 
x 
x 
 
 
 
Adverse eventss 
x 
x 
x 
x 
x 
x 
x 
x 
 
Subsequent 
therapy for NSCLC 
 
 
 
 
 
 
x 
x 
xq 
Drug dispensing 
and accountabilityt 
 
 
x 
x 
x 
x 
x 
x (accountability 
only) 
 
Blood Sample for 
Roche Clinical 
Repository (10 mL) 
 
 
x 
 
 
 
 
 
 
ALK = anaplastic lymphoma kinase; ALP = alkaline phosphatase;  CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse 
Events; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30 = European Organization for the Research and 
Treatment of Cancer Quality of Life Questionnaire−Core; EQ-5D = EuroQoL 5 Dimension; FSH = follicle-stimulating hormone; LH = luteinizing 


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Schedule of Assessments (cont.) 
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Protocol BO28984, Version 1 
110 
hormone; MRI = magnetic resonance imaging; NCI = National Cancer Institute; NSCLC = non−small cell lung cancer; PD = progressive disease; 
PK = pharmacokinetic; PRO = patient-reported outcome; ULN = upper limit of normal. 
Notes: First dose of study drug to be taken as soon as patient has been randomized and appropriate drug has been provided–within ≤ 24 hours.  
Post-baseline assessments are to be performed within ± 1 week for the first two 4 weekly and subsequent 8 weekly assessments. 
a Urine or serum, to be repeated as necessary. 
b Including an ophthalmologic examination if clinically indicated. 
c At screening, Visit 0 (baseline), Visit 1 (Week 4), Visit 4 (Week 24), Visit 8 (Week 56), last treatment visit, and as clinically indicated throughout 
the study. 
d Screening laboratory assessment done within 3 days can be counted as the baseline assessment. 
e Preferably blocks fixed in neutral buffered formalin; if blocks are not available, a minimum of 10 to 15 unstained 5-µm slides are required.  Tumor 
ALK status will be assessed by central laboratory before randomization. 
f Optional tumor sample could be taken from the tumor block obtained at screening. 
g At the time of disease progression from progressive lesions. 
h Mandatory blood sample (12 mL) for CTCs should match in time to tumor progression (CNS progression and/or systemic disease progression) at 
discretion of the investigator. 
i Blood sample (20 mL) to obtain plasma for exploratory biomarkers will be collected at Visit 0 (baseline), during the study every second visit (i.e., 
every 16 weeks) until disease progression and during post-progression on treatment in case of isolated, asymptomatic CNS progression. 
j This sample is required in all patients in alectinib arm, and in those patients in the crizotinib arm who wish to participate in optional genomics 
sequencing. 
k Tumor assessment consists at minimum of a CT/MRI scan of chest and abdomen (for imaging of liver and adrenal glands).  Patients who are 
known to have bone metastasis or who display clinical or laboratory signs (e.g., serum ALP >1.5 × ULN) of bone metastasis should undergo 
radionuclide bone scan.  Post-baseline assessments are to be performed within ±1 week for the 8 weekly assessments.  If there is suspicion of 
disease progression on the basis of clinical or laboratory findings, a tumor assessment should be performed as soon as possible before the next 
scheduled evaluation. 
l Screening tumor assessment done within 14 days will be counted as the baseline assessment. 
m Tumor assessment can be performed whenever clinically indicated.  Brain assessment scans should be performed at every systemic imaging 
tumor assessment.  Tumor assessment should continue until disease progression if a patient discontinues treatment prior to PD, regardless of 
whether they subsequently receive non-study, anti-cancer therapy (a use of subsequent non-study, anti-cancer therapy prior to disease 
progression would be considered a protocol violation).  


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n If treatment was permanently discontinued due to disease progression. 
o Pre-dose PK (2 mL) sampling for all patients on alectinib treatment will be performed at each visit during the treatment period and at the final 
study visit.  The pre-dose PK samples should be taken immediately before (within 2 hours) intake of study medication at all study visits. Remind 
the patient not to take a daily dose at home on the day of scheduled study visit.  For a subset of patients on alectinib treatment (10%−15%, at 
least n = 20) participating in serial/intensive PK sample collection, additional PK will be collected on Visits 0 (baseline) and 1 (Week 4) at 
pre-dose (within 60 min before intake of study medication), 1, 2, 4, 6, 8, 10, and 12 hours post-dose. 
p PRO questionnaires are to be completed every 4 weeks until disease progression and during post-progression on treatment in case of isolated, 
asymptomatic CNS progression; at the post-treatment visit (4 weeks after permanent treatment discontinuation); and every follow up visit (every 
8 weeks) after post-treatment visit for 6 months..  Further guidelines on PRO questionnaire administration will be provided in the study manual. 
q Performed every 8 weeks after post-treatment visit during the first 6 months and then every 12 weeks or performed as appropriate.  The PRO 
assessments should be performed during the first 6 months. 
r Male patients only, using institutional standard assay. The recommended time of day to have a blood sample taken for this test is between 7 a.m. 
and 10 a.m.  Free testosterone calculator: http://www.issam.ch/freetesto.htm. 
s Graded according to NCI CTCAE (version 4.0).  Serious adverse events collection must start from first study-specific procedure. 
t For details on drug dispensing and accountability, see Section 4.3.3. 
 


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Appendix 2  
Schedule of Alectinib Pharmacokinetic Assessments 
Visit 
Timepoint 
Visit 0 (baseline) 
Pre-dose (within 2 hours before intake of alectinib)
Visit 1 (Week 4) 
Pre-dose (within 2 hours before intake of alectinib)
Visit 2 (Week 8) 
Pre-dose (within 2 hours before intake of alectinib)
All subsequent visits (every 
8 weeks) until PD or 
death/withdrawal from study prior to 
PD 
Pre-dose (within 2 hours before intake of alectinib)
Visit 0 (baseline) and Visit 1 
(Week 4)a 
Pre-dose (within 2 hours before intake of 
alectinib), 1, 2, 4, 6, 8, 10, and 12b hours post-
dose 
PD = progressive disease; PK = Pharmacokinetic 
a For patients participating in the serial/intensive PK sample collection only. 
b A time window of ± 1 hour may be considered for the 12-hour PK sample only 


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Appendix 3  
List of Substrates, Inhibitors, and Inducers of Drug-Metabolizing 
Enzymes and Transporters 
This representative list is not intended to be an exhaustive list.  Each patient’s 
concomitant medications should be carefully considered by the investigator with regard 
to the risk-benefit for the particular patient and appropriate monitoring, including any 
concomitant medication, dose adjustment, or therapeutic alternatives, which should be 
determined by the investigator caring for the patient. 
CYP3A Inducers 
CYP3A Potent Inhibitors 
avasimibe, aminoglutethimide, barbiturates, 
carbamazepine, dexamethasone, efavirenz, 
ethosuximide, garlic supplements, 
glucocorticoids, glutethimide, griseofulvin, 
modafinil, nafcillin, nevirapine, oxcarbazepine, 
phenobarbital, phenytoin, pioglitazone, 
primidone, rifabutin, rifampin, rifapentine, St. 
John’s wort, troglitazone 
aprepitant, atazanavir, boceprevir, 
ciprofloxacin, clarithromycin, conivaptan, 
diltiazem, erythromycin, fluconazole, grapefruit 
juice, indinavir, itraconazole, ketoconazole, 
lopinavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, troleandomycin, verapamil, 
voriconazole 
 
P-gp 
Substrates 
Inhibitors 
Inducers 
aliskiren, ambrisentan, 
colchicine, dabigatran, 
digoxin, everolimus, 
fexofenadine, imatinib, 
lapatinib, maraviroc, nilotinib, 
posaconazole, pravastatin, 
ranolazine, saxagliptin, 
sirolimus, sitagliptin, talinolol, 
tolvaptan, topotecan 
amiodarone, azithromycin, 
captopril, carvedilol, 
clarithromycin, conivaptan, 
cyclosporine, diltiazem, 
erythromycin, felodipine, 
itraconazole, ketoconazole, 
lopinavir, quercetin, quinidine, 
ranolazine, verapamil 
avasimibe, carbmazepine, 
phenytoin, rifampin, St John’s 
wort, tipranavir 
Dual UGT1A1/CYP3A 
Substrates 
Inhibitors 
Inducers 
buprenorphine, raltegravir 
atazanavir 
rifampin 
Sensitive CYP3A and 2C8 substrates 
alfentanil, aprepitant, budesonide, buspirone, conivaptan, darifenacin, darunavir, dasatinib, 
dronedarone, eletriptan, eplerenone, everolimus, felodipine, indinavir, fluticasone, lopinavir, 
lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, quetiapine, saquinavir, sildenafil, 
simvastatin, sirolimus, tolvaptan, tipranavir, triazolam, ticagrelor, vardenafil, astemizole, 
cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus, terfenadine, repaglinide, paclitaxol 
 


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Enzymes and Transporters (cont.) 
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114 
This information in this appendix is adapted from Levien and Baker 20031, Zhang 20102, 
and FDA Guidance on Drug-Drug Interactions. 
Also see: 
• 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dr
ugInteractionsLabeling/ucm080499.htm  
• 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx  
Potent inhibitors of CYP3A are those considered to be “strong CYP3A inhibitors” 
previously shown to result in a ≥ 5-fold increase in the AUC of a concomitantly 
administered CYP3A substrate.  These are based on the available published literature 
and, thus, are not considered exhaustive or inclusive.  See FDA Guidance on Drug-Drug 
Interactions for further detail. 
                                            
 
1 Levien TL, and Baker DE Cytochrome PͶͷͲ Drug )nteractions. Therapeutic Research Center 
Pharmacist’s Letter/Prescriber’s Letter [resource on the )nternet]. ʹͲͲ͵. Available from: 
www.pharmacistsletter.com and www.prescribersletter.com. 
2 Zhang L. Transporter Mediated Drug‐Drug )nteractions. FDA. Clinical Pharmacology Advisory 
Committee Meeting Topic Ͷ: Transporter‐Mediated Drug‐Drug )nteractions Atlanta, GA, March ͳ7, 
ʹͲͳͲ. 


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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1: Excerpt from Original Publication 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1,1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2 
MEASURABILITY OF TUMOR AT BASELINE 
DEFINITIONS 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below. 
Measurable tumor lesions 
Tumor lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 
• 
10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater than 
5 mm) 
• 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
• 
20 mm by chest X-ray 
Malignant lymph nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
≥ 15 mm in the short axis when assessed by CT scan (CT scan slice thickness is 
recommended to be no greater than 5 mm).  At baseline and follow-up, only the short 
axis will be measured and followed.  See also notes below on “Baseline Documentation 
of Target and Non-Target Lesions” for information on lymph node measurement. 
Non-Measurable tumor lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
                                            
 
1  Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors:  
revised REC)ST guideline ȋVersion ͳ.ͳȌ. Eur J Cancer ʹͲͲͻ;Ͷͷ:ʹʹͺ–Ͷ7. 
2  For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made. 


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mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone lesions 
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions.  However, these techniques 
can be used to confirm the presence or disappearance of bone lesions. 
Lytic bone lesions or mixed lytic−blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques, such as CT or MRI, can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
Blastic bone lesions are non-measurable. 
Cystic lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
TARGET LESIONS: SPECIFICATIONS BY METHODS OF MEASUREMENTS  
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
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Method of assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 
Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested. 
Chest X-Ray 
Chest CT is preferred over chest X-Ray, particularly when progression is an important 
endpoint, because CT is more sensitive than X-Ray, particularly in identifying new 
lesions.  However, lesions on chest X-Ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 
CT, MRI 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  This guideline has defined measurability of lesions on CT 
scan on the basis of the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable.  
If, prior to enrollment, it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease and should be 
optimized to allow for comparison with the prior studies if possible.  Each case should be 
discussed with the radiologist to determine if the substitution of these other approaches 
is possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of non-target disease or new lesions because the same lesion may 
appear to have a different size using a new modality. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. 
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Endoscopy, laparoscopy, tumor markers, cytology, histology 
The utilization of these techniques for objective tumor evaluation cannot generally be 
advised. 
TUMOR RESPONSE EVALUATION 
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least one 
measurable lesion, as detailed above. 
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions, up to a 
maximum of five lesions total and a maximum of two lesions per organ, representative of 
all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be recorded as non-measurable lesions (even if the size is > 10 mm by CT scan).   
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but, in addition, the lesions 
should lend themselves to reproducible repeated measurements.  It may be the case 
that, on occasion, the largest lesion does not lend itself to reproducible measurement, in 
which circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT this is 
almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or 
coronal).  The smaller of these measures is the short axis.  For example, an abdominal 
node that is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node.  In this example, 20 mm should be recorded as the 
node measurement.  All other pathological nodes (those with short axis ≥ 10 mm but 
< 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
< 10 mm are considered non-pathological and should not be recorded or followed. 
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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
All other lesions or sites of disease, including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression”. 
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). 
RESPONSE CRITERIA 
Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
• 
CR:  Disappearance of all target lesions 
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm. 
• 
PR:  At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum of diameters. 
• 
PD:  At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (nadir), including baseline. 
In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered progression. 
• 
SD:  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum on study. 
Special notes on the assessment of target lesions 
Lymph nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to < 10 mm on study.  This means that when 
lymph nodes are included as target lesions, the sum of lesions may not be zero even if 
CR criteria are met, since a normal lymph node is defined as having a short axis of 
< 10 mm. 
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Target lesions that become too small to measure 
During the study, all lesions (nodal and non-nodal) recorded at baseline should have 
their actual measurements recorded at each subsequent evaluation, even when very 
small (e.g., 2 mm).  However, sometimes lesions or lymph nodes that are recorded as 
target lesions at baseline become so faint on the CT scan that the radiologist may not 
feel comfortable assigning an exact measure and may report them as being too small to 
measure.  When this occurs, it is important that a value be recorded on the CRF, as 
follows:   
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
If the lesion is believed to be present and is faintly seen but is too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should be 
ticked.  (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such as 
in the retroperitoneum; however, if a lymph node is believed to be present and is faintly 
seen but is too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well and BML should also be ticked). 
To reiterate:  if the radiologist is able to provide an actual measure, this 
measurement should be recorded, even if it is below 5 mm, and, in that case, BML 
should not be ticked. 
Lesions that split or coalesce on treatment 
When non-nodal lesions fragment, the longest diameters of the fragmented portions 
should be added together to calculate the target lesion sum.  Similarly, as lesions 
coalesce, a plane between them may be maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion.  If the lesions have truly coalesced 
such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximum longest diameter for the coalesced lesion. 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  Whereas some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the protocol. 
• 
CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• 
Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
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• 
PD:  Unequivocal progression of existing non-target lesions 
The appearance of one or more new lesions is also considered progression. 
Special notes on assessment of progression of non-target disease 
When the patient also has measurable disease 
In this setting, to achieve unequivocal progression on the basis of the non-target 
disease, there must be an overall level of substantial worsening in non-target disease in 
a magnitude that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy.  A modest increase 
in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or PR of target disease will 
therefore be extremely rare. 
When the patient has only non-measurable disease 
This circumstance arises in some Phase III trials when it is not a criterion of study entry 
to have measurable disease.  The same general concepts apply here as noted above; 
however, in this instance, there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden.  Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly 
non-measurable), a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden on the 
basis of the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease, that is, an 
increase in tumor burden representing an additional 73% increase in volume (which is 
equivalent to a 20% increase in diameter in a measurable lesion).  Examples include an 
increase in a pleural effusion from “trace” to “large” or an increase in lymphangitic 
disease from localized to widespread.  Examples may be described in protocols as 
“sufficient to require a change in therapy”.  If unequivocal progression is seen, the 
patient should be considered to have had overall PD at that point.  Though it would be 
ideal to have objective criteria to apply to non-measurable disease, the very nature of 
that disease makes it impossible to do so; therefore, the increase must be substantial. 
New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(e.g., some “new” bone lesions may be simply healing or flare of preexisting lesions).  
This is particularly important when the patient’s baseline lesions show PR or CR (e.g., 
necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, 
which it is not). 
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A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal (e.g., because of its small size) continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan. 
EVALUATION OF RESPONSE 
Timepoint response (overall response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used. 
Table 1 
Timepoint Response: Patients with Target Lesions (with or 
without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
 
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Table 2 
Timepoint Response: Patients with Non-Target Lesions Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised. 
 
Missing assessments and not-evaluable designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned timepoint response.  This would be most likely 
to happen in the case of PD (e.g., if a patient had a baseline sum of 50 mm with three 
measured lesions and during the study only two lesions were assessed, but those gave 
a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution 
of the missing lesion).  
If one or more target lesions were not assessed either because the scan was not done 
or because the scan could not be assessed due to poor image quality or obstructed 
view, the response for target lesions should be “unable to assess” since the patient is 
not evaluable.  Similarly, if one or more non-target lesions are not assessed, 
the response for non-target lesions should be “unable to assess”, except where there is 
clear progression.  Overall response would be “unable to assess” if either the target 
response or the non-target response is “unable to assess”, except where this is clear 
evidence of progression, as this equates with the case being not evaluable at that 
timepoint. 
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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 1 
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Table 3 
Best Overall Response When Confirmation Is Required 
Overall Response at First 
Timepoint 
Overall Response at 
Subsequent Timepoint 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR a 
CR 
SD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
CR 
PD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
CR 
NE 
SD, provided minimum 
duration for SD was met; 
otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum 
duration for SD was met; 
otherwise, PD 
PR 
NE 
SD, provided minimum 
duration for SD was met; 
otherwise, NE 
NE 
NE 
NE 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even 
disease meeting PR criteria relative to baseline, qualifies as PD at that point (since disease 
must have reappeared after CR).  Best response would depend on whether the minimum 
duration for SD was met.  However, sometimes CR may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR, at the 
first timepoint.  Under these circumstances, the original CR should be changed to PR and the 
best response is PR. 
 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (< 10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
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Appendix 4  
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 1 
125 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Table 1 to Table 3. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes, or necrosis in existing lesions), treatment may continue until the 
next scheduled assessment.  If at the next scheduled assessment, progression is 
confirmed, the date of progression should be the earlier date when progression was 
suspected. 
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or non-target lesion.
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Appendix 5  
Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework or 
office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about > 50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair > 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair 
5 
Dead 


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Appendix 6  
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires 
 


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Appendix 6 
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.) 
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Protocol BO28984, Version 1 
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Appendix 6 
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 1 
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Appendix 6 
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.) 
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Protocol BO28984, Version 1 
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Appendix 6 
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 1 
131 
 
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Appendix 6 
EORTC QLQ-C30/LC13 and EQ-5D-3L Questionnaires (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 1 
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Appendix 7  
Modification of Diet in Renal Disease (MDRD) Formula 
The estimating glomerular filtration rate (eGFR) will be calculated on the basis of the 
following formula: 
eGFR = 175 × SCRT -1.154 × AGE -0.203 [× 0.742 if female] [× 1.212 if African 
American] (conventional units) 
Reference: Miller WG. Estimating glomerular filtration rate. Clin Chem Lab Med 
2009;47(9):1017-9.


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Appendix 8  
Anaplastic Lymphoma Kinase (ALK) Immunohistochemistry 
Overview 
The VENTANA anti-ALK (D5F3) Rabbit Monoclonal Primary Antibody (VENTANA 
anti-ALK [D5F3]) IHC assay will be used to determine anaplastic lymphoma kinase (ALK) 
IHC status and to select patients with positive ALK for enrollment in Study BO28984.  
The anti-ALK (D5F3) rabbit monoclonal antibody IHC assay is currently being developed 
by Ventana Medical Systems as a companion diagnostic to Roche’s ALK inhibitor, 
alectinib.  For Study BO28984, the VENTANA anti-ALK (D5F3) assay will be used for 
investigational purposes only. 
VENTANA anti-ALK (D5F3) is intended for laboratory use in the detection of the ALK 
protein in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) 
tissue stained with using a VENTANA automated slide stainer.  It is indicated as an aid 
in identifying patients eligible for treatment with alectinib. 
Device Description 
The VENTANA anti-ALK (D5F3) IHC assay is an automated IHC staining assay system 
comprising a pre-diluted, ready to-use anti-ALK (D5F3) rabbit monoclonal primary 
antibody, the BenchMark® automated slide staining platform, OptiView DAB detection kit, 
OptiView Amplification kit, Rabbit Monoclonal Negative Control Ig, and VENTANA 
anti-ALK 2-in-1 cell line control slides or other appropriate system run control. 
Scoring System 
The IHC scoring system evaluates specific VENTANA anti-ALK (D5F3) staining in 
NSCLC tumor cells by the presence of a strong, granular, cytoplasmic staining pattern.  
Pathologists must rely on the Negative Reagent Control (NRC) slides to distinguish 
non-specific staining from specific ALK positivity.  Samples must be assessed for 
morphological damage and the presence of viable tumor versus necrosis.  Light, 
granular, cytoplasmic stippling in alveolar macrophages can occur on anti-ALK (D5F3) 
and/or NRC slides as an artifact of the detection system.  This staining artifact should be 
noted on the Slide Evaluation Form comment field but should NOT be interpreted as 
ALK-positive staining.  Some background staining has also been observed on normal 
mucosa in NSCLC specimens, as well as in necrotic tumor areas; this staining also 
should not be interpreted as ALK-positive staining.  Case slide sets failing to show 
specific staining of the case tissue with VENTANA anti-ALK (D5F3) cannot be 
considered ALK-positive.  Refer to VENTANA ALK Scoring Interpretation Guide for non-
small cell lung carcinoma (NSCLC) for additional information. 
 


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Appendix 9  
Drug Metabolism Enzymes, Transporters (DMET), and Liver Injury Polymorphisms 
ABCB1 
CHST13 
CYP3A5 
HNMT 
SLC22A3 
UGT1A4 
ADRB3 
HSP90AA1 
STAT6 
ABCB11 
CHST2 
CYP3A7 
MAOA 
SLC22A4 
UGT1A5 
ALG10B 
IGF1 
TNF 
ABCB4 
CHST3 
CYP46A1 
MAOB 
SLC22A5 
UGT1A6 
APOA1 
IGF2 
TNFRSF1B 
ABCB7 
CHST4 
CYP4A11 
MAT1A 
SLC22A6 
UGT1A7 
APOC3 
IL10 
TXNIP 
ABCC1 
CHST5 
CYP4B1 
METTL1 
SLC22A7 
UGT1A8 
ARHGAP24 
IL22 
UBC 
ABCC2 
CHST6 
CYP4F11 
NAT1 
SLC22A8 
UGT1A9 
ATF3 
IL4 
UCP1 
ABCC3 
CHST7 
CYP4F12 
NAT2 
SLC25A27 
UGT2A1 
ATIC 
IL4R 
VDR 
ABCC4 
CHST8 
CYP4F2 
NNMT 
SLC28A1 
UGT2B11 
BIRC2 
IL6 
 
ABCC5 
CHST9 
CYP4F3 
NQO1 
SLC28A2 
UGT2B15 
BIRC3 
IL8 
 
ABCC6 
COMT 
CYP4F8 
NR1I2 
SLC28A3 
UGT2B17 
C3orf38 
INSR 
 
ABCC8 
CROT 
CYP4Z1 
NR1I3 
SLC29A1 
UGT2B28 
CALCA 
IRS1 
 
ABCC9 
CYP11A1 
CYP51A1 
NR3C1 
SLC29A2 
UGT2B4 
CASP9 
IRS2 
 
ABCG1 
CYP11B1 
CYP7A1 
ORM1 
SLC5A6 
UGT2B7 
CD33 
IRS4 
 
ABCG2 
CYP11B2 
CYP7B1 
ORM2 
SLC6A6 
UGT8 
CD36 
ITPA 
 
ABP1 
CYP17A1 
CYP8B1 
PGAP3 
SLC7A5 
VKORC1 
CD44 
JAK1 
 
ADH1A 
CYP19A1 
DCK 
PNMT 
SLC7A7 
XDH 
CDK4 
JUN 
 
ADH1B 
CYP1A1 
DPYD 
PON1 
SLC7A8 
 
CDK6 
KCNIP4 
 
ADH1C 
CYP1A2 
EPHX1 
PON2 
SLCO1A2 
 
CEBPB 
KRT18 
 
ADH4 
CYP1B1 
EPHX2 
PON3 
SLCO1B1 
 
CEP44 
KRT8 
 
ADH5 
CYP20A1 
FAAH 
POR 
SLCO1B3 
 
CES1 
LEP 
 
ADH6 
CYP21A2 
FMO1 
PPARD 
SLCO2B1 
 
CTLA4 
LEPR 
 
ADH7 
CYP24A1 
FMO2 
PPARG 
SLCO3A1 
 
CYP3A 
LMX1A 
 
AHR 
CYP26A1 
FMO3 
PPP1R9A 
SLCO4A1 
 
EGFR 
LPL 
 


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Drug Metabolism Enzymes, Transporters (DMET), and Liver Injury Polymorphisms (cont.) 
Alectinib—F. Hoffmann-La Roche Ltd 
Protocol BO28984, Version 1 
136 
AKAP9 
CYP26C1 
FMO4 
PRSS53 
SLCO5A1 
 
ETNK2 
MCTP2 
 
ALB 
CYP27A1 
FMO5 
PTGIS 
SPG7 
 
FASLG 
MT-CO2 
 
ALDH1A1 
CYP27B1 
FMO6 
QPRT 
SPN 
 
FMOD 
MTHFR 
 
ALDH2 
CYP2A13 
G6PD 
RALBP1 
SULT1A1 
 
FOS 
NFE2L2 
 
ALDH3A1 
CYP2A6 
GSTA1 
RPL13 
SULT1A2 
 
FPGS 
NOS2 
 
ALDH3A2 
CYP2A7 
GSTA2 
RXRA 
SULT1A3 
 
GGH 
NOS3 
 
AOX1 
CYP2B6 
GSTA3 
SERPINA7 
SULT1B1 
 
GPNMB 
OR5H2 
 
APOA2 
CYP2B7P1 
GSTA4 
SLC10A1 
SULT1C2 
 
GPT 
PARD3B 
 
ARNT 
CYP2C18 
GSTA5 
SLC10A2 
SULT1C4 
 
GPX1 
PRKCZ 
 
ARSA 
CYP2C19 
GSTM1 
SLC13A1 
SULT1E1 
 
GPX3 
RASGRP1 
 
ATP7A 
CYP2C8 
GSTM2 
SLC15A1 
SULT2A1 
 
GPX4 
RB1 
 
ATP7B 
CYP2C9 
GSTM3 
SLC15A2 
SULT2B1 
 
GYS1 
RDH5 
 
CA5P 
CYP2D6 
GSTM4 
SLC16A1 
SULT4A1 
 
GYS2 
RIPK1 
 
CBR1 
CYP2E1 
GSTM5 
SLC19A1 
TBXAS1 
 
HCP5 
SOCS3 
 
CBR3 
CYP2F1 
GSTO1 
SLC22A1 
TPMT 
 
HGF 
SOD1 
 
CDA 
CYP2J2 
GSTP1 
SLC22A11 
TPSG1 
 
HLA-A 
SOD2 
 
CES2 
CYP2S1 
GSTT1 
SLC22A12 
TYMS 
 
HLA-B 
SPP1 
 
CHST1 
CYP39A1 
GSTT2 
SLC22A13 
UGT1A1 
 
HLA-DQA1 
SQSTM1 
 
CHST10 
CYP3A4 
GSTZ1 
SLC22A14 
UGT1A10 
 
HLA-DQB1 
ST6GAL1 
 
CHST11 
CYP3A43 
HMGCR 
SLC22A2 
UGT1A3 
 
HLA-DRB1 
STAT1 
 
 
 

SAP_000.pdf: 
 
Document Type: 
SAP 
Official Title: 
RANDOMIZED, MULTICENTER, PHASE III, OPEN-LABEL 
STUDY OF ALECTINIB VERSUS CRIZOTINIB IN 
TREATMENT-NAIVE ANAPLASTIC LYMPHOMA KINASE-
POSITIVE ADVANCED NON－SMALL CELL LUNG CANCER 
NCT Number: 
NCT02075840 
Document Date: 
SAP: 30 November 2015 
 
 
 




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Protocol BO28984     Report Number 1078196
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2/Statistical Analysis Plan BO28984, Version 4 
 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 6 
2. 
STUDY DESIGN ........................................................................................... 6 
2.1 
Protocol Synopsis .................................................................... 6 
2.2 
Determination of Sample Size ................................................. 7 
2.3 
Analysis Timing ....................................................................... 8 
3. 
STUDY CONDUCT ....................................................................................... 8 
3.1 
Randomization Issues ............................................................. 8 
3.2 
Independent Review Facility .................................................... 8 
3.3 
Data Monitoring ....................................................................... 9 
4. 
STATISTICAL METHODS ............................................................................ 9 
4.1 
Analysis Populations ............................................................... 9 
4.1.1 
Intent-To-Treat Population ....................................................... 9 
4.1.2 
Safety Population .................................................................... 9 
4.1.3 
FISH Positive Population ......................................................... 9 
4.1.4 
Pharmacokinetic-Evaluable Population ................................. 10 
4.2 
Analysis of Study Conduct ..................................................... 10 
4.3 
Analysis of Treatment Group Comparability .......................... 10 
4.4 
Efficacy Analysis .................................................................... 11 
4.4.1 
Primary Efficacy Endpoint ...................................................... 11 
4.4.2 
Secondary Efficacy Endpoints ............................................... 12 
4.4.2.1 
PFS by IRC ............................................................................ 12 
4.4.2.2 
Time to CNS Progression by IRC RECIST 
Criteria ................................................................................... 13 
4.4.2.3 
Objective Response Rate ...................................................... 13 
4.4.2.4 
Duration of Response ............................................................ 14 
4.4.2.5 
Overall Survival ..................................................................... 14 
4.4.2.6 
CNS Objective Response Rate according to 
RECIST v1.1 and RANO Criteria by IRC ............................... 14 
4.4.2.7 
CNS Duration of Response according to 
RECIST v1.1 and RANO Criteria by IRC ............................... 15 
4.4.3 
Exploratory Efficacy Endpoints .............................................. 15 


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4.4.4 
Sensitivity Analyses ............................................................... 15 
4.4.5 
Subgroup Analyses ............................................................... 16 
4.5 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 16 
4.6 
Safety Analyses ..................................................................... 17 
4.6.1 
Exposure of Study Medication ............................................... 17 
4.6.2 
Adverse Events ..................................................................... 17 
4.6.3 
Laboratory Data ..................................................................... 18 
4.6.4 
Vital Signs and ECOG Performance Status ........................... 19 
4.6.5 
Electrocardiograms ................................................................ 19 
4.7 
Patient-Reported Outcome Analyses .................................... 19 
4.7.1 
Time to Deterioration of Patient-Reported Lung 
Cancer Symptoms, Global Health Status, and 
Cognitive Function ................................................................. 20 
4.7.2 
Additional Patient-Reported Outcomes Analyses .................. 21 
4.8 
Exploratory Analyses ............................................................. 23 
4.9 
Interim Analyses .................................................................... 23 
5. 
REFERENCES ........................................................................................... 24 
 
 
LIST OF FIGURES 
Figure 1 
Summary of Study Design ............................................................ 6 
 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 25 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
or Term 
Definition 
ALK 
anaplastic lymphoma kinase 
CDOR 
CNS duration of response 
CORR 
CNS objective response rate 
CR 
complete response 
CSR 
Clinical Study Report 
CT 
computed tomography 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EORTC 
European Organization for Research and Treatment of Cancer 
FDA 
U.S. Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FPP 
FISH positive population 
HR 
hazard ratio 
iDCC 
independent Data Coordinating Cente 
iDMC 
independent Data Monitoring Committee 
IHC 
immunohistochemistry 
IRC 
Independent Review Committee 
ITT 
intent-to-treat 
IxRS 
interactive voice or Web-based response system 
MRI 
magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NE 
not evaluable 
NSCLC 
non−small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PRO 
patient-reported outcome 
PS 
Performance Status 
QLQ-C30 
Core Quality of Life Questionnaire 
QLQ-LC13 
Quality of Life Questionnaire Lung Cancer Module 
QoL 
quality of life 


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Abbreviation 
or Term 
Definition 
RANO 
Response Assessment in Neuro-Oncology 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SDF 
survival distribution function 
TTD 
time to deterioration 
ULN 
upper limit of normal 




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2.2 
DETERMINATION OF SAMPLE SIZE 
The focus of this clinical trial is hypothesis testing, and the primary endpoint of 
progression-free survival (PFS) was used to determine the sample size of the study. 
The Phase III PROFILE 1014 study of crizotinib versus standard 
pemetrexed−platinum-based chemotherapy in previously untreated patients with 
ALK-positive non-squamous NSCLC reported a median PFS of 10.9 months for 
crizotinib (Solomon et al. 2014).  A hazard ratio (HR) of 0.65 for alectinib versus 
crizotinib (i.e., an increase in median PFS from 10.9 months to 16.8 months) will be 
targeted. 
In this study, 286 patients will be enrolled in a 1:1 randomization allocation.  Enrollment 
will take approximately 24 months on the basis of an assumption of non-linear 
recruitment as follows: 
• 
Month 1:  1 patient per month 
• 
Month 2:  2 patients per month 
• 
Month 3:  4 patients per month 
• 
Month 4:  6 patients per month 
• 
Month 5:  8 patients per month 
• 
Month 6:  10 patients per month 
• 
Month 7:  12 patients per month 
• 
Months 8−12:  13 patients per month 
• 
Months 13−14:  14 patients per month 
• 
Month 15 onwards:  15 patients per month 
 
Approximately 170 PFS events are required to achieve 80% power of the log-rank test at 
a two-sided alpha level of 5%.  This number of events is estimated to occur 
approximately 33 months after the first patient has been enrolled. 
To illustrate sensitivity, if only 160 PFS events are observed by the clinical cutoff, the 
study has 78.1% power; if only 165 PFS events are observed, the study has 79.3% 
power with the assumed HR of 0.65 and an alpha of 0.05. 
No interim analysis for efficacy or futility is planned. 
An analysis of overall survival (OS) will be performed at the time of the final analysis of 
the primary endpoint of PFS.  A survival follow-up analysis will be performed once 
approximately 50% of patients (i.e., 143 patients) have died.  The median OS in the 
crizotinib arm is assumed to be 24 months and the expected median OS in the alectinib 
treatment arm is 30 months, equating to an HR of 0.83.  On the basis of the sample size 
(n = 286), the trial will not be powered to demonstrate a statistically significant difference 


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8/Statistical Analysis Plan BO28984, Version 4 
in OS of this magnitude.  At the time of the final analysis of the primary endpoint of PFS, 
on the basis of the above assumptions, 106 OS events are expected to have occurred.  
The events required for the survival follow-up analysis are expected to occur 
approximately 42 months after the first patient has been enrolled. 
2.3 
ANALYSIS TIMING 
This study is event driven with a recruitment period of approximately 24 months.  The 
required number of events for the primary analysis of the primary endpoint 
(investigator-assessed PFS) is expected approximately 33 months after the first patient 
has been enrolled.  If the alectinib median PFS by investigator is not estimable at the 
time of the primary analysis due to an insufficient number of events in this treatment arm, 
an exploratory update of PFS analysis will be performed when approximately 50% 
patients in the alectinib arm will have experienced a PFS event.  This analysis will be 
conduced purely for the purpose of obtaining a median estimate of PFS in the alectinib 
treatment arm, no formal treatment comparisons will be performed for this endpoint after 
the primary analysis.  
A survival follow-up analysis will be performed once approximately 50% of patients have 
died, which is estimated to occur approximately 42 months after the first patient has 
been enrolled. 
The study will formally end once the survival follow-up analysis is complete. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
Patients will be randomly assigned in a 1:1 allocation ratio to the two treatment arms via 
a block stratified randomization procedure. 
Randomization will guard against systematic selection bias and should ensure the 
comparability of treatment groups.  To assist balance in important prognostic factors, 
randomization will be stratified by Eastern Cooperative Oncology Group Performance 
Status (ECOG PS; 0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at 
baseline (yes vs. no). 
The randomization is checked three times during the study conduct by the independent 
Data Coordinating Center (iDCC). 
3.2 
INDEPENDENT REVIEW FACILITY 
An independent imaging group will be used to evaluate tumor assessments for 
determination of progression and response rate according to Response Evaluation 
Criteria in Solid Tumors (RECIST), Version 1.1 for the primary analysis.  Imaging studies 
(computed tomography [CT]/magnetic resonance imaging [MRI]/bone scans) will be 
acquired according to a standard protocol and will be forwarded to the independent 


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reviewers.  In addition, relevant cytologic and medical data (e.g., relevant cytology 
reports documenting malignant pleural effusions, bone marrow aspirations, cerebral 
spinal fluid, CNS symptoms, corticosteroid use, etc.) may be forwarded, if available, to 
the independent reviewers to aid with assessment of progressive disease (PD) and 
response.  Investigator tumor assessments will not be reconciled with the Independent 
Review Committee (IRC) tumor assessments.  Further details are included in the IRC 
Charter.  Details of imaging handling procedures are also described in a separate 
laboratory manual.  
For evaluation of the CNS endpoints, the IRC will perform an assessment of scans 
based on RECIST v1.1 and Response Assessment in Neuro-Oncology (RANO) criteria.  
More details are given in the IRC charter. 
3.3 
DATA MONITORING 
Although the study is open label, the Sponsor will not analyze aggregated data by 
treatment group before analysis of the primary endpoint of PFS. 
An independent Data Monitoring Committee (iDMC) has been incorporated into the trial 
design to objectively and carefully review the accumulating safety data for alectinib.  
Regular safety interim analyses to be reviewed by the iDMC have been planned to 
evaluate safety information from the study.  Outputs for these reviews are prepared by 
an external iDCC. 
4. 
STATISTICAL METHODS 
The analyses outlined in this Statistical Analysis Plan (SAP) supersede those specified 
in the protocol for the purpose of a regulatory filing. 
4.1 
ANALYSIS POPULATIONS 
4.1.1 
Intent-To-Treat Population 
The primary analysis population for efficacy is the intent-to-treat (ITT) population, 
defined as all randomized patients.  Patients will be assigned to the treatment group to 
which they were randomized. 
4.1.2 
Safety Population 
The primary analysis population for safety is the Safety Population, defined as all 
patients who received at least one dose of study medication.  Patients will be assigned 
to treatment groups as treated, and all patients who received any dose of alectinib will 
be included in the alectinib treatment arm. 
4.1.3 
FISH Positive Population 
A secondary analysis population for efficacy is the fluorescence in situ hybridization 
(FISH) Positive Population (FPP), defined as all patients in the ITT population who were 
ALK-positive as assessed using the Vysis FISH assay.  Patients will be assigned to the 


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treatment group to which they were randomized.  A supportive efficacy analysis will be 
performed based on the FISH assay rather than the IHC. 
An analysis of the primary endpoint of investigator-assessed PFS based on the FPP will 
be performed at the time of the primary analysis.  T-tests to compare baseline 
characteristics by treatment group will be performed to assess any imbalance between 
treatment arms in the FPP.  In the event that the randomization is not maintained in the 
FPP (t-test p<0.01), log-rank analyses of investigator-assessed PFS will be stratified by 
randomization strata and the significant baseline characteristics will be included in the 
Cox model.  A major discrepancy between the Ventana IHC assay and the Vysis FISH 
assay may necessitate a follow-up analysis of the primary endpoint based on 
approximately 170 PFS events observed in the FPP to ensure 80% power of the 
log-rank test under the assumption of an HR of 0.65 in this secondary population. 
4.1.4 
Pharmacokinetic-Evaluable Population 
The Pharmacokinetic-Evaluable Population is defined as all patients who received any 
dose of study medication and who have at least one post-baseline pharmacokinetic (PK) 
sample available. 
4.2 
ANALYSIS OF STUDY CONDUCT 
Study enrollment, patient disposition, reasons for discontinuation from the study 
treatment, and reason for study termination will be summarized for all patients in the ITT 
population. 
Protocol deviations, including violations of inclusion and/or exclusion criteria and 
deviations during study conduct will be reported and summarized. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Demographic, baseline disease characteristics, and lung cancer history, including prior 
brain radiation, will be compared descriptively between both treatment arms for the ITT 
population.  Descriptive baseline summaries of continuous data will present the group 
mean, standard deviation, median, minimum, and maximum.  Descriptive baseline 
summaries of discrete data will present the category counts as frequencies and 
percentages. 
A summary of concordance of stratification factors determined by electronic Case Report 
Form (eCRF) versus interactive voice or Web-based response system (IxRS) will also be 
reported. 
The baseline value of any variable will be defined as the last available value recorded 
prior to the first administration of study medication. 


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Previous and concomitant cancer therapy will also be summarized, including 
radiotherapy and surgery, as well as subsequent anti-cancer therapy.  Previous and 
concurrent diseases and medications will also be summarized. 
The Abbott Vysis FISH test will be used as an exploratory assay after patients have 
been enrolled in this study.  A descriptive summary of baseline characteristics, including 
randomization strata by treatment arm, will be produced for the FPP to assess treatment 
group comparability. 
4.4 
EFFICACY ANALYSIS 
4.4.1 
Primary Efficacy Endpoint 
PFS is defined as the time from date of randomization to the date of first documented 
disease progression or death, whichever occurs first.  The primary endpoint of PFS will 
be determined on the basis of investigator assessment of progression using 
RECIST v1.1.  Patients who have not experienced disease progression or death at the 
time of analysis will be censored at the last tumor assessment date either during study 
treatment or during follow-up.  Patients with no post-baseline tumor assessment will be 
censored at the date of randomization. 
Patients who discontinue treatment prior to disease progression (e.g., due to toxicity) will 
continue in the study and will be followed until disease progression and for OS 
regardless of whether they subsequently receive anti-cancer therapy. 
The treatment comparison of PFS will be based on a stratified log-rank test at the 
5% level of significance (two-sided).  The randomization stratification factors are 
ECOG PS (0/1 vs. 2) and race (Asian vs. non-Asian), as recorded on the eCRF, and 
CNS metastases at baseline (yes vs. no).  These factors will be included in the stratified 
log-rank analysis as long as an individual stratum includes > 10% of the ITT population.  
For analysis purposes, stratification according to CNS metastases at baseline will be 
performed on the basis of the IRC assessment rather than the investigator assessment, 
given that the independent assessment by neuroradiologists is deemed to be the most 
reliable and will correspond to the populations used to assess the CNS efficacy 
endpoints.  Results from an unstratified log-rank test will also be presented as a 
supportive analysis. 
Because patients were stratified on the basis of CNS metastases at baseline by 
investigator assessment, baseline characteristics grouped by CNS metastases at 
baseline by IRC will be summarized by treatment arm.  Concordance of CNS 
metastases at baseline between investigator and IRC will also be reported.  
Additional supportive analyses include Kaplan-Meier and Cox modelling approaches.  
The Kaplan-Meier method will be used to estimate the median PFS for each treatment 
arm with 95% confidence limits, and a Kaplan-Meier curve will be constructed to provide 
a visual description of the difference between the treatment arms.  A stratified Cox 


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proportional hazard regression model will be used including treatment in order to provide 
an estimate of the treatment effect expressed as an HR (alectinib vs. crizotinib), as well 
as a 95% CI.  The proportional hazards assumption will be assessed both graphically 
from the Kaplan-Meier plot as well as by adding a treatment by time interaction term to 
the Cox regression model.  If the proportional hazards assumption is not met, alternative 
appropriate methods will be used. 
The difference between the two treatment groups for the primary objective will be 
assessed and tested for the following hypothesis:  the survival distribution function (SDF) 
of the alectinib treatment group is the same as for the crizotinib treatment group versus 
the alternative that the two distributions are different:  
H0:  SDF (alectinib) = SDF (crizotinib) 
versus 
HA:  SDF (alectinib) ≠
 SDF (crizotinib), 
where SDF denotes the survival distribution function of the parameter PFS. 
4.4.2 
Secondary Efficacy Endpoints 
All secondary efficacy endpoints will be analyzed in the ITT population unless otherwise 
specified. 
If the primary endpoint of investigator-assessed PFS is statistically significant at a 
two-sided 5% significance level based on the stratified log-rank test, the following 
secondary endpoints will be tested in the following sequential order (O’Neill 1997), each 
at a two-sided 5% significance level: 
• 
PFS by IRC 
• 
Time to CNS progression by IRC RECIST criteria 
• 
Objective response rate (ORR) by investigator assessment  
• 
OS 
 
All tests in the sequence will be based on a stratified log-rank test at the 5% level of 
significance (two-sided).  The stratification factors included and the analysis population 
will be the same as for the primary hypothesis test.  Results from unstratified tests will 
also be presented as supportive analyses. 
4.4.2.1 
PFS by IRC 
An analysis of PFS on the basis of the IRC assessments will be performed using the 
same methodology as specified for PFS on the basis of investigator assessment. 
A concordance analysis between the IRC-determined and the investigator-determined 
PD status (yes vs. no) will be provided by treatment arm together with a summary of 
agreement between the IRC-determined and the investigator-determined PD dates.  The 
early discrepancy rate (investigator assessed prior to IRC) and the late discrepancy rate 


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(investigator assessed after IRC) will be calculated for each treatment arm and the 
differential discordance calculated as the rate on the alectinib arm minus the rate on the 
crizotinib arm (Amit et al. 2011).  In addition, a table will be created displaying the 
number of visits with investigator tumor assessment but missing IRC assessment. 
4.4.2.2 
Time to CNS Progression by IRC RECIST Criteria 
Time to CNS progression is defined as the time from randomization until first 
radiographic evidence of CNS progression by independent review.  An independent 
central radiological review will be performed for all patients, and the analysis of CNS 
progression will be based on the data from the independent review.  All patients in the 
ITT population will be included in the analysis regardless of their baseline status of CNS 
metastases.  CNS progression is defined as progression due to newly developed CNS 
lesions and/or progression of preexisting baseline CNS lesions.  On the basis of 
RECIST v1.1, this is defined as a new post-baseline CNS/brain lesion(s) and/or an 
increase of ≥ 20% in the sum of longest diameters of the measurable baseline CNS 
lesions compared with nadir and/or unequivocal progression of non-measurable baseline 
CNS lesions. 
In order to account for the competing risks inherent in the comparison of CNS 
progression between alectinib and crizotinib, a stratified two-sided log-rank test will be 
computed on the basis of a cause-specific hazard function.  Results from unstratified 
tests will also be presented as supportive analyses. 
The probability of CNS progression, non-CNS progression, and death by treatment 
group with 95% CIs will each be estimated using cumulative incidence functions.  Gray’s 
test to compare the risk of CNS progression between alectinib and crizotinib will also be 
performed as a supportive analysis. 
Similar analyses of CNS progression based on IRC RANO criteria will be performed. 
4.4.2.3 
Objective Response Rate 
ORR, on the basis of investigator assessment, is defined as the percentage of patients 
in the ITT population with measurable disease at baseline who attain a complete 
response (CR) or partial response (PR).  Per RECIST v1.1, confirmation of objective 
response is not required for this secondary endpoint.  Patients without a post-baseline 
tumor assessment will be considered non-responders, as will patients with a best overall 
response of stable disease (SD), PD, or not evaluable (NE). 
An estimate of ORR and its two-sided 95% CI will be calculated using the 
Clopper-Pearson method for each treatment arm.  Response rates in the treatment 
groups will be compared using a stratified Mantel-Haenszel test, including the 
randomization stratification factors.  Results from unstratified tests will also be presented 
as supportive analyses.  The difference in ORR between the two treatment arms will be 


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presented together with a two-sided 95% CI on the basis of a normal approximation to 
the binomial distribution. 
ORR by IRC will be analyzed similarly as a supportive analysis in the population of 
patients identified to have measureable disease at baseline according to the IRC. 
4.4.2.4 
Duration of Response 
For patients with measurable disease at baseline who have experienced an objective 
response (CR or PR) during the study as assessed by the investigator, duration of 
response (DOR) is defined as the duration from the first tumor assessment that supports 
the patient’s objective response (CR or PR, whichever is first recorded) to first 
documented disease progression or death due to any causes, whichever occurred first.  
Patients who have not progressed or died at the time of analysis will be censored at the 
last tumor assessment date.  Because the determination of DOR is based on a 
non-randomized subset of patients, formal hypothesis testing will not be performed.  
DOR will be estimated using Kaplan-Meier methodology and an HR and its 95% CI on 
the basis of a Cox proportional regression model with stratification factors will be 
calculated.  The proportional hazards assumption will be assessed graphically. 
4.4.2.5 
Overall Survival 
OS is defined as the time from the date of randomization to the date of death due to any 
cause.  Patients who are not reported as having died at the time of analysis will be 
censored at the date when they were last known to be alive.  Patients who do not have 
post-baseline information will be censored at the date of randomization.  OS will be 
analyzed using the same methodology as specified for the primary endpoint.  A survival 
follow-up analysis will be performed based on more mature data. 
4.4.2.6 
CNS Objective Response Rate according to RECIST v1.1 and 
RANO Criteria by IRC 
CNS objective response rate (CORR) will be summarized by treatment group in the 
subgroup of patients in the ITT population who have measurable CNS lesions at 
baseline as determined by the IRC.  These summaries will be provided for both 
RECIST v1.1 and RANO.  CNS responses according to RECIST v1.1 do not have to be 
confirmed, whereas confirmation is incorporated into the RANO criteria. 
CORR will be summarized by treatment group in the subgroup of patients in the ITT 
population who have measurable and non-measurable CNS lesions at baseline as 
determined by the IRC.  For this analysis, patients with non-measurable CNS disease at 
baseline by IRC who experience a CR in CNS lesions will be included as responders. 
In addition, a subgroup analysis of CORR will be performed according to prior brain 
radiation status (yes vs. no) for the two analysis populations above. 


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4.4.2.7 
CNS Duration of Response according to RECIST v1.1 and 
RANO Criteria by IRC 
This analysis will be performed including all patients in the ITT population who have 
measurable CNS lesions at baseline as determined by the IRC who had a CNS 
response (CR or PR).  CNS duration of response (CDOR) is the time from CNS 
response to CNS PD by IRC. 
4.4.3 
Exploratory Efficacy Endpoints 
The Abbott Vysis FISH test will be used as an exploratory assay after patients have 
been enrolled in this study.  As part of the rationale for the biomarker assessment, 
results from these analyses will be used to quantify the degree of correlation between 
FISH and IHC for the detection of ALK-positive NSCLC.  The proportion of patients in 
the ITT population who have ALK-positive NSCLC by the FISH assay will be 
summarized.  The FPP will be a secondary analysis population for efficacy.  This 
analysis population will be used to perform a supportive analysis of the study data based 
on the FISH assay rather than the IHC.   
4.4.4 
Sensitivity Analyses 
A sensitivity analysis will be performed on the primary endpoint of PFS with the following 
changes from the primary analysis: 
• 
Censor patients at the last adequate tumor assessment prior to the start of 
non−protocol-specified anti-cancer therapy received prior to observing 
progression. 
• 
Censor patients for whom documentation of disease progression or death 
occurs after ≥ 2 missed tumor assessments.  These patients will be censored at 
the last tumor assessment prior to the missed assessments. 
• 
Censor patients who discontinue study treatment (due to personal preference 
or toxicity) and/or withdraw or are lost to follow-up prior to observing 
progression. 
 
Two additional sensitivity analyses for PFS include: 
• 
The effect of missing tumor assessments will be assessed if the number of 
missing assessments in either arm is > 5%.  For patients with progression 
determined following one or more missing tumor assessments, the progression 
will be backdated to the first missing tumor assessment. 
• 
The effect of loss to follow-up will be assessed depending on the number of 
patients who are lost to follow-up.  If > 5% of patients are lost to follow-up for 
PFS in either treatment arm, a “worst-case” analysis will be performed in which 
patients who are lost to follow-up will be considered to have progressed at the 
last date they were known to be progression-free. 
 


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Summary statistics on timing of scans (regardless of outcome) will be provided by 
treatment arm.  Nelson-Aalen methods may be used to estimate the cumulative hazard 
rate. 
A sensitivity analysis for PFS and OS will be performed based on the stratification 
factors entered at randomization in the IxRS system. 
4.4.5 
Subgroup Analyses 
PFS by investigator and IRC assessments will be presented separately for important 
subgroups including age (< 65, ≥ 65), sex, race (Asian, non-Asian), and smoking status 
and baseline prognostic characteristics including baseline ECOG PS, CNS metastases 
at baseline as determined by IRC, and prior brain radiation (in patients with CNS 
metastases at baseline).  The HR including a 95% CI will be presented separately for 
each level of the categorical variables. 
4.5 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Standard non-compartmental analysis may be conducted for PK data collected from 
patients participating in serial and/or intensive PK collections for relevant analytes, as 
data allow, as appropriate, and if needed.  PK parameters, including but not limited to 
area under the concentration-time curve, maximum concentration, and time to maximum 
concentration, will be calculated on the basis of the available data as appropriate and 
where data allow.  Additional PK parameters may be calculated as deemed appropriate. 
Individual and mean plasma concentrations at each sampling timepoint and/or PK 
parameters for alectinib and metabolite(s) will be listed, as appropriate. 
Summary statistics (e.g., means, standard deviation, coefficient of variation percent, 
geometric means, medians, and ranges) for plasma concentrations and/or PK 
parameters for alectinib and metabolite(s) will be presented by nominal collection times 
(plasma concentrations only), as appropriate.  Additional plots or summary statistics may 
be constructed or calculated, as appropriate. 
Results of PK and/or any PK/pharmacodynamic analyses may be reported outside the 
Clinical Study Report (CSR). 
Non-linear mixed-effects modeling (with software NONMEM) will be used to analyze the 
sparse and/or serial/intensive plasma concentration-time data for alectinib.  The PK data 
from this study may be pooled with data from other studies.  Population and individual 
PK parameters will be estimated and the influence of various covariates (such as age, 
sex, and body weight) on these parameters will be investigated. 
Exploratory analyses will be conducted to investigate the relationship between alectinib 
PK exposure and efficacy/safety parameters. 


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Results of the mixed-effects modeling and exploratory analyses will be reported in a 
document separate from the CSR. 
4.6 
SAFETY ANALYSES 
All safety analyses will be performed on the Safety Population; that is, all patients who 
receive any dose of study medication (see Section 4.1.2) by treatment arm with all 
patients who received any dose of alectinib will be included in the alectinib treatment 
arm. 
4.6.1 
Exposure of Study Medication 
Study treatment (alectinib and crizotinib) exposure, including treatment duration, dose 
intensity, number of doses, percentage of planned dose, and total cumulative dose will 
be summarized with descriptive statistics.  The number of missed doses will also be 
displayed.  
4.6.2 
Adverse Events 
Verbatim description of adverse events will be mapped to MedDRA thesaurus terms and 
graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 4.0 (NCI CTCAE v4.0).  All adverse events occurring during or 
after the first study treatment will be listed and summarized by mapped term, appropriate 
thesaurus level and NCI CTCAE grade. 
Summary tables of the following will be provided: 
• 
All adverse events 
• 
Serious adverse events 
• 
Severe adverse events (Grade 3 or higher) 
• 
Adverse events leading to study treatment discontinuation  
• 
Adverse events leading to dose reduction 
• 
Adverse events leading to dose interruption 
• 
Treatment-related adverse events 
• 
Adverse events leading to death 
• 
Adverse events by highest NCI CTCAE grade 
• 
Selected adverse events relating to ALK inhibitors and/or the tyrosine kinase 
inhibitor class and alectinib data 
 
A summary table of common adverse events, that is, those occurring in at least 10% of 
patients, will be provided. 


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Selected adverse events are defined as follows: 
• 
Hepatotoxicity 
• 
Interstitial lung disease 
• 
Vision disorders 
• 
Skin disorders (e.g., photosensitivity, rash) 
• 
Anemia 
• 
Gastrointestinal disorders (e.g., nausea, vomiting, diarrhea) 
• 
Abnormal renal function (e.g., serum creatinine increase, renal impairment, 
renal failure) 
• 
Severe myalgia and CPK elevations 
• 
Edema 
• 
Bradycardia 
 
Rates of each selected adverse event group will be summarized including incidence of 
Grade 3 or higher events, serious adverse events, and treatment-related events. 
Multiple occurrences of the same event will be counted once at the maximum severity.  
All deaths and causes of death will be summarized. 
Adverse events by sex, age (< 65 vs. ≥ 65 years), race (non-Asian vs. Asian), and CNS 
metastases at baseline (yes vs. no) will be presented. 
4.6.3 
Laboratory Data 
Laboratory data will be classified according to NCI CTCAE v4.0 and will be summarized 
descriptively over time, including change from baseline.  Highest NCI CTCAE grade after 
baseline will also be reported and shift tables from baseline to worst value during the 
study post-baseline will be presented.  An additional shift table for serum creatinine will 
include only elevations above the upper limit of normal (ULN) (i.e., elevations above 
baseline, which are included in the full NCI CTCAE v4.0 definition, will be excluded from 
this shift table). 
A Hy’s law analysis will be provided.  The potential Hy’s law quadrant is defined as ALT 
or AST increases above 3-fold the ULN with concomitant total bilirubin increases above 
2-fold the ULN.  
In order to evaluate and compare potential hypogonadism in the two treatment arms, 
total and free testosterone, sex hormone-binding globulin (if available), 
follicle-stimulating hormone, and luteinizing hormone levels in the blood will be 
summarized for males by treatment arm over time. 


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4.6.4 
Vital Signs and ECOG Performance Status 
Vital signs will be summarized descriptively by treatment group over time, including 
change from baseline.  ECOG PS will also be tabulated over time by treatment group. 
4.6.5 
Electrocardiograms 
The following parameters are captured on the eCRF and will be listed and summarized 
by treatment group over time:  heart rate; RR (time from one R wave to next R wave); 
PQ; QRS and QT duration; and QT interval corrected using Fridericia’s formula. 
4.7 
PATIENT-REPORTED OUTCOME ANALYSES 
Through the use of the European Organization for Research and Treatment of Cancer 
(EORTC) Core Quality of Life Questionnaire (QLQ-C30) and EORTC Quality of Life 
Questionnaire Lung Cancer Module (QLQ-LC13), lung cancer symptoms, symptoms 
commonly associated with cancer treatments, and disease and treatment’s impact on 
patients’ functioning and health-related quality of life will be collected at every study visit 
(Week 4, Week 8, and then after every 4 weeks) until disease progression and during 
post-progression treatment in case of isolated, asymptomatic CNS progression; at 
post-treatment visit (4 weeks after permanent treatment discontinuation); and at 
subsequent 8-weekly survival follow-up visits for 6 months.  For patients who discontinue 
treatment for reasons other than disease progression and who progress within the first 
6 months of survival follow-up, patient-reported outcome (PRO) measures will be 
administered every 4 weeks until disease progression and then decreased to every 
8 weeks until 6 months post-treatment.  For patients who discontinue treatment for 
reasons other than disease progression and have not yet progressed at 6 months 
post-treatment, PRO measures will be administered every 4 weeks until disease 
progression and will no longer be required thereafter.  
The baseline PRO assessment will be the first PRO assessment completed within 
7 days of randomization.  For the following PRO analyses, there may be multiple PRO 
assessments completed within the same calendar day; the earliest assessment will be 
used for analysis.  In the cases that there are multiple PRO assessments completed 
within the same time window scheduled for PRO assessments, the PRO assessment 
closest to the visit will be chosen for analysis. 
The EORTC QLQ-C30 and EORTC QLQ-LC13 will be scored according to the EORTC 
scoring manual 3rd edition (Fayers et al. 2001).  The QLQ-C30 and QLQ-LC13 are 
composed of both multi-item scales and single-item measures including functional 
scales, symptom scales, and a global health status/quality of life (QoL) scale. 
For multi-item subscales, if ≤ 50% of items within the multi-item subscale are missing at 
a given timepoint, the multi-item score will be calculated on the basis of the non-missing 
items.  If > 50% of items are missing or if a single-item measure is missing, the subscale 
is missing. 


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All of the scales and single-item measures will be linearly transformed so that each 
score will range from 0 to 100.  A high score for a functional scale represents a 
high/healthy level of functioning, a high score for the global health status/QoL represents 
a high QoL; however, a high score for a symptom scale/item represents a high level of 
symptomatology/problems. 
The EuroQoL 5 Dimension questioannire analyses are out of scope of this SAP. 
4.7.1 
Time to Deterioration of Patient-Reported Lung Cancer 
Symptoms, Global Health Status, and Cognitive Function 
Time to deterioration (TTD) analyses will be performed on lung cancer symptom scores, 
global health status scores, and cognitive function scale scores in the ITT population and 
will include all data collected through disease progression and survival follow-up. 
TTD is defined as the time from randomization until the first confirmed clinically 
meaningful deterioration.  Confirmed clinically meaningful deterioration in lung cancer 
symptoms is defined as a ≥ 10-point increase from baseline in a symptom score that 
must be held for at least two consecutive assessments or an initial ≥ 10-point increase 
above baseline followed by death within 5 weeks from the last assessment.  Conversely, 
confirmed clinically meaningful deterioration in global health status or function is defined 
as a ≥ 10-point decrease from baseline in a symptom score that must be held for at least 
two consecutive assessments or an initial ≥ 10-point decrease from baseline followed by 
death within 5 weeks from the last assessment.  A ≥ 10-point change in the score is 
perceived by patients as being clinically significant (Osoba et al. 1998).   
TTD will be documented for each of the following symptom, global health status, or 
cognitive function scale scores: 
• 
Cough (Question 31 on the EORTC QLQ-LC13) 
• 
Dyspnea single item (Question 8 on the QLQ-C30) 
• 
Dyspnea multi-item subscale (Questions 33-35 on the QLQ-LC13) 
• 
Chest pain (Question 40 on the QLQ-LC13) 
• 
Arm and/or shoulder pain (Question 41 on the QLQ-LC13) 
• 
Fatigue multi-item subscale (Questions 10, 12, and 18 on the QLQ-C30) 
• 
Global Health Status scale (Questions 29 and 30 on the QLQ-C30) 
• 
Cognitive Function Scale (Questions 20 and 25 on the QLQ-C30) 
 
In addition to those single symptom endpoints, a 3-symptom composite endpoint will 
also be assessed.  In this instance, symptom deterioration will be determined as 
a ≥ 10-point increase above baseline in any of the following lung cancer symptom scores, 
whichever occurs first (cough, chest pain, and dyspnea multi-item subscale).  In the 
same manner as the single symptom endpoints, symptom deterioration will need to be 
confirmed for the original symptom; a ≥ 10-point increase from baseline in a symptom 


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score (i.e., cough) that must be held for at least two consecutive assessments 
(i.e., cough for two assessments) or an initial ≥ 10-point increase above baseline 
followed by death within 5 weeks from the last assessment. 
Patients without baseline or post-baseline EORTC symptom or scale scores will be 
censored at the date of randomization.  Patients without deterioration at the time of 
analysis will be censored at the last time they were known to have not deteriorated.  
There will be no imputation for missing data for the TTD analysis.  If there is a 
substantial amount of missingness, patient baseline and disease characteristics will be 
compared between patients with and without missing baseline assessments using 
descriptive statistics.  
TTD of the prespecified symptoms will be summarized using the Kaplan-Meier method.  
The estimated Kaplan-Meier plots will be provided for each score previously described 
(including the 3-symptom composite score).  A stratified log-rank test will be the primary 
method to compare the time to first deterioration between the treatment groups.  The 
median time and two-sided 95% CI for the median will also be provided.  Estimates of 
the treatment effect will be expressed as HRs with use of a stratified Cox model, 
including 95% CIs for the ITT population.   
A sensitivity analysis will be performed to account for multiple PRO assessments 
completed within 7 days of randomization, the same day, or multiple assessments 
completed within the same time window scheduled for PRO assessments.  The 
sensitivity analyses will use the following data: 
• 
In the case that there are multiple baseline PRO assessments completed within 
7 days of randomization, the assessment with the best score (lowest score for 
symptoms, highest score for global health status or function scales) for any of 
the pre-specified scores will be selected. 
• 
In case of multiple assessment within the same calendar day, the worst score 
(highest score for symptoms, lowest score for global health status or function 
scales) for any of the prespecified scores will be selected. 
• 
In the case of multiple assessments within a single time window scheduled for 
PRO assessments, the assessment with the worst score (highest score for 
symptoms, lowest score for global health status or function scales) for any of 
the prespecified scores will be selected. 
 
There is risk that PFS endpoints (or death) may confound differences in CNS events and 
in PRO cognitive function, therefore, a competing risks analysis may be done on the 
TTD for Cognitive Function. 
4.7.2 
Additional Patient-Reported Outcomes Analyses 
Only patients in ITT population with a baseline assessment and at least one 
post-baseline assessment (PRO-evaluable subset) will be included in the following 


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analyses.  Missing post-baseline items and subscales will not be imputed and will be 
summarized as observed.   
Compliance rates will be summarized by listing the number and proportion of patients in 
the PRO-evaluable subset who completed the PRO assessments at each timepoint by 
treatment arm.  Reasons for non-completion will be summarized, if available, in the CRF. 
All of the following analyses will be performed on all timepoints during the treatement 
period as well as at the time of disease progression per RECIST v1.1 (PRO assessment 
completed within ± 7 days of date of radiographic pharmacodynamic) at the last dose of 
treatment received before treatment discontinuation of any cause, at the 4-week 
post-treatment discontinuation visit, and at the 8-weekly survival follow-up visits through 
6 months. 
• 
EORTC scores and change from baseline will be descriptively analyzed using 
means, standard deviations, medians, and range, by treatment arm at baseline 
and each of the timepoints previously defined.   
• 
The number and proportion of patients at each of the 4-response category 
reflecting no symptom/impairment to severe symptom/impairment will be 
documented at baseline. 
• 
Graphs of the mean changes and standard errors over time from the baseline 
assessment of items and subscales will be provided for each treatment arm.   
• 
The number and proportion of patients who improved, worsened, or remained 
stable compared with baseline score will be summarized for all item-score and 
subscales score of the EORTC QLQ-C30 questionnaire and the QLQ-LC13 by 
treatment arm at baseline and each of the timepoints previously defined.  This 
analysis should be performed for the PRO-evaluable population as well as the 
subgroups of the patients with/without CNS metastases at baseline.  A patient 
will be deemed improved at a timepoint if there is a ≥ 10-point decrease from 
baseline for any symptom or a ≥ 10-point increase from baseline for any 
functioning scales or global health status scale.  A patient will be deemed 
worsened at that timepoint if they have a ≥ 10-point increase from baseline for 
any symptom or a ≥ 10-point decrease from baseline for any functioning scales 
or global health status.  If patients do not fit the improved or worsened criteria, 
they will be defined as stable for that specific item/scale at that timepoint.   
 
Additional analyses will be conducted specifically for the cognitive function scale per the 
EORTC QLQ-C30: 
• 
The number and proportion (%) of patients with ≥ 10-point decrease from 
baseline in the Cognitive Function Scale score per the EORTC QLQ-C30 in 
each treatment arm at (1) any point during the treatment or (2) at date of CNS 
Progression (PRO assessment completed within ± 7 days of date of CNS PD).  
This analysis will not include PRO data from the 4-week post-treatment 
discontinuation visit or the PRO data collected at the 8-weekly survival 
follow-up visits through 6 months. 


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• 
A histogram of worst change scores from baseline (decline of 16.66 vs. 33.33 
vs. 50 vs. 66.66 vs. 83.33 vs. 100 points from baseline) in the Cognitive 
Function Scale score in each treatment arm at any point on treatment.  This 
analysis will not include PRO data from the 4-week post-treatment 
discontinuation visit or the PRO data collected at the 8-weekly survival 
follow-up visits through 6 months.  
 
4.8 
EXPLORATORY ANALYSES 
Exploratory outcome measures defined in the protocol other than the Abbot Vysis FISH 
subgroup analysis (see Section 4.4.3) and onset of hypogonadism in adult men are 
outside of the scope of this SAP and will not be included in the CSR. 
The objective to determine the correlation between ALK status as assessed by plasma 
ALK polymerase chain reaction and/or plasma ALK sequencing tests with ALK status 
obtained using the Ventana ALK IHC and FISH Vysis ALK Break Apart FISH Probe Kit 
(Abbott) is out of scope of this SAP and will be conducted outside of the CSR analyses. 
4.9 
INTERIM ANALYSES 
No interim analysis for efficacy or futility is planned.  
 


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5. 
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Fayers PM, Aaronson N, Bjordal K, et al. The EORTC QLQ-C30 Scoring Manual (3rd 
Edition). Brussels: EORTC, 2001. 
Osoba D, Rodriguez G, Myles J, et al. Interpreting the significance of changes in 
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ALK-positive lung cancer. N Engl J Med 2014;371:2167−77.