Clinical trial NCT02604342
Conditions: Non-small Cell Lung Cancer
Sponsor: Hoffmann-La Roche
Start date: 2015-11-03; Completion date: 2018-08-13
Enrollment: 119 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized active-controlled multicenter Phase III open-label study will evaluate and compare between treatment groups the efficacy of alectinib versus chemotherapy in participants with ALK-positive advanced NSCLC who were previously treated with chemotherapy and crizotinib, as measured by investigator-assessed progression-free survival (PFS) and to evaluate and compare between treatment groups the central nervous system (CNS) objective response rate (C-ORR) in participants with measurable CNS metastases at baseline, as assessed by an Independent Review Committee (IRC).

Detailed description:

Arms: arm 1: Participants will receive oral alectinib at a dose of 600 milligrams (mg) twice daily, taken with food until disease progression, unacceptable toxicity, withdrawal of consent or death. arm 2: Participants will receive chemotherapy with either pemetrexed (500 milligrams per square meter \[mg/m\^2\] of body surface area) or docetaxel (75 mg/m\^2) intravenously.
Interventions: intervention 1: Alectinib intervention 2: Docetaxel intervention 3: Pemetrexed
Intervention descriptions: intervention 1: Participants will receive oral alectinib at a dose of 600 mg twice daily, taken with food until disease progression, unacceptable toxicity, withdrawal of consent or death. intervention 2: Participants will receive docetaxel at a dose of 75 mg/m\^2 of body surface area intravenously every 3 weeks, until disease progression, unacceptable toxicity, withdrawal of consent or death. intervention 3: Participants will receive pemetrexed at a dose of 500 mg/m\^2 of body surface area intravenously every 3 weeks, until disease progression, unacceptable toxicity, withdrawal of consent or death.

Protocol documents:
Prot_002.pdf: 
 
Official Title: 
 
RANDOMIZED, MULTICENTER, PHASE III, OPEN-LABEL 
STUDY OF ALECTINIB VERSUS PEMETREXED OR DOCETAXEL 
IN ANAPLASTIC LYMPHOMA KINASE-POSITIVE ADVANCED 
NON-SMALL CELL LUNG CANCER PATIENTS PREVIOUSLY 
TREATED WITH PLATINUM-BASED CHEMOTHERAPY AND 
CRIZOTINIB 
NCT Number: NCT02604342 
Document Date: Protocol Version 7.1: 01-Dec-2017 
 
 


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 MO29750, Final Version 7.1
1
PROTOCOL
TITLE:
RANDOMIZED, MULTICENTER, PHASE III, OPEN-
LABEL STUDY OF ALECTINIB VERSUS 
PEMETREXED OR DOCETAXEL IN ANAPLASTIC 
LYMPHOMA KINASE-POSITIVE ADVANCED NON-
SMALL CELL LUNG CANCER PATIENTS 
PREVIOUSLY TREATED WITH PLATINUM-BASED 
CHEMOTHERAPY AND CRIZOTINIB
PROTOCOL NUMBER:
MO29750
VERSION NUMBER:
7.1
EUDRACT NUMBER:
2015-000634-29
IND NUMBER:
111723
TEST PRODUCT:
Alectinib (RO5424802) 
MEDICAL MONITOR:
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1.0: 28 May 2015
DATE AMENDED
Version 2.0: 26 Nov 2015
Version 3.0: Not submitted (due to typos)
Version 4.0: 20 May 2016
Version 5.0: 7 December 2016
Version 6.0: 20 June 2017 (Hong Kong and Turkey)
Version 7.1: See electronic stamp below
 
01-Dec-2017 18:49:16
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Alectinib—F. Hoffmann-La Roche Ltd
2/Protocol MO29750, Final Version 7.1
Rationale for Revisions
PROTOCOL AMENDMENT, VERSION 7.1:
RATIONALE
Specific changes in Version 7.1 and their rationale are as follows:

Subsequent to its primary completion date (January 26, 2017), Study MO29750 was 
found to have met its primary objective, i.e., median PFS assessed by the 
investigator was 9.6 months for alectinib (95% CI: 6.9–12.2 months) versus 
1.4 months for chemotherapy (95% CI: 1.3–1.6; p<0.001).1  Furthermore, the safety 
profile for alectinib was consistent with previous studies and compared favorably 
with chemotherapy.  Given these results—as well as the fact that participants now 
have access to alectinib by other means, either as a marketed and reimbursed drug 
(per prescription) (Alecensa®), in a Roche Post-Trial Access program or in a roll-
over extension study (BO39694), depending on the drug approval and 
reimbursement status in the country—the number of assessments and patient visits
during the follow-up period has been reduced in an effort to improve patient 
convenience.  Specifically, the follow-up period after last patient randomized has 
been reduced from 24 months to 14 months.  

Efficacy analyses of Study MO29750 also showed that median PFS assessed by 
the IRC was 7.1 months for alectinib versus 1.6 months for chemotherapy (HR=0.32, 
95% CI 0.17–0.59; p<0.001).  As the primary objective has now been addressed, 
and as both the investigator and IRC assessments found similar highly significant 
benefits of alectinib relative to chemotherapy, the protocol has been amended such 
that it no longer mandates ongoing IRC review.  To ensure that all patients are 
captured in final analyses (a small number of participants [n=12] enrolled after the 
primary analysis cut-off date), the IRC will continue its review for up to 12 weeks 
after the last patient in.  This will allow the IRC to analyze one baseline scan and 
two on-treatment scans for each patient who enrolled after the primary analysis date,
which is deemed adequate for assessment of alectinib efficacy.

In prior versions of the protocol, the post treatment study visit occurred 3 months 
after the last administration of study drug.  This choice was made based on the 
known safety profiles of pemetrexed and docetaxel.  However, with the observed 
difference in PFS between test agents, it is expected that very soon all remaining 
patients in the trial will be from the alectinib arm exclusively.  Thus, the post 
treatment visit has been changed in Version 7 to occur 4 weeks after last 
administration of study drug to align more closely to other alectinib clinical trials.
Additional minor changes, including removal of an inadvertent link to an internal Roche 
list of contact numbers (Section 5.4.1), have been made to improve clarity, consistency, 
and accuracy.  Substantive new information appears in italics.  This amendment 
represents cumulative changes to the original protocol.
                                           
1 Novello, S et al. Primary results from the phase III ALUR study of alectinib versus chemotherapy 
in previously treated ALK+ non-small-cell lung cancer (NSCLC). Presented at: ESMO 2017 
Congress; 2017 Sept 8-12. Abstract #1299O.


Alectinib—F. Hoffmann-La Roche Ltd
3/Protocol MO29750, Final Version 7.1
Rationale for Revisions
PROTOCOL AMENDMENT, VERSION 7.1:
SUMMARY OF CHANGES
PROTOCOL SYNOPSIS
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable.
Section 3.2: END OF STUDY 
The end the of study will occur when each patient is followed up for OS for up to 24 14
months or when 50% of randomized patients have died, whichever occurs first.  
Section 5.4.1: Emergency Medical Contacts
Toll-free numbers for the Help Desk as well as Medical Monitor contact information will 
be distributed to all investigators.  The list can be generated using contact numbers 
found at the following link: http://gcpcenter.roche.com/synergy/portal/view/pdq
spi/gcpcenter/34 64711453.
Section 9.4:
ADMINISTRATIVE STRUCTURE
An IRC will review the tumor assessments to determine the secondary endpoints.  IRC 
assessments will continue until 12 weeks after the last patient in, after which time the IRC 
assessments will be halted.
Appendix 1:
Schedule of Assessments 
Footnote c: Three months Four weeks after permanent treatment discontinuation for 
patients who do not receive alectinib treatment beyond progression, or at 
the end of randomized treatment for patients who enter the post 
progression period.


Alectinib—F. Hoffmann-La Roche Ltd
4/Protocol MO29750, Final Version 7.1
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 26
1.1
Background on Anaplastic Lymphoma Kinase-
Positive Non-Small Cell Lung Cancer.................................... 26
1.2
Background on Alectinib........................................................ 31
1.2.1
Study AF-001JP .................................................................... 32
1.2.1.1
Efficacy ................................................................................ 32
1.2.1.2
Safety................................................................................... 34
1.2.2
Studies NP28761 and NP28673............................................ 34
1.2.2.1
Primary Efficacy................................................................... 34
1.2.2.2
Central Nervous System Response..................................... 36
1.2.2.3
Safety................................................................................... 37
1.3
Study Rationale and Benefit-Risk Assessment...................... 38
1.3.1
Study Rationale ..................................................................... 38
1.3.2
Benefit-Risk Assessment....................................................... 39
2.
OBJECTIVES.............................................................................................. 40
2.1
Efficacy Objectives ................................................................ 40
2.2
Safety Objectives................................................................... 41
2.3
Pharmacokinetic Objectives .................................................. 41
2.4
Patient-Reported Outcome Objectives .................................. 41
2.5
Exploratory Objectives........................................................... 41
3.
STUDY DESIGN......................................................................................... 41
3.1
Description of Study .............................................................. 41
3.2
End of Study.......................................................................... 44
3.3
Rationale for Study Design.................................................... 45
3.3.1
Rationale for Design Features............................................... 45
3.3.2
Rationale for Study Population .............................................. 45
3.3.3
Rationale for Alectinib Dose and Schedule............................ 46
3.3.4
Rationale for Control Group................................................... 46


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3.3.5
Rationale for Efficacy Endpoint Selection.............................. 47
3.3.6
Rationale for Pharmacokinetics Assessments....................... 48
3.3.7
Rationale for PRO Assessments ........................................... 48
3.3.7.1
EORTC QLQ-C30 and QLQ-LC13....................................... 48
3.3.7.2
EQ-5D-5L............................................................................. 49
3.3.8
Rationale for Exploratory Assessments................................. 50
3.3.8.1
Selected Questions From the EORTC QLQ-
BN20
............................................................................................. 50
3.3.8.2
Biomarkers........................................................................... 50
3.4
Outcome Measures ............................................................... 51
3.4.1
Efficacy Outcome Measures.................................................. 51
3.4.2
Safety Outcome Measures .................................................... 52
3.4.3
Pharmacokinetic Outcome Measures.................................... 52
3.4.4
Patient-Reported Outcome Measures ................................... 53
3.4.5
Exploratory Outcome Measures ............................................ 53
4.
MATERIALS AND METHODS .................................................................... 54
4.1
Patients.................................................................................. 54
4.1.1
Inclusion Criteria.................................................................... 54
4.1.2
Exclusion Criteria................................................................... 55
4.2
Method of Treatment Assignment and Blinding..................... 56
4.3
Study Treatment.................................................................... 57
4.3.1
Formulation, Packaging, and Handling.................................. 57
4.3.1.1
Alectinib ............................................................................... 57
4.3.1.2
Pemetrexed.......................................................................... 57
4.3.1.3
Docetaxel............................................................................. 57
4.3.2
Dosage, Administration, and Compliance.............................. 57
4.3.2.1
Alectinib ............................................................................... 57
4.3.2.2
Pemetrexed.......................................................................... 58
4.3.2.3
Docetaxel............................................................................. 59
4.3.3
Investigational Medicinal Product Accountability ................... 59
4.3.4
Continued Access to Alectinib ............................................... 60
4.4
Concomitant Therapy ............................................................ 60
4.4.1
Permitted Therapy................................................................. 60


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4.4.1.1
Alectinib ............................................................................... 61
4.4.1.2
Pemetrexed.......................................................................... 61
4.4.1.3
Docetaxel............................................................................. 61
4.4.2
Prohibited Therapy ................................................................ 61
4.4.2.1
Alectinib ............................................................................... 61
4.4.2.2
Pemetrexed.......................................................................... 62
4.4.2.3
Docetaxel............................................................................. 62
4.4.3
Prohibited Food ..................................................................... 63
4.5
Study Assessments ............................................................... 63
4.5.1
Informed Consent Forms and Screening Log........................ 63
4.5.2
Medical History and Demographic Data ................................ 63
4.5.3
Medication Use for Control of Pain........................................ 63
4.5.4
Physical Examinations........................................................... 63
4.5.5
Vital Signs.............................................................................. 64
4.5.6
ECOG Performance Status ................................................... 64
4.5.7
Tumor and Response Evaluations......................................... 64
4.5.8
Laboratory, Biomarker, and Other Biological 
Samples
.............................................................................................. 65
4.5.8.1
Laboratory Assessments ..................................................... 65
4.5.8.2
Biomarker Assessments ...................................................... 65
4.5.8.3
Samples for Pharmacokinetic Assessments ........................ 66
4.5.9
Electrocardiograms................................................................ 67
4.5.10
Patient-Reported Outcomes .................................................. 67
4.5.11
Samples for Roche Clinical Repository.................................. 68
4.5.11.1
Overview of the Roche Clinical Repository ........................ 68
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee ............................................................................... 68
4.5.11.3
Sample Collection.............................................................. 68
4.5.11.4
Confidentiality .................................................................... 69
4.5.11.5
Consent to Participate in the Roche Clinical 
Repository .......................................................................................... 69
4.5.11.6
Withdrawal from the Roche Clinical Repository ................. 70
4.5.11.7
Monitoring and Oversight................................................... 70


Alectinib—F. Hoffmann-La Roche Ltd
7/Protocol MO29750, Final Version 7.1
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 70
4.6.1
Patient Discontinuation.......................................................... 70
4.6.2
Study Treatment Discontinuation........................................... 71
4.6.3
Study and Site Discontinuation.............................................. 71
5.
ASSESSMENT OF SAFETY....................................................................... 72
5.1
Safety Plan ............................................................................ 72
5.1.1
Risks Related to Study Drugs................................................ 72
5.1.1.1
Adverse Events Relating to ALK Inhibitors and 
Alectinib Data ..................................................................................... 72
5.1.1.2
Risks Associated With Pemetrexed ..................................... 75
5.1.1.3
Risks Associated With Docetaxel......................................... 76
5.1.2
Management of Specific Adverse Events .............................. 77
5.1.2.1
Management of Specific Adverse Events with 
Alectinib ............................................................................................. 77
5.1.2.2
Management of Specific Adverse Events With 
Pemetrexed........................................................................................ 81
5.1.2.3
Management of Specific Adverse Events With 
Docetaxel ........................................................................................... 82
5.2
Safety Parameters and Definitions ........................................ 84
5.2.1
Adverse Events ..................................................................... 84
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ........................................................................................ 84
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
Infusion-Related Reactions.................................................. 88
5.3.5.2
Diagnosis versus Signs and Symptoms............................... 88


Alectinib—F. Hoffmann-La Roche Ltd
8/Protocol MO29750, Final Version 7.1
5.3.5.3
Adverse Events That Are Secondary to Other 
Events
............................................................................................. 88
5.3.5.4
Persistent or Recurrent Adverse Events .............................. 89
5.3.5.5
Abnormal Laboratory Values................................................ 89
5.3.5.6
Abnormal Vital Sign Values.................................................. 90
5.3.5.7
Abnormal Liver Function Tests ............................................ 90
5.3.5.8
Deaths ................................................................................. 91
5.3.5.9
Preexisting Medical Conditions............................................ 91
5.3.5.10
Lack of Efficacy or Worsening of Non-Small 
Cell Lung Cancer................................................................................ 92
5.3.5.11
Hospitalization or Prolonged Hospitalization...................... 92
5.3.5.12
Adverse Events Associated with an Overdose 
or Error in Drug Administration........................................................... 92
5.3.5.13
Patient-Reported Outcome Data........................................ 92
5.3.5.14
Adverse Events in Individuals Not Enrolled in 
the Study ........................................................................................... 93
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 93
5.4.1
Emergency Medical Contacts................................................ 93
5.4.2
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of Special Interest .................. 94
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 94
5.4.2.2
Events That Occur after Study Drug Initiation...................... 94
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 ............................................................................................. 95
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 ................................................................ 96
5.6
Post-Study Adverse Events................................................... 96
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 96


Alectinib—F. Hoffmann-La Roche Ltd
9/Protocol MO29750, Final Version 7.1
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 97
6.1
Determination of Sample Size ............................................... 97
6.2
Summaries of Conduct of Study............................................ 98
6.3
Summaries of Treatment Group Comparability ..................... 98
6.4
Efficacy Analyses .................................................................. 98
6.4.1
Primary Efficacy Endpoint...................................................... 98
6.4.2
Secondary Efficacy Endpoints............................................... 99
6.5
Safety Analyses................................................................... 101
6.6
Pharmacokinetic Analyses................................................... 101
6.7
Patient-Reported Outcome Analyses .................................. 102
6.8
Biomarker Analyses............................................................. 102
6.9
Interim Analyses .................................................................. 103
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 ............................................ 104
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.................. 106
8.4
Confidentiality...................................................................... 107
8.5
Financial Disclosure ............................................................ 107
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 107
9.1
Study Documentation .......................................................... 107
9.2
Protocol Deviations.............................................................. 107
9.3
Site Inspections ................................................................... 108
9.4
Administrative Structure....................................................... 108
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 108


Alectinib—F. Hoffmann-La Roche Ltd
10/Protocol MO29750, Final Version 7.1
9.6
Protocol Amendments ......................................................... 109
10. REFERENCES ......................................................................................... 109
LIST OF TABLES
Table 1
Randomized Phase III Trials in ALK-Positive Advanced 
NSCLC........................................................................................ 27
Table 2
Randomized Phase III Trials in Previously Untreated 
Patients With Advanced NSCLC................................................. 29
Table 3
Randomized Phase III Trials of Second-Line Therapy for 
Advanced NSCLC....................................................................... 30
Table 4
Overall Response Rates and Time to Response in Patients 
in Part 2 of Study AF-001JP (Data Cutoff Date: 
31 January 2014)........................................................................ 33
Table 5
Overview of Efficacy Results From Studies NP28761 and 
NP28673 (Cutoff Date: 27 April 2015) ........................................ 35
Table 6
Side Effects Associated With Docetaxel ..................................... 77
Table 7
Dose Reduction Schedule........................................................... 77
Table 8
Guidelines for Management of Specific Adverse Events with 
Alectinib ...................................................................................... 78
Table 9
Guidelines for Management of Specific Docetaxel-Related 
Adverse Events........................................................................... 82
Table 10
Guidelines for Management of Hepatotoxicity in Docetaxel-
Treated Patients.......................................................................... 83
Table 11
Guidelines for the Management of Edema in Docetaxel-
Treated Patients.......................................................................... 83
Table 12
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 87
Table 13
Summary of Determination of Sample Size a.............................. 97
LIST OF FIGURES
Figure 1
Change in Size of Target Lesions as Assessed by the IRC in 
Part 2 of Study AF-001JP Using RECIST v1.1 (Data Cutoff 
Date: 31 January 2014) .............................................................. 33
Figure 2
Comparison of PFS in Patients With and Without CNS 
Metastases at Baseline in Study AF-001JP (Data Cutoff Date: 
31 January 2014)........................................................................ 34
Figure 3
Study Schema............................................................................. 42


Alectinib—F. Hoffmann-La Roche Ltd
11/Protocol MO29750, Final Version 7.1
LIST OF APPENDICES
Appendix 1
Schedule of Assessments – Alectinib Arm................................ 114
Appendix 2
Schedule of Assessments – Chemotherapy Arm...................... 119
Appendix 3
Schedule of Pharmacokinetic Assessments ............................. 124
Appendix 4
List of Substrates, Inhibitors and Inducers of  Drug-
Metabolizing Enzymes and Transporters.................................. 125
Appendix 5
Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1: Excerpt from Original Publication.......................... 127
Appendix 6
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 139
Appendix 7
EORTC QLQ-C30/LC13 and EQ-5D-5L Questionnaires .......... 140
Appendix 8
Modification of Diet in Renal Disease (MDRD) Formula ........... 145


Alectinib—F. Hoffmann-La Roche Ltd
12/Protocol MO29750, Final Version 7.1
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
RANDOMIZED, MULTICENTER, PHASE III, OPEN-
LABEL STUDY OF ALECTINIB VERSUS 
PEMETREXED OR DOCETAXEL IN ANAPLASTIC 
LYMPHOMA KINASE-POSITIVE ADVANCED NON
SMALL CELL LUNG CANCER PATIENTS 
PREVIOUSLY TREATED WITH PLATINUM-BASED 
CHEMOTHERAPY AND CRIZOTINIB
PROTOCOL NUMBER:
MO29750
VERSION NUMBER:
7.1
EUDRACT NUMBER:
2015-000634-29
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 retain the signed original of this form for your study files.  Please return a copy 
(as instructed by XX [e.g., your local study monitor, the CRO]) [or] (to the contact 
provided below).
(Name) 
(Address)


Alectinib—F. Hoffmann-La Roche Ltd
13/Protocol MO29750, Final Version 7.1
PROTOCOL SYNOPSIS
TITLE:
RANDOMIZED, MULTICENTER, PHASE III, OPEN-LABEL STUDY 
OF ALECTINIB VERSUS PEMETREXED OR DOECTAXEL IN 
ANAPLASTIC LYMPHOMA KINASE-POSITIVE ADVANCED 
NON -SMALL CELL LUNG CANCER PATIENTS PREVIOUSLY 
TREATED WITH PLATINUM-BASED CHEMOTHERAPY AND 
CRIZOTINIB
PROTOCOL NUMBER:
MO29750
VERSION NUMBER:
7.1
EUDRACT NUMBER:
2015-000634-29
IND NUMBER:
111723
TEST PRODUCT:
Alectinib (RO5424802)
PHASE:
III
INDICATION:
Anaplastic lymphoma kinase-positive (ALK-positive) non-small cell 
lung cancer (NSCLC)
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is as follows:

To evaluate and compare between treatment groups the efficacy of alectinib versus 
chemotherapy in patients with anaplastic lymphoma kinase (ALK)-positive advanced non-
small cell lung cancer (NSCLC) who were previously treated with chemotherapy and 
crizotinib (progressed or intolerant to crizotinib), as measured by investigator-assessed 
progression-free survival (PFS)   
Key Secondary Efficacy Objective
The key secondary efficacy objective for this study is as follows:

To evaluate and compare between treatment groups the central nervous system (CNS) 
objective response rate (C-ORR) in patients with measurable CNS metastases at baseline, 
as assessed by an Independent Review Committee (IRC)
Other Secondary Efficacy Objectives
Other secondary efficacy objectives for this study are to evaluate and compare between 
treatment arms:

PFS (assessment by IRC)

Objective response rate (ORR), disease control rate (DCR) and duration of response (DOR) 
in all patients according to Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) (assessment by investigator and IRC) 

PFS in patients with baseline CNS metastases (assessment by investigator and IRC)

Time to CNS progression in all patients, patients with baseline CNS metastases and 
patients without baseline CNS metastases  (assessment by IRC)


Alectinib—F. Hoffmann-La Roche Ltd
14/Protocol MO29750, Final Version 7.1

CNS duration of response (C-DOR), CNS disease control rate (C-DCR) and C-ORR for all 
patients with baseline CNS metastasis (assessment by IRC)

C-DOR and C-DCR for patients with baseline measurable CNS metastasis (assessment by 
IRC)

Overall survival (OS)
Safety Objectives
The safety objectives for this study are as follows:

To evaluate the safety and tolerability of alectinib compared with chemotherapy in all 
patients and patients with CNS metastases at baseline
Pharmacokinetics Objective

To characterize the pharmacokinetics of alectinib and its major metabolite(s)
Patient-Reported Outcomes Objectives

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 (single item) 
pain in arm/shoulder 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 TTD in a composite of 
three symptoms (cough, dyspnea (multi-item subscales QLQ-LC13)  and chest pain) To 
evaluate and compare patient-reported outcomes (PROs) of health-related quality of life 
(HRQoL), patient functioning and side effects of treatment, as measured by the EORTC 
QLQ-C30, EORTC QLQ-LC13 and EQ-5D-5L 
Exploratory Objectives
The exploratory objectives for this study may include but are not limited to the following:

To evaluate and compare PROs of patients with CNS metastases, as measured by specific 
questions from the EORTC QLQ-BN20 questionnaire 

Need and dosing for corticosteroids in case of CNS metastasis

To assess exploratory biomarkers relevant in NSCLC biology and alectinib mechanism of 
action (including but not limited to ALK genetic alterations) and their association with 
disease status, clinical outcome, efficacy and safety

To investigate molecular mechanisms of resistance to ALK inhibitors

To develop biomarker or diagnostic assays to detect ALK mutations/fusions in 
plasma/tumor and to establish performance characteristics of these assays
Study Design
Description of Study
This will be a randomized active-controlled multicenter Phase III open-label study.  The study 
will consist of a Screening Period, a Treatment Period and a Post Progression and Post 
Treatment Period (Synopsis Figure).  Day 1 (baseline) will be defined as the first day a patient 
receives study medication.  The Post Treatment Period for patients who do not receive 
crossover treatment or treatment beyond progression will include one additional clinic visit 
where patients will complete PRO questionnaires.  This visit will be conducted within the Post 
Progression period for patients who do cross over or receive treatment beyond progression.  
The study will be conducted in approximately 60 centers located in approximately 15 countries 
worldwide.




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Patients on both arms will be treated with study drug (including those who cross over from 
chemotherapy to alectinib) until disease progression, unacceptable toxicity, withdrawal of 
consent or death.  At the discretion of the patient and the investigator, patients on the alectinib 
arm who show radiological progression per RECIST v1.1 will be allowed to continue receiving 
alectinib beyond disease progression if he or she is clinically benefitting from the drug until no 
further clinical benefit is to be expected, unacceptable toxicity, withdrawal of consent or death.  
Patients on the control (chemotherapy) arm who do not have any safety-related issues that 
might render the patient ineligible to receive alectinib treatment (as per safety-based inclusion 
criteria of the study) will be allowed to cross over to receive alectinib treatment.  Patients with 
any safety-related issues rendering the patient ineligible to receive alectinib treatment (as per 
safety-based inclusion criteria of the study) will have the possibility to cross over after the 
safety-related issues have resolved or normalized.  Upon progression on cross-over treatment 
with alectinib, patients will be allowed to continue receiving alectinib beyond disease 
progression if he or she is clinically benefitting from the drug until further disease progression, 
no further clinical benefit is to be expected, unacceptable toxicity, withdrawal of consent or 
death.  Patients on either arm who opt not to continue or to cross over to alectinib will be treated 
at the discretion of the investigator according to local practice.
In all patients, information regarding the type and duration of subsequent therapies following 
disease progression, as well as overall survival follow-up, will be collected.  Patients who 
discontinue treatment prior to disease progression (e.g., due to unacceptable toxicity) will 
continue to be followed until disease progression and for OS, regardless of whether they 
subsequently receive non-study anti-cancer therapy.  
The assessments to be conducted in this study are described below and will be carried out at 
the time points designated in the Schedule of Assessments (Appendix 1 and 2).

Disease progression will be assessed using Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1).  The primary efficacy objective will be investigator-assessed 
PFS, and the key secondary efficacy objective will be IRC-assessed C-ORR.  Other 
secondary objectives will include the following assessments by the IRC: PFS; PFS in 
patients with CNS metastases at baseline; time to CNS progression in all patients and in 
patients with and without baseline CNS metastases; and C-DOR and C-DCR in all patients 
with baseline CNS metastases and in patients with measurable CNS metastases.  The IRC 
and the investigator will evaluate ORR, DCR and DOR.  Finally, OS will be determined

Safety will be monitored by assessing serious and non-serious adverse events (AEs), 
safety laboratory tests, vital signs and electrocardiogram (ECG).  The incidence, nature and 
severity of all AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0).  Laboratory safety 
tests will include hematology and blood chemistry.  Vital sign assessments will include 
blood pressure and pulse rate; additional vital signs will be collected only if clinically 
warranted.  In addition, the study will have a baseline urinalysis assessment (dipstick); 
additional urinalyses will be conducted only if clinically warranted 

Pharmacokinetic (PK) parameters for alectinib and its major metabolite(s) will be assessed 
on sparsely collected pre-dose blood samples.  The specific PK parameters will be 
determined as appropriate, where data allow

HRQoL will be assessed using three PRO instruments: the EORTC QLQ-C30, the EORTC 
QLQ-LC13, and the EuroQoL 5D-5L.  PRO scores will be determined for all patients and for 
patients with CNS metastases at baseline and will be compared across treatment groups  

Finally, the study will have exploratory analyses examining biomarkers and assessing the 
HRQoL effects of brain metastases in patients with CNS metastases at baseline.  The latter 
PRO assessments will be based on two selected questions from the EORTC QLQ-BN20, a 
QoL instrument specific for brain neoplasms  
An independent data monitoring committee (iDMC) is planned for this study to review safety 
data periodically.  More details will be provided in the iDMC charter.


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Number of Patients
At least 90 and a maximum of 120 patients (as per previous protocol) will be randomly assigned 
in a 2:1 allocation ratio to the two treatment arms) via a block-stratified randomization procedure 
and over a planned recruitment period of approximately 12 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) and CNS metastases at baseline (yes vs. no).  In addition, 
patients with baseline CNS metastasis will be stratified by history of radiotherapy (yes vs. no).
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:
1.
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.  
ALK positivity must have been determined by a validated FISH test (recommended probe, 
Vysis ALK Break-Apart Probe) or a validated IHC test (recommended antibody, clone D5F3)
2.
Patient had received two prior systemic lines of therapy for advanced or metastatic disease 
(stage IIIB or IV), which must have included one line of platinum-based chemotherapy and 
one line of crizotinib (progression on or intolerability to crizotinib)
3.
Prior CNS or leptomeningeal metastases allowed if asymptomatic.  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 and local treatment is 
indicated, patients need to complete the local treatment (surgery or radiotherapy).  In all 
cases, radiation treatment must be completed at least 14 days before enrollment and 
patients must be clinically stable 
4.
Patients with symptomatic CNS metastases for whom radiotherapy is not an option will be 
allowed to participate in this study 
5.
Measurable disease (by RECIST v1.1) prior to the administration of study treatment 
(Appendix 5)
6.
Age ≥18 years old 
7.
Life expectancy of at least 12 weeks 
8.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2 (Appendix 6) 
9.
Adequate hematologic function: 

Platelet count ≥100 x109/L 

Absolute neutrophil count (ANC) ≥1500 cells/µL

Hemoglobin ≥9.0 g/dL
10. 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 (Appendix 8)
11. 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 
12. For all females of childbearing potential, a negative pregnancy test must be obtained prior 
to randomization and within 3 days before starting study treatment 


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13. 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, proper use of combined oral or injected 
hormonal contraceptives, and certain intrauterine devices
14. For men: agreement to remain abstinent or use a contraceptive method that results 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 (in addition, refer to the local label for pemetrexed and docetaxel).  
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 
15. Able and willing to provide written informed consent prior to performing any study related 
procedures and to comply with the study protocol, including being 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:
1.
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 or in situ carcinoma of the cervix) 
2.
Patients who have received any previous ALK inhibitor other than crizotinib
3.
Any GI disorder that may affect absorption of oral medications, such as mal-absorption 
syndrome or status post-major bowel resection
4.
Liver disease characterized by:

Alanine aminotransaminase (ALT) or aspartate aminotransferase (AST) > 2.5 x upper 
limit of normal (ULN) (> 5 x ULN for patients with concurrent liver metastases) 
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 or bleeding from esophageal varices
      OR

Acute viral or active autoimmune, alcoholic or other types of acute hepatitis
5.
NCI CTCAE v4.0 Grade 3 or higher toxicities due to any prior therapy (excluding alopecia), 
which have not shown improvement and are strictly considered to interfere with current 
study medication
6.
Any exclusion criteria based on local label of pemetrexed or docetaxel
7.
History of organ transplant
8.
Patients with baseline QTc > 470 ms or symptomatic bradycardia
9.
Administration of strong/potent CYP3A4 inhibitors or inducers within 14 days prior to the 
first dose of study treatment and while on treatment with alectinib or docetaxel
10. 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] or magnesium stearate) 
11. History of severe hypersensitivity reaction to pemetrexed or docetaxel or any known 
excipients of these drugs


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12. Patients not eligible for treatment with docetaxel or pemetrexed according to the local 
labels
13. Pregnant or lactating women 
14. Known HIV positivity or AIDS-related illness 
15. 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 
16. 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 the first patient randomized to the end of study (defined below) will be up to 
26 months (includes 12 months of recruitment period and a maximum of 14 months of follow up 
for OS for all participants).  Since a maximum of 120 patients may be enrolled as per previous 
protocol version, this may result in an extension of the 12-month recruitment period.
End of Study
The end the of study will occur when each patient is followed up for OS for up to 14 months or 
when 50% of randomized patients have died, whichever occurs first.  
Patients who are receiving and benefitting from study treatment at the end of the study may be 
offered the possibility of rolling over into a long-term extension study, following the approval of 
this extension study by Competent Authorities and the Ethics Committees of the respective 
investigational sites.  During the long-term extension study, minimum data will be collected and 
SAE’s will be reported to Roche and entered into the Roche safety data base.  Study MO29750 
will be closed and an updated analysis performed once all patients have either withdrawn or 
enrolled in the extension study.
Outcome Measures
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:

Progression-free survival (PFS) is defined as the time from randomization to the first 
documented disease progression, as determined using RECIST v1.1, or death from any 
cause, whichever occurs first.  Similar definitions of PFS will be used by the investigator 
(primary endpoint) and the IRC.  Patients without an event will be censored at the last tumor 
assessment.  Patients with no post-baseline assessments will be censored at the date of 
randomization.  PFS for patients with CNS metastasis at baseline will be defined in a  
similar way, taking into account all lesions in the body

Overall response rate (ORR) is defined as the percentage of patients who attain complete 
response (CR) or partial response (PR), as determined using RECIST v1.1.  Similar 
definitions of ORR will be used by the investigator and the IRC.  Patients without any post-
baseline assessments will be regarded as non-responders.  ORR for patients with CNS 
metastasis at baseline (C-ORR) will be defined in a similar way for lesions in the CNS.  (It 
should be noted that patients with non-measurable disease can achieve only CR and not 
PR)

Disease control rate (DCR) is defined as the percentage of patients who attain complete 
response (CR), partial response (PR) or stable disease (SD) of at least 5 weeks, as 
determined using RECIST v1.1.  Similar definitions of DCR will be used by the investigator 
and the IRC.  Patients without any post-baseline assessments will be regarded as non-
responders.  CNS DCR (C-DCR) for patients with CNS metastasis at baseline will be 
defined in a similar way for lesions in the CNS.  (It should be noted that patients with non-
measurable disease can achieve only CR or SD and not PR).


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
Duration of response (DOR) 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.  
Similar definitions of DOR will be used by the investigator and the IRC.  Patients who do not 
progress or die after they have had a response are censored at the date of their last tumor 
measurement.  DOR for patients with CNS metastasis at baseline (C-DOR) will be defined 
in a similar way for lesions in the CNS, taking into account all lesions in the body

Overall survival (OS) 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

Time to CNS progression is defined as the time from randomization to the first documented 
disease progression in the CNS
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Serious and non-serious AEs 

Safety laboratory tests

Vital signs

ECG
The incidence, nature and severity of all AEs events will be graded according to 
NCI CTCAE v.4.0.
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
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.
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are the following:

Sparse (pre-dose) PK samples for measurement of alectinib and its major metabolite(s) will 
be collected in all study patients receiving alectinib treatment

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, as 
appropriate.  The potential influence of covariates that contribute significantly to the 
between-patient differences in PK parameters of alectinib will also be explored and 
quantified, as appropriate
Additional PK parameters may be calculated as deemed appropriate.
Patient-Reported Outcome Measures
The PRO outcome measures for this study are as follows (see Appendix 7):


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
EORTC QLQ-C30 and EORTC QLQ-LC13 scores to determine the impact of alectinib 
compared with chemotherapy in the overall population, as well as in patients with CNS 
metastases, as measured by time to deterioration (TTD) in patient-reported lung cancer 
symptoms ( e.g. cough, chest pain (single item) dyspnea (single item and multi-item 
scales)pain in chest, pain in arm/shoulder and fatigue), and as well by TTD for the 
composite of three symptoms (cough, dyspnea(multi-item subscales QLQ-LC13)  and chest 
pain).  

The EORTC QLQ-C30 and EORTC QLQ-LC13 scores to measure PROs of HRQoL, patient 
functioning and side effects of therapy compared between patients treated with alectinib 
and those treated with chemotherapy.  The comparison will be done for the overall patient 
population, as well as in patients with CNS metastases at baseline

The EuroQoL 5 Dimension (EQ-5D-5L) questionnaire score to will be used for the overall 
patient population, as well as for patients with CNS metastases at baseline, to assess 
patients’ health status and generate utility scores for use in pharmacoeconomic models for 
reimbursement purposes only
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows (additional exploratory 
parameters may be assessed as deemed appropriate):

Scores from three specific questions extracted from the EORTC QLQ-BN20 questionnaire, 
a QoL instrument specific to brain neoplasms.  The three questions are as follows: "Do you 
have headaches?"; "Do you have problems with coordination/balance?"; and "Did you have 
trouble communicating your thoughts?"  Each of the three questions will be scored on a 4-
point scale (1, Not at all; 2, A little; 3, Quite a bit; 4, Very much), which will subsequently be 
linearly transformed to a 0–100-point scale

To assess exploratory biomarkers relevant in NSCLC biology and alectinib mechanism of 
action (including but not limited to ALK genetic alterations) and their association with 
disease status, clinical outcome, efficacy and safety

To investigate molecular mechanisms of resistance to ALK inhibitors

To develop biomarker or diagnostic assays to detect ALK mutations/fusions in 
plasma/tumor and to establish performance characteristics of these assays
Investigational Medicinal Products
Test Product (Investigational Drug)
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, SLS, and magnesium stearate.
Alectinib 600 mg (four 150-mg capsules) should be administered orally BID with food in the 
morning and evening.  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.  Treatment will continue until disease progression, unacceptable toxicity, 
withdrawal of consent or death.  
If a dose is missed, patients can make up that dose unless the next dose is due within 6 hours.  
If the time is less 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 5.1.2.
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 alectinib should be recorded on the Adverse Event 
eCRF.


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Comparators
For information on administration of pemetrexed (Alimta®) and docetaxel (Taxotere®), refer to 
the local prescribing information. 
Guidelines for dosage modifications and treatment interruptions or discontinuation due to 
specified adverse events on pemetrexed or docetaxel are provided in Section 5.1.2.
Non-Investigational Medicinal Products
In addition to the test product or comparators, all patients in this study will receive standard-of-
care therapy for advanced NSCLC, as assessed by the investigator.
Statistical Methods
Primary Analysis
The main primary endpoint is PFS assessed by the investigator as defined above.
The main efficacy analysis will be based on the intent-to-treat (ITT) population that includes all 
randomized patients.  The per protocol (PP) population will be defined as the subset of the ITT 
population who have received at least one dose of study medication and have at least one post 
baseline tumor assessment with no major protocol violations (which will be defined in the 
statistical analysis plan).
The main analysis for investigator assessed PFS will be a stratified Cox model analysis that will 
include a treatment group variable and stratification factors, defined as:

ECOG PS (0/1 vs. 2),

CNS metastases at baseline (yes vs. no)
In addition, patients with baseline CNS metastases will be stratified by history of 
radiotherapy (yes vs. no)
The un-stratified Cox model analysis for PFS and also stratified with stratification factors 
recorded in the eCRF will also be provided as sensitivity analyses.
Estimates for the survivor function for PFS will be obtained by the Kaplan-Meier approach.  The 
p-value of log-rank test will be displayed together with estimated hazard ratios and associated 
95% confidence intervals (CIs).  
Hypotheses testing for the primary endpoint:

H0: the distribution of the PFS time is the same in the two treatment groups

H1: the distribution of the PFS time is different in the two treatment groups.

If the hazard ratio (HR) of the investigational arm compared with the control arm with 
respect to PFS is assumed to be constant over time (λ), then the null (H0) and alternative 
hypotheses (H1) are: H0: λ=1 vs. H1: λ ≠1
Unless otherwise specified, all tests will be performed at two-sided alpha of 5%.
Safety endpoints will be analyzed for the safety population, which will include all patients who 
received at least one dose of study medication.  For analysis purposes, patients will be 
assigned to treatment groups based on actual received study medication.  More details are 
provided in Section 6.5.
PK data will be analyzed with summary statistics (e.g., means, standard deviation, coefficient of 
variation %, geometric means, medians and ranges).  Further details are provided in Section 
6.6. 
The PRO measures, EORTC QLQ-C30, EORTC QLC-LC13, and EQ-5D 3L and questions 
specific to CNS metastases (a part of EORTC BN20 questionnaire) will be summarized using 
descriptive statistics.  Selected single or multi-item subscales will be graphically presented and 
difference between two treatment groups over time will be explored using mixed models.  The 
Cochran-Mantel-Haenszel statistic test will be applied to take the ordinal nature of a variable 
EORTC QOQ-BN20.  More details will be specified in the SAP.


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Descriptive analysis for biomarkers will be provided and further association between biomarkers 
and clinical endpoints (e.g. PFS, OS, ORR, etc.) will be explored using Cox regression model or 
logistic model.  More information will be provided in the SAP.
Determination of Sample Size  
The sample size estimation was performed using EAST Software, Version 6.0, based on the 
statistical hypotheses in Section 6.4.
Synopsis Table: Summary of Determination of Sample Size 
Primary 
endpoint  
Median Time to PFS 
(Chemo vs. Alectinib) 
Months/HR
Number of 
Patients/Events
Number of Patients 
Per Treatment arm
(Chemo vs Alectinib)
PFS
3 vs. 7/0.43
90/50
30 vs. 60
Key 
Secondary 
endpoint
Response
(Chemo vs. Alectinib)
Number of Patients
C-ORR b
15% vs. 55%
24
8 vs. 16
a. 80% power, two sided alpha test at 0.05; 2:1 randomization. 
b. Patients with measurable CNS metastases at baseline, 70% power, one-sided test at 0.05.
Assuming an accrual period of 12 months and a primary analysis with at least 50 PFS events 
planned approximately after 13 months, a sample size of 90 patients (60 patients in the 
experimental arm [alectinib] and 30 patients in the control arm [chemotherapy]) with at least 50 
PFS events will provide 80% power to detect a significant improvement in the median time of 
the primary endpoint from 3 to 7 months (i.e., HR of 0.43), based on a two-sided log-rank test at 
an alpha level of 0.05.  In the pivotal Profile 1007 trial (Shaw et al. 2013), median PFS in the 
chemotherapy arm among 174 patients previously treated with one platinum-based 
chemotherapy regimen and treated in second line with either pemetrexed or docetaxel was 
3 months (95% CI, 2.6–4.3).  Hence, a median PFS of 3 months for the chemotherapy arm 
(control arm) has been assumed.
The objective response (Shaw et al. 2013) was reported in the chemotherapy group as 20% 
(95% CI, 14%–26%).  Also, we expect that at least 25% of patients with measurable CNS 
metastases at baseline will be randomized in 2 treatment arms in this study.  Approximately 24 
patients with measurable CNS metastases at baseline (8 patients in control and 16 patients in 
experimental arm) will provide power of 70% (one-sided 5% alpha test) to detect clinically 
meaningful difference in C-ORR of 40%, assuming C-ORR in control arm of 15%. 
If superiority for the PFS endpoints is concluded, subsequent hierarchical testing for the key 
secondary endpoint, C-ORR in patients with measurable CNS metastases at baseline, will be 
performed.
Interim Analyses
No interim analyses for efficacy or futility are planned.  Safety review of data will be performed 
as explained in the iDMC charter.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
adverse event
AGC
absolute granulocyte count
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the drug concentration-time curve
BID
twice daily
BOR
best overall rate
C-DCR
CNS disease control rate
C-DOR
CNS duration of response
CI
confidence interval
Cmax
maximum (peak) concentration of drug in blood 
plasma
CNS
central nervous system
CPK
creatine phosphokinase
C-ORR
CNS objective response rate
CR
complete response
DCR
disease control rate
DLT
dose-limiting toxicity
DOR
duration of response
DOT
duration of treatment
EC
Ethics Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
eGFR
estimated glomerular filtration rate
EGFR
epidermal growth factor receptor
EORTC
European Organization for the Research and 
Treatment of Cancer
EQ-5D-5L
EuroQoL 5 Dimension questionnaire
ESMO
European Society for Medical Oncology
EU
European Union
FDA
Food and Drug Administration


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Abbreviation
Definition
FISH
fluorescence in situ hybridization
FSH
follicle stimulating hormone
GGT
gamma glutamyl transferase
GI
gastrointestinal
HR
hazard ratio
HRQoL
health-related quality of life
iDMC
independent data monitoring committee
IHC
immunohistochemistry
INR
international normalized ratio
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
MedDRA
Medical Dictionary for Regulatory Activities
MET
mesenchymal epithelial transition factor
NCI CTCAE
National Cancer Institute Common Terminology 
Criteria for Adverse Events
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PFS
progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetic
PP
per protocol
PR
partial response
PRO
patient-reported outcome
PS
performance status
PT
prothrombin time
QLQ-C30
Quality of Life Questionnaire Core
QLQ-LC13
Quality of Life Questionnaire Supplemental Lung 
Cancer Module
QoL
quality of life
RBC
red blood cell
RE
response-evaluable
RECIST
Response Evaluation Criteria in Solid Tumors


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Abbreviation
Definition
ROS1
ROS proto-oncogene 1
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SHBG
sex hormone-binding globulin
SLS
sodium lauryl sulfate
SOC
system organ class
SPF
skin protection factor
TBP
treatment beyond progression
TKI
tyrosine kinase inhibitor
Tmax
time after drug administration at which peak plasma 
concentration occurs
TTD
time to deterioration
ULN
upper limit of normal
US
United States
WBC
white blood cell
1.
BACKGROUND
1.1
BACKGROUND ON ANAPLASTIC LYMPHOMA KINASE-
POSITIVE NON-SMALL CELL LUNG CANCER
It is estimated that nearly 1.6 million people perish from lung cancer every year, making 
it the leading cause of cancer-related mortality worldwide (GLOBOCAN 2012).  In the 
European Union, 313,000 new cases of lung cancer were diagnosed in 2012 (214,000 
men and 99,000 women) and 268,000 people died of the disease (186,000 men and 
82,000 women).  An estimated 158,040 US citizens are expected to die from lung cancer 
in 2015, accounting for approximately 27 percent of all cancer deaths 
(American Lung Association 2015).  The primary form of lung cancer is non-small cell 
lung cancer (NSCLC), which occurs in approximately 85% of all lung cancer cases (the 
other forms include small cell lung cancer [10%–15%] and lung carcinoid tumor [5%]) 
(Molina et al. 2008).  The two predominant histologic types of NSCLC are 
adenocarcinoma (more than half of cases) and squamous cell carcinoma (approximately 
25% of cases) (Langer et al. 2010; Travis et al. 2011).  
Survival rates are lower for NSCLC than for other common cancers.  Thus, the expected 
5-year survival rate in NSCLC 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).  The overall 5-year 
survival rate for advanced NSCLC, is 2%−4% depending on geographic location (Cetin 
et al. 2011).  Poor prognostic factors for survival in patients with NSCLC include 
advanced stage of disease at the time of initial diagnosis, poor Eastern Cooperative 


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Oncology Group (ECOG) performance status (PS) and a history of unintentional weight 
loss.  More than half of patients with NSCLC present with distant metastatic disease at 
the time of initial diagnosis, which directly contributes to poor survival prospects. 
Approximately 5% of patients with NSCLC 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 (Rikova et al. 2007; Soda et al. 
2007; Soda et al. 2008; Kwak et al. 2010).  Presence of the ALK rearrangement is 
observed predominantly in non-smoking younger female patients with adenocarcinoma, 
especially those diagnosed in the advanced stages of NSCLC (Fan et al. 2014; Wang et 
al. 2014; Zhao et al. 2015).  NSCLC patients with ALK rearrangements rarely have 
mutations in the epidermal growth factor receptor (EGFR) or the Kirsten rat sarcoma 
viral oncogene homolog (KRAS), suggesting that these genetic alterations tend to be 
mutually exclusive (Fan et al. 2014; Wang et al. 2014; Zhao et al. 2015).  However, 
EGFR mutations may develop as a resistance mechanism following treatment of ALK-
positive NSCLC with crizotinib (see below) (Doebele et al. 2012).
Few studies have assessed the activity of chemotherapy specifically against ALK-
positive advanced NSCLC, although some retrospective studies suggested that ALK 
rearrangements may be associated with enhanced sensitivity to pemetrexed-based 
regimens (Camidge et al. 2011; Lee et al. 2011).  Two recent randomized Phase III 
studies, however, compared chemotherapeutic regimens in patients with advanced ALK-
positive NSCLC (Shaw et al. 2013; Solomon et al. 2014) (Table 1). 
Table 1
Randomized Phase III Trials in ALK-Positive Advanced NSCLC
ORR
(%)
Median PFS
(months)
Median OS
(Months)
First-line therapy (PROFILE 1014) a
Pemetrexed plus cisplatin or carboplatin (n=171)
45
7.0
NR
Crizotinib (n=172)
74
10.9
NR
Second-line therapy following a platinum-based 
regimen (PROFILE 1007) b
Pemetrexed or docetaxel (n=174)
20
3.0
22.8
Crizotinib (n=173)
65
7.7
20.3
NR = not reached; ORR = objective response rate; OS = overall survival; PFS = progression-free 
survival.
a. Solomon, B. J., T. Mok, et al. First-line crizotinib versus chemotherapy in ALK-positive lung 
cancer. N Engl J Med 2014;371:2167-2177. 
b. Shaw, A. T., D. W. Kim, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung 
cancer. N Engl J Med 2013;368:2385-2394..


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In the PROFILE 1014 study (Solomon et al. 2014), 342 patients with advanced 
ALK-positive nonsquamous NSCLC who had received no previous systemic treatment 
for advanced disease were randomized 1:1 to one of two treatments.  The first group 
(n=171) received pemetrexed plus cisplatin or carboplatin every 3 weeks for up to 
6 cycles, a standard therapeutic regimen for first-line treatment of advanced 
ALK-positive NSCLC.  The second group (n=172) received twice-daily crizotinib, an oral 
small-molecule tyrosine kinase inhibitor of ALK, MET and ROS1 kinases (Kwak et al. 
2010; Ou et al. 2011; Bergethon et al. 2012).  Progression-free survival (PFS) was 
significantly longer with crizotinib than with chemotherapy (median, 10.9 months vs. 
7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% confidence 
interval [CI], 0.35 to 0.60; P<0.001).  Objective response rates (ORRs) were 74% and 
45%, respectively (P<0.001).  Median overall survival (OS) was not reached in either 
group; the probability of 1-year survival was 84% with crizotinib and 79% with 
chemotherapy.  The most common adverse events with crizotinib were vision disorders, 
diarrhea, nausea and edema, and the most common events with chemotherapy were 
nausea, fatigue, vomiting and decreased appetite.  As compared with chemotherapy, 
crizotinib was associated with greater reduction in lung cancer symptoms and greater 
improvement in quality of life (QoL).
In the PROFILE 1007 study (Shaw et al. 2013), 347 patients with locally advanced or 
metastatic ALK-positive lung cancer who had received one prior platinum-based regimen 
were randomized 1:1 to one of two treatments.  The first group (n=174) received 
pemetrexed or docetaxel every 3 weeks, a standard therapeutic regimen for second-line 
treatment of advanced NSCLC (Reck et al. 2014).  The second group (n=173) received 
twice-daily crizotinib.  The median PFS was 7.7 months in the crizotinib group and 
3.0 months in the chemotherapy group.  The response rates were 65% (95% CI, 58% to 
72%) with crizotinib, as compared with 20% (95% CI, 14% to 26%) with chemotherapy 
(P<0.001).  An interim analysis of OS showed no significant improvement with crizotinib 
as compared with chemotherapy.  Common adverse events associated with crizotinib 
were visual disorder, gastrointestinal side effects and elevated liver aminotransferase 
levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and 
dyspnea.  Patients reported greater reductions in symptoms of lung cancer and greater 
improvement in global QoL of life with crizotinib than with chemotherapy.
The previous studies make two key points related to treatment of advanced ALK-positive 
NSCLC:

First, response to standard chemotherapy (platinum-based regimens, pemetrexed, 
docetaxel, etc., and their combinations) appears to be relatively similar in advanced 
ALK-positive NSCLC patients compared to a general population of unselected 
advanced NSCLC patients, although very subtle differences in outcomes may be 
observable (compare Table 1 vs. Table 2 and 3) (Fossella et al. 2000; Shepherd et 
al. 2000; Schiller et al. 2002; Hanna et al. 2004; Shepherd et al. 2005; Sandler et al. 
2006; Pirker et al. 2009; Ramlau et al. 2012).  Thus, to a first approximation, 


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treatment outcomes with standard chemotherapy are similar in advanced ALK-
positive NSCLC and other types of advanced NSCLC.  

Second, ALK inhibitor therapy appears to be superior to standard chemotherapy in 
ALK-positive NSCLC patients (Table 1).  Based on these and other data, crizotinib 
was approved in 2011 in the US in 2011, where it is currently indicated for the 
treatment of patients with metastatic NSCLC whose tumors are ALK-positive as 
detected by an FDA-approved test (US Food and Drug Administration).  Crizotinib 
was approved in 2012 in the EU, where it is indicated for the treatment of adults with 
previously treated ALK-positive advanced NSCLC (European Medicines Agency).
Table 2
Randomized Phase III Trials in Previously Untreated Patients 
With Advanced NSCLC
First-Line Therapy Regimen
ORR
(%)
Median PFS
(months)
Median OS
(Months)
Chemotherapy a
Cisplatin and paclitaxel (n=288)
21
3.4
7.8
Cisplatin and gemcitabine (n=288)
22
4.2
8.1
Cisplatin and docetaxel (n=289)
17
3.7
7.4
Carboplatin and paclitaxel (n=290)
17
3.1
8.1
Chemotherapy and bevacizumab b
Carboplatin and paclitaxel (n=444)
15
4.5
10.3
Carboplatin, paclitaxel and bevacizumab (n=434)
35
6.5
12.3
Chemotherapy and cetuximab c
Cisplatin and vinorelbine (n=568)
29
4.8
10.1
Cisplatin, vinorelbine and cetuximab (n=557)
36
4.8
11.3
ORR = objective response rate; OS = overall survival; PFS = progression-free survival.
a. Schiller JH, Harrington D, Belani CP, et al. Eastern Cooperative Oncology Group. Comparison 
of four chemotherapy regimens for advanced non–small-cell lung cancer. N Engl J Med 
2002;346:92−8. 
b. Sandler A, Gray R, Perry MC, et al. Paclitaxel–carboplatin alone or with bevacizumab for 
non−small-cell lung cancer. N Engl J Med 2006;355:2542−50.
c. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with 
advanced non-small-cell lung cancer (FLEX): an open-label randomised Phase III trial. Lancet 
2009;373:1525−31.


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Table 3
Randomized Phase III Trials of Second-Line Therapy for 
Advanced NSCLC
First-Line Therapy Regimen
ORR
(%)
Median OS
(months)
1-Year OS
(%)
TAX 317 (2000) a
Docetaxel 100 mg/m2, q3w
7.1
5.9
19
Docetaxel 75 mg/m2, q3w
7.1
7.5
37
Best supportive care
NA
4.6
11
TAX 320 (2000) b
Docetaxel 100 mg/m2, q3w
10.8
5.5
21
Docetaxel 75 mg/m2, q3w
6.7
5.7
32
Vinorlebine or ifosfamide
0.8
5.6
19
JMEI (2004) c
Docetaxel 75 mg/m2, q3w
8.8
7.9
29.7
Pemetrexed 500 mg/m2, q3w
9.1
8.3
29.7
BR.21 (2004) d
Erlotinib 150 mg, QD
8.9
6.7
31
Best supportive care
NA
4.7
21
VITAL (2012) e
Docetaxel 75 mg/m2, q3w
8.9
10.4
NA
NA = not applicable; ORR = overall response rate; OS = overall survival; q3w = every 3 weeks; 
QD = every day.
Note: This table is adapted from Stinchcombe TE, Socinski MA. Considerations for second-line 
therapy of non-small cell lung cancer. Oncologist 2008;13:28–36.
a. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus 
best supportive care in patients with non–small-cell lung cancer previously treated with 
platinum-based chemotherapy. J Clin Oncol 2000;18:2095–103. 
b. Fossella FV, DeVore R, Kerr RN, et al. Randomized Phase III trial of docetaxel versus 
vinorelbine or ifosfamide in patients with advanced non-small cell lung cancer previously 
treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung 
Cancer Study Group. J Clin Oncol 2000;18:2354–63. 
c. Hanna Nasser, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed 
versus docetaxel in patients with non–small cell lung cancer previously treated with 
chemotherapy. J Clin Oncol 2004;22:1589–97. 
d. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated nonsmall-
cell lung cancer. N Engl J Med 2005;353:123–32.
e. Ramlau R, Gorbunova V, Ciuleanu TE, et al. Aflibercept and docetaxel versus docetaxel alone 
after platinum failure in patients with advanced or metastatic non–small-cell lung cancer: a 
randomized, controlled Phase III trial. J Clin Oncol 2012;30:3640−7.


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Although substantial benefit has been observed with crizotinib therapy, relapse remains 
the norm.  Studies with patients who had progression on crizotinib treatment reveal three 
potential reasons for treatment failure: 1) development of resistance due to 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); 
2) CNS progression; and 3) an as yet unknown mechanism.  CNS progression may be 
particularly important for crizotinib-treated patients as the CNS is the primary site of 
initial treatment failure in 46%–60% of patients with ALK-positive NSCLC treated with 
this agent (Costa et al. 2011; Chun et al. 2012; Weickhardt et al. 2012; Costa et al. 2015; 
Gainor et al. 2015).  Since significant morbidity is associated with CNS metastases due 
to the CNS involvement and to the standard forms of treatment (corticosteroids, surgery 
and radiation), an unmet medical need exists in this setting for chemotherapeutic agents 
with better activity in the CNS.
1.2
BACKGROUND ON ALECTINIB
Alectinib (also RO5424802 or CH5424802) is a newly developed highly-selective CNS-
active 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 alterations, including NSCLC and anaplastic large 
cell lymphoma lines harboring an ALK translocation and a neuroblastoma line harboring 
an amplified ALK gene.
Nonclinical pharmacology studies showed that alectinib was efficacious in a model of 
tumors expressing an ALK fusion bearing the L1196M mutation, which is associated with 
resistance to crizotinib, and alectinib was effective in mouse NCI H2228 NSCLC 
xenografts that were already maximally suppressed by crizotinib.  Alectinib also 
prolonged survival in an intracerebral NCI H2228 implantation model, and it reduced 
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 and two ongoing phase III 
studies:  
The ongoing Phase I/II studies include:

Study AF-001JP, a supportive first-in-human study conducted in Japan in crizotinib-
naive patients with locally advanced or metastatic ALK-positive NSCLC who have 
progressed on at least one line of chemotherapy

Study NP28761, conducted in the United States and Canada, in patients with ALK-
positive NSCLC who have progressed on or are intolerant to crizotinib

Study NP28673, conducted globally, in patients with ALK-positive NSCLC who have 
progressed on or are intolerant to crizotinib; the study also included a drug-drug 
interaction sub-study, where a single oral dose of midazolam was administered 
alone and in combination with multiple doses of alectinib


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The enrollment of patients in the Phase I/II studies is complete and follow-up is ongoing. 
The ongoing phase III studies include: 

Study BO28984 (ALEX), conducted globally, is comparing alectinib to crizotinib in 
treatment-naive ALK-positive NSCLC patients

J-ALEX, conducted in Japan, is comparing alectinib to crizotinib in ALK-positive 
NSCLC patients who have progressed on prior chemotherapy  
Results from the Phase III trials are not available to report at this time. 
Please refer to the current Investigators Brochure for the most recent updates.
1.2.1
Study AF-001JP
1.2.1.1
Efficacy
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.  AF-001JP has completed 
enrollment but 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 portion of the study, 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 escalation of the dose.  
In the Phase II portion of the study, 46 patients were treated with alectinib 300 mg BID.  
As of 31 January 2014, 43 patients (93.5%; 95% CI: 82.1% to 98.6%) achieved an 
objective response and 9 patients (19.6%; 95% CI: 9.4% to 33.9%) had a CR on the 
basis of an independent radiological review (Table 4).  Median PFS was 27.7 months 
(95% CI: 26.9 months, NR) and the 2-year OS rate was 79% (95% CI: 63%, 89%).  
Thirty-one patients remained on alectinib at the cut-off date.


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Table 4
Overall Response Rates and Time to Response in Patients 
in Part 2 of Study AF-001JP (Data Cutoff Date: 31 January 2014)
Response (n=46)
n (%)
95% CI (%)
CR
9 (19.6)
9.4–33.9
PR
34 (73.9)
58.9–85.7
SD
1 (2.2)
0.1–11.5
PD
0 (0.0)
0.0–7.7
Not evaluated
2 a
–
ORR (CR + PR)
43 (93.5)
82.1–98.6
Disease control (CR + PR + SD)
44 (95.7)
–
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease.
a. One patient withdrew early due to an AE (brain edema) and so had no response data; one had 
investigator-assessed PD that was later determined not to be PD by the IRC
Figure 1 shows the waterfall plot of the best change from baseline in the size of target 
lesions in Study AF-001JP, as determined by independent radiological review.  
Figure 1
Change in Size of Target Lesions as Assessed by the IRC in 
Part 2 of Study AF-001JP Using RECIST v1.1 (Data Cutoff Date: 
31 January 2014)
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease.
* Three of 9 patients who were assessed as having a CR had lymph nodes as the target lesions.  
Per 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%.


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PFS was favorable regardless of the presence or absence of CNS metastases at 
baseline (Figure 2).
Figure 2
Comparison of PFS in Patients With and Without CNS Metastases 
at Baseline in Study AF-001JP (Data Cutoff Date: 31 January 2014)
1.2.1.2
Safety
The safety results of Study AF-001JP, conducted in Japan, were consistent with the 
results observed in the pivotal Studies NP28761 and NP28673 (see next section).  Refer 
to the Alectinib Investigator's Brochure for more details.
1.2.2
Studies NP28761 and NP28673
1.2.2.1
Primary Efficacy
In Phase II of Study NP28761, the study met its primary objective of demonstrating a 
clinically meaningful and statistically significant ORR based on IRC assessments (52.2%; 
95% CI: 39.7%, 64.6%) in patients with ALK-positive advanced NSCLC whose disease 
had progressed on crizotinib treatment.  The result of the secondary endpoint, 
investigator-assessed ORR (50.6%; 95% CI: 39.6%, 61.5%), was consistent with the 
primary endpoint.
In Study NP28673, the study met its main objective of demonstrating a clinically 
meaningful and statistically significant ORR based on IRC assessments (50.8%; 95% CI: 
41.6%, 60.0%) in patients with ALK-positive advanced NSCLC whose disease had 
progressed on crizotinib treatment.  The co-primary objective of IRC-assessed ORR in 


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the subgroup of chemotherapy pretreated patients, although not statistically significant, 
was clinically meaningful (44.8%; 95% CI: 34.6%, 55.3%).  Due to the hierarchical order 
of testing, the overall study was considered positive as the first co-primary endpoint met 
statistical significance.  The result of the secondary endpoint, investigator-assessed 
ORR (50.7%; 95% CI: 42.1%, 59.3%), was supportive of the primary endpoints.
An overview of efficacy results from Studies NP28761 and NP28673 are shown in 
following table.
Table 5
Overview of Efficacy Results From Studies NP28761 and 
NP28673 (Cutoff Date: 27 April 2015)
Alectinib 600 mg BID
NP28761
Phase II
NP28673
Phase II
Primary Efficacy Parameters
ORR (IRC) in RE population
n=67a
N=122a
Responders, n (%)
35 (52.2)
62 (50.8)
[95% CIb]
[39.7, 64.6]
[41.6, 60.0]
ORR (IRC) in patients pre-treated with 
chemotherapyc
N=52
N=96
Responders, n (%)
30 (57.7)
43 (44.8)
[95% CIb]
[43.2, 71.3]
[34.6, 55.3]
Secondary Efficacy Parameters
ORR (investigator) in RE population
N=87
N=138
Responders, n (%)
44 (50.6)
70 (50.7)
[95% CIb]
[39.6, 61.5]
[42.1, 59.3]
ORR (investigator) in patients pre-treated with 
chemotherapy
N=64
N=110
Responders, n (%)
33 (51.6)
54 (49.1)
[95% CIb]
[38.7, 64.3]
[39.4, 58.8]
Exploratory Efficacy Parameters
DCR (IRC) in RE population
N=67a
N=122a
CR + PR + SD, n (%)
43 (64.2)d
78 (63.9)e
[95% CIb]
[51.5, 75.5]
[54.8, 72.4]


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Alectinib 600 mg BID
NP28761
Phase II
NP28673
Phase II
DCR (investigator) in RE population
N=87
N=138
CR + PR + SD, n (%)
41 (61.2)d
95 (68.8)e
[95% CIb]
[48.5, 72.9]
[60.4, 76.5]
DOR (IRC) in RE population
N=67
N=122
Median time to event, months
13.5
14.1
[95% CIf]
[6.7, NE]
[10.9, NE]
DOR (investigator) in RE population
N=87
N=138
Median time to event, months
11.1
11.2
[95% CIf]
[8.8, NE]
[9.6, NE]
PFS (IRC) in safety population
N=87
N=138
Median time to event, months
8.1
8.9
[95% CIf]
[6.2, 12.6]
[5.6, 12.8]
PFS (investigator) in safety population
N=87
N=138
Median time to event, months
8.4
9.3
[95% CIf]
[5.5, 12.3]
[7.4, 12.8]
BID = twice daily; CI = confidence interval; CR = complete response; DCR = disease control rate; 
DOR = duration of response; IRC = independent review committee; NE = not estimated; ORR = 
objective response rate; PFS = progression-free survival; PR = partial response; RE = response-
evaluable; SD = stable disease.
a There were 20 patients (NP28761) and 16 patients (NP28673) who did not have measurable 
disease at baseline according to the IRC and therefore were not included in the IRC RE 
population.
b 95% CI for rates were constructed using Clopper-Pearson method.
c Primary efficacy parameter only in Study NP28673.
d DCR is defined as the percentage of patients with a BOR of CR, PR, or SD lasting for at least 
12 weeks after the first dose of alectinib.
e DCR is defined as the percentage of patients with a BOR of CR, PR, or SD lasting for at least 
16 weeks.
f 95% CI for median was computed using the method of Brookmeyer and Crowley.
1.2.2.2
Central Nervous System Response
CNS response on the basis of radiological imaging was examined in a pooled analysis 
that included patients from Phase I [600 mg BID] and II of Study NP28761, as well as 
Phase II and the midazolam drug-drug interaction sub-study of Study NP28673.  Among 
50 pooled and evaluable patients who had either measurable or non-measurable CNS 
lesions at a baseline scan and at least one follow-up scan, 11 patients achieved a 
confirmed CR, 21 achieved PR, 13 achieved SD and 3 achieved PD in the IRC-


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assessed population (data cutoff date: 27 April 2015).  Two patients were unevaluable.  
The CNS DCR in this group was 90.0% (i.e., 45 of the 50 total evaluable patients).
Similarly, in 136 patients who had either measurable or non-measurable CNS lesions at 
a baseline scan, 37 patients achieved a confirmed CR, 58 achieved SD and 12 achieved 
PD in the IRC-assessed population.  Twenty-one patients were noted as achieving PR 
(NB, patients with only non-measurable lesions cannot achieve PR).  Eight patients were 
unevaluable.  The CNS DCR was 85.3% (116 of the 136 total evaluable patients).
The median CNS DOR for evaluable patients with measurable CNS lesions at baseline
in the pooled analysis was 10.8 months (95% CI: 7.6, 14.1 months).  The median CNS 
DOR for evaluable patients with measurable and non-measurable CNS lesions at 
baseline was 11.1 months (95% CI: 10.3, NE months).
1.2.2.3
Safety
In Study NP28761, no DLTs were observed in the dose-escalation cohorts up to a dose 
of 900 mg BID.  However, 2 patients in the subsequent 900-mg BID bridging cohort 
experienced a DLT, one each of Grade 3 headache and Grade 3 neutrophil count 
decreased, and both patients continued study treatment at reduced dose of 600 mg BID.  
On the basis of efficacy, safety, and PK data, the recommended Phase 2 dose was 
600 mg BID.  
Safety findings were consistent between the pivotal Studies NP28761 and NP28673 and 
overall findings are summarized here.
In a pooled safety analysis (includes patients from Phase I [600 mg BID] and II of 
Study NP28761 and Phase II and the midazolam drug-drug interaction sub-study of 
Study NP28673), almost all patients (98.4%) reported at least one AE as of the cutoff 
date of 27 April 2015.  The most commonly reported AEs were constipation (33.6%), 
fatigue (30.0%), peripheral edema (26.1%), and myalgia (24.1%).  The majority of AEs 
were of Grade 1 or 2 severity. Grade ≥ 3 AEs occurred in 86 of 253 patients (34.0%), 
with the most commonly reported being increased blood CPK (3.6%), dyspnea (3.6%), 
increased ALT (3.2%), and increased AST (2.8%).  
Forty-nine of 253 patients (19.4%) in the pooled analysis had at least one SAE.  The 
majority of the SAEs were single cases, and no SAE was reported in more than 3 
patients.  Of the 74 of 253 patients (29.2%) who died in the pooled analysis, the majority 
(66 patients [89.2% of the deaths]) were due to disease progression.  Seven of 253 
patients (2.8%) had an AE with fatal outcome.  Rates of AEs leading to study drug 
withdrawal (5.9%), interruption (26.9%), or dose reduction (11.5%) indicated that 
alectinib treatment was well tolerated.
Selected AEs were defined in the study protocols based on potential risks identified from 
clinical and non-clinical data with alectinib and from data with ALK inhibitors.  Selected 


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AEs that were reported in ≥ 10% of patients were constipation (34%); myalgia (24%); 
nausea (18%); diarrhea and AST increased (each 16%); ALT increased and anemia 
(each 14%); and vomiting, rash, blood CPK increased, and back pain (each 12%).
See the Alectinib Investigator's Brochure for additional details on nonclinical and clinical 
studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
1.3.1
Study Rationale
In patients with advanced NSCLC who lack an EGFR activating mutation or ALK gene 
rearrangement (~85% of all cases), standard first-line treatment is platinum-based 
chemotherapy (in patients with PS 0–2), although addition of bevacizumab improved 
outcome over platinum-based chemotherapy alone (Reck et al. 2014).  Following 
treatment failure on first-line agents, patients with advanced NSCLC lacking EGFR/ALK 
alterations are then recommended to receive either pemetrexed or docetaxel as second-
line therapy (Reck et al. 2014). 
NSCLC patients with ALK gene rearrangements have an additional therapeutic option in 
the EU, where crizotinib is indicated for previously-treated ALK-positive advanced 
NSCLC (European Medicines Agency).  Approval for this indication was based largely 
on the results from the PROFILE 1007 study (Shaw et al. 2013).  In this randomized 
Phase III study, 347 patients with locally advanced or metastatic ALK-positive lung 
cancer who had received one prior platinum-based regimen were randomized 1:1 to one 
of two treatments.  The first group (n=174) received pemetrexed or docetaxel every 
3 weeks.  The second group (n=173) received twice-daily crizotinib.  The median PFS 
was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group.  The 
response rates were 65% (95% CI, 58% to 72%) with crizotinib, as compared with 20% 
(95% CI, 14% to 26%) with chemotherapy (P<0.001).  An interim analysis of OS showed 
no significant improvement with crizotinib as compared with chemotherapy.  Patients 
also reported greater reductions in symptoms of lung cancer and greater improvement in 
global QoL of life with crizotinib than with chemotherapy.
Although substantial benefit has been observed with crizotinib therapy, relapse 
nonetheless eventually occurs.  This is thought to happen for three potential reasons: 1) 
the development of drug resistance due to a secondary (e.g., gatekeeper) mutation(s), 
2) CNS progression; and 3) an as yet unknown mechanism(s) (Katayama et al. 2011; 
Doebele et al. 2012; Kim et al. 2013).  The CNS relapse is most likely attributable to the 
fact that crizotinib is a P-glycoprotein (P-gp) substrate and, thus, may not be retained at 
significant levels in brain tissue.  Consequently, in ALK-positive NSCLC, crizotinib 
exhibits impaired control of CNS metastases relative to other sites of systemic disease, 
with 46%–60% of progressions in patients treated with crizotinib involving the CNS 
(Costa et al. 2011; Chun et al. 2012; Weickhardt et al. 2012; Costa et al. 2015; Gainor et 


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al. 2015).  In other words, the CNS becomes a sanctuary site for ALK-positive NSCLC 
treated with crizotiniba physiologic and anatomic mechanism of drug resistance.
As crizotinib provides a median of 7.7 months of PFS following failure of platinum-based 
therapies, it becomes vitally important to identify optimal rescue therapies following 
failure of both platinum-based therapy and crizotinib.  In the EU, current options in this 
setting include pemetrexed and docetaxel (Reck et al. 2014), with pemetrexed being 
favored by a recent ESMO consensus statement (Besse et al. 2014).  Nonetheless, as 
shown in PROFILE 1007 (Shaw et al. 2013), the latter two agents have very poor 
efficacy as second-line agents (ORR, 20%; PFS, 3 months), and there is no reason to 
expect that the same is not true in the third-line setting. 
The purpose of this study is therefore to determine whether alectinib, an ALK-specific 
TKI, provides more clinical benefit than pemetrexed or docetaxel in advanced ALK-
positive NSCLC following relapse on platinum-based chemotherapy and crizotinib.  The 
study will examine the effects of alectinib in all eligible patients, as well as in the 
subgroup of patients with CNS metastases at baseline.
Several prior observations predict that alectinib may be efficacious in both of these 
patient populations:

Nonclinical data for alectinib suggest that it may be active in NSCLC even after 
progression on prior crizotinib therapy when the mechanism of resistance is due to 
acquired mutation in the ALK gene (Alectinib Investigator's Brochure for details)

Alectinib is lipophilic and not a substrate for P-gp or the ABC transporter breast 
cancer resistance protein, known efflux transporters at the blood-brain barrier.  
Indeed, promising efficacy within the CNS has been observed with alectinib in 
pivotal Phase 2 studies in patients who have progressed on prior crizotinib therapy 
(see Section 1.2.2 and Alectinib Investigator's Brochure for details)  

In NSCLC patients treated with alectinib, PFS was favorable regardless of the 
presence or absence of CNS metastases at baseline (see Sections 1.2.2 and 1.2.2) 
Finally, this study will also carry out PK, PRO and exploratory biomarker assessments.  
The rationales for these latter assessments are presented in detail in Sections 3.3.6, 
3.3.7 and 3.3.8.
1.3.2
Benefit-Risk Assessment
Overall, the efficacy and safety data from the pivotal Studies NP28761 and NP28673
and the supporting studies show a favorable benefit/risk ratio for alectinib treatment, 
when administered at a dose of 600 mg BID (1200 mg/day), in patients with ALK-positive 
advanced NSCLC.  The compound has been well tolerated in clinical studies in which 
patients with locally advanced or metastatic ALK-positive NSCLC have been treated with 
multiple doses of up to 760 mg BID.


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Identified and potential risks associated with alectinib treatment will continue to be 
closely monitored throughout this study.  Patient safety will be ensured by targeting the 
appropriate patient population (advanced ALK-positive NSCLC with and without CNS 
metastases at baseline) using carefully chosen inclusion/exclusion criteria, by stringent 
safety monitoring carried out by the Sponsor and Independent Data Monitoring 
Committee (iDMC) and by protocol-specified study drug interruption criteria.  
With the above safety precautions in place, the estimated benefits of alectinib treatment 
outweigh the risks in this study, especially given the potential of alectinib—and the 
dearth of effective chemotherapeutic agents currently available—in patients with 
advanced ALK-positive NSCLC who have failed on prior platinum-based therapy and 
crizotinib.  
2.
OBJECTIVES
2.1
EFFICACY OBJECTIVES
The primary efficacy objective for this study are as follows:

To evaluate and compare between treatment groups the efficacy of alectinib versus 
chemotherapy in patients with anaplastic lymphoma kinase (ALK)-positive advanced 
non-small cell lung cancer (NSCLC) who were previously treated with chemotherapy 
and crizotinib (progressed or intolerant to crizotinib), as measured by investigator-
assessed progression-free survival (PFS)
The key secondary efficacy objective for this study is as follows:

To evaluate and compare between treatment groups the central nervous system 
(CNS) objective response rate (C-ORR) in patients with measurable CNS 
metastases at baseline, as assessed by an Independent Review Committee (IRC)
Other secondary efficacy objectives for this study are to evaluate and compare between 
treatment arms:

PFS (assessment by IRC)

Objective response rate (ORR), disease control rate (DCR) and duration of 
response (DOR) in all patients according to Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST v1.1) (assessment by investigator and IRC) 

PFS in patients with baseline CNS metastases (assessment by investigator and IRC)

Time to CNS progression in all patients, patients with baseline CNS metastases and 
patients without baseline CNS metastases  (assessment by IRC)

CNS duration of response (C-DOR), CNS disease control rate (C-DCR) and C-ORR 
for all patients with baseline CNS metastasis (assessment by IRC)

C-DOR and C-DCR for patients with baseline measurable CNS metastasis 
(assessment by IRC)

Overall survival (OS)


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2.2
SAFETY OBJECTIVES
The safety objectives for this study are as follows:

To evaluate the safety and tolerability of alectinib compared with chemotherapy in 
all patients and patients with CNS metastases at baseline
2.3
PHARMACOKINETIC OBJECTIVES
The pharmacokinetic (PK) objectives for this study are as follows:

To characterize the pharmacokinetics of alectinib and its major metabolites
2.4
PATIENT-REPORTED OUTCOME OBJECTIVES
The 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, chest pain (single item), dyspnea (single item and multi-item 
subscales), pain in arm/shoulder 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 by a composite of three symptoms (cough, dyspnea (multi-item 
subscales QLQ-LC13)  and chest pain).  Analysis will be performed for all patients, 
as well as in the subgroup of patients with CNS metastases 

To evaluate and compare patient-reported outcomes (PROs) of health-related 
quality of life (HRQoL), patient functioning and side effects of treatment, as
measured by the EORTC QLQ-C30, EORTC QLQ-LC13 and EQ-5D-5L.  Analysis 
will be performed for all patients, as well as in the subgroup of patients with CNS 
metastases
2.5
EXPLORATORY OBJECTIVES
The exploratory objectives for this study may include but are not limited to the following: 

To evaluate PROs of patients with CNS metastases, as measured by specific 
questions from the EORTC QLQ-BN20 questionnaire 

To assess exploratory biomarkers relevant in NSCLC biology and alectinib 
mechanism of action (including but not limited to ALK genetic alterations) and their 
association with disease status, clinical outcome, efficacy and safety

To investigate molecular mechanisms of resistance to ALK inhibitors

To develop biomarker or diagnostic assays to detect ALK mutations/fusions in 
plasma/tumor and to establish performance characteristics of these assays
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This will be a randomized active-controlled multicenter Phase III open-label study.  The 
study will consist of a Screening Period, a Treatment Period and a Post Progression and 
Post Treatment Period (Figure 3).  Day 1 (baseline) will be defined as the first day a 
patient receives study medication.  The Post Treatment Period for patients who do not 




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
CNS metastases at baseline (yes vs. no)
In addition, patients with baseline CNS metastases will be stratified by history of 
radiotherapy (yes vs. no)
Enrollment caps will be used to ensure that at least 50% of randomized patients will 
have baseline CNS metastases.  An IxRS manual containing relevant information will be 
provided to each study site.
Following randomization, the experimental arm will receive oral alectinib at a dosage of 
600 mg twice daily (BID), taken with food.  The control arm will receive chemotherapy 
with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 
mg per square meter) every 3 weeks.  The first dose of the study drug (and the required 
premedication, when applicable) should be administered as soon as possible after 
randomization, preferably within 24 hours, and no later than 48 hours after 
randomization.  
Patients on both arms will be treated with study drug (including those who cross over 
from chemotherapy to alectinib) until disease progression, unacceptable toxicity, 
withdrawal of consent or death.  At the discretion of the patient and the investigator, 
patients on the alectinib arm who show radiological progression per RECIST v1.1 will be 
allowed to continue receiving alectinib beyond disease progression if he or she is 
clinically benefitting from the drug until no further clinical benefit is to be expected, 
unacceptable toxicity, withdrawal of consent or death.  Patients on the control 
(chemotherapy) arm who do not have any safety-related issues that might render the 
patient ineligible to receive alectinib treatment (as per safety-based inclusion criteria of 
the study) will be allowed to cross over to receive alectinib treatment.  Patients with any 
safety-related issues rendering the patient ineligible to receive alectinib treatment (as per 
safety-based inclusion criteria of the study) will have the possibility to cross over after 
the safety-related issues have resolved or normalized.  Upon progression on cross-over 
treatment with alectinib, patients will be allowed to continue receiving alectinib beyond 
disease progression if he or she is clinically benefitting from the drug until further 
disease progression, no further clinical benefit is to be expected, unacceptable toxicity, 
withdrawal of consent or death.  Patients on either arm who opt not to continue or to 
cross over to alectinib will be treated at the discretion of the investigator according to 
local practice.  
In all patients, information regarding the type and duration of subsequent therapies 
following disease progression, as well as overall survival follow-up, will be collected.  
Patients who discontinue treatment prior to disease progression (e.g., due to 
unacceptable toxicity) will continue to be followed until disease progression and for OS, 
regardless of whether they subsequently receive non-study anti-cancer therapy.  


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The assessments to be conducted in this study are described below and will be carried 
out at the time points designated in the Schedule of Assessments (Appendix 1 and 2):

Disease progression will be assessed using Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST v1.1).  The primary efficacy objective will be 
investigator-assessed PFS, and the key secondary efficacy objective will be IRC-
assessed C-ORR.  Other secondary objectives will include the following 
assessments by the IRC: PFS; PFS in patients with CNS metastases at baseline; 
time to CNS progression in all patients and in patients with and without baseline 
CNS metastases; and C-DOR and C-DCR in all patients with baseline CNS 
metastases and in patients with measurable CNS metastases.  The IRC and the 
investigator will evaluate ORR, DCR and DOR.  Finally, OS will be determined

Safety will be monitored by assessing serious and non-serious adverse events 
(AEs), safety laboratory tests, vital signs and electrocardiogram (ECG).  The 
incidence, nature and severity of all AEs will be graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI 
CTCAE v4.0).  Laboratory safety tests will include hematology and blood chemistry.  
Vital sign assessments will include blood pressure and pulse rate; additional vital 
signs will be collected only if clinically warranted.  In addition, the study will have a 
baseline urinalysis assessment (dipstick); additional urinalyses will be conducted 
only if clinically warranted 

Pharmacokinetic (PK) parameters for alectinib and its major metabolite(s) will be 
assessed on sparsely collected pre-dose blood samples.  The specific PK 
parameters will be determined as appropriate, where data allow

HRQoL will be assessed using three PRO instruments: the EORTC QLQ-C30, the 
EORTC QLQ-LC13, and the EuroQoL 5D-5L.  PRO scores will be determined for all 
patients and for patients with CNS metastases at baseline and will be compared 
across treatment groups  

Finally, the study will have exploratory analyses examining biomarkers and 
assessing the HRQoL effects of brain metastases in patients with CNS metastases 
at baseline.  The latter PRO assessments will be based on two selected questions 
from the EORTC QLQ-BN20, a QoL instrument specific for brain neoplasms  
An independent data monitoring committee (iDMC) is planned for this study to review 
safety data periodically.  More details will be provided in the iDMC charter.
3.2
END OF STUDY
The end the of study will occur when each patient is followed up for OS for up to 14 
months or when 50% of randomized patients have died, whichever occurs first.  
Patients who are receiving and benefitting from study treatment at the end of the study 
may be offered the possibility of rolling over into a long-term extension study, following 
the approval of this extension study by Competent Authorities and the Ethics 
Committees of the respective investigational sites.  During the long-term extension study, 
minimum data will be collected and SAE’s will be reported to Roche and entered into the 


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Roche safety data base.  Study MO29750 will be closed and an updated analysis 
performed once all patients have either withdrawn or enrolled in the extension study.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Design Features
This Phase III study design is based on the hypothesis that, in advanced ALK-positive 
NSCLC patients who have failed prior platinum-based therapies and crizotinib, treatment 
with alectinib will prolong investigator-assessed PFS compared to treatment with 
pemetrexed or docetaxel.  Its key secondary hypothesis is that treatment with alectinib 
will improve IRC-assessed C-ORR compared to pemetrexed and docetaxel in the same 
patient population.  Results from this randomized prospective study will help regulatory
agencies decide whether alectinib is an effective post-progression therapy in advanced 
ALK-positive NSCLC patients who have failed prior platinum-based therapies and 
crizotinib.  
The open-label design is necessitated by the fact that alectinib is administered orally, 
whereas the comparator chemotherapies are administered intravenously.  Furthermore, 
pemetrexed is normally administered over 10 minutes and docetaxel is administered 
over an hour.  Blinding of treatments in this scenario would therefore place undue 
burden on both patients and investigators. 
Patients will be randomized 2:1 into one of two treatment arms to receive either alectinib 
or chemotherapy (pemetrexed or docetaxel).  To ensure comparability between 
treatment groups, patients will be randomized using the following stratification factors: 
ECOG PS (0/1 vs. 2); and CNS metastases at baseline (yes vs. no). In addition, patients 
with baseline CNS metastasis will be stratified by history of radiotherapy (yes vs. no).  
Enrollment caps will be used to ensure that 50% of randomized patients will have 
baseline CNS metastases and, in the comparator group, 50% of patients will use each 
type of chemotherapy.  
3.3.2
Rationale for Study Population
Crizotinib is indicated in the EU as second-line therapy for advanced ALK-positive 
NSCLC after relapse on first-line chemotherapy (European Medicines Agency 2015), 
which is typically a platinum doublet chemotherapy.  However, as it only provides a 
median of 7.7 months of PFS in this setting, it is vitally important to ascertain an optimal 
rescue therapy.  The purpose of this study is to directly determine whether alectinib, an 
ALK-specific TKI, provides more clinical benefit than standard chemotherapy 
(pemetrexed or docetaxel) in this specific study population, i.e., in advanced ALK-
positive NSCLC following relapse on platinum-based chemotherapy and crizotinib.  
Efforts will be taken to ensure that at least 50% of patients enrolled have CNS
metastases.  Furthermore, the key secondary efficacy objective of the study is to 
determine C-ORR.  This focus on CNS metastases reflects the fact that 46%–60% of 


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progressions in patients treated with crizotinib involve the CNS, i.e., that the CNS 
becomes a sanctuary site for ALK-positive NSCLC treated with crizotinib (Costa et al. 
2011; Chun et al. 2012; Weickhardt et al. 2012; Costa et al. 2015; Gainor et al. 2015).  
Hence, in determining the efficacy of alectinib in this setting, a fully representative 
sample of patients must contain this difficult-to-treat class.
3.3.3
Rationale for Alectinib Dose and Schedule
Selection of the alectinib dose for the study is based on the clinical safety, efficacy and 
PK data observed in the pivotal Phase I/II studies, NP28761/AF-002JG and NP28673, 
and supportive nonclinical data for alectinib.
Phase I of Study NP28761 evaluated escalating doses of alectinib from 300 to 900 mg 
BID using a modified 3+3 design to determine the RP2D.  The starting dose in 
Study NP28761 was the highest dosage evaluated in Study AF-001JP, 300 mg BID.  
Alectinib was generally well tolerated across the doses tested and was well tolerated in 
the study population.  Dose escalation revealed two patients with DLTs at 900 mg; both 
patients resumed treatment at a reduced dose of 600 mg where no further DLTs were 
observed.  These clinical safety data, together with PK data and available efficacy data 
from Phase I of Study NP28761 showing promising antitumor activity of alectinib 600 mg 
BID supported the selection of the 600 mg BID dosing regimen as the RP2D.  
Phase II of Study NP28761 and Study NP28673 confirmed the selection of the 600 mg 
BID dosing regimen, as the primary efficacy endpoint was met, and the dosing regimen 
was generally well tolerated in the crizotinib-progressed patient population.
On the basis of available nonclinical 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 clinical dose level for this crizotinib-progressed patient 
population.
Alectinib 600 mg should be administered orally BID with food in the morning and evening.
3.3.4
Rationale for Control Group
In this comparative study, the control group will receive either pemetrexed or docetaxel.  
According to a recent ESMO consensus report, patients with ALK-positive NSCLC are 
recommended to receive a platinum-based chemotherapy in the first-line setting and 
crizotinib in the second-line setting (Besse et al. 2014).  Following progression on 
second-line crizotinib, the ESMO guidelines then recommend third-line pemetrexed in 
patients with nonsquamous NSCLC.  Pemetrexed may therefore be considered the 
standard therapeutic option in the third-line setting and will thus be used as one control 
agent in this trial.  


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In addition to pemetrexed, current ESMO guidelines recommend docetaxel following 
failure of first-line platinum-based doublets in general populations of advanced NSCLC 
patients (which are largely ALK-negative) (Reck et al. 2014).  Consequently, since many 
practicing oncologists may view it as a standard option following failure of platinum-
based therapies and crizotinib, docetaxel will be used as the other control agent in this 
trial. 
3.3.5
Rationale for Efficacy 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 efficacy 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.  The trial will test the hypothesis that alectinib will significantly 
improve PFS from 3 months—the currently expected value in advanced ALK-positive 
NSCLC patients who receive pemetrexed or docetaxel following failure of platinum-
based therapies and crizotinib—to 7 months, which is considered a clinically significant 
improvement over the dismal norm.  The total number of planned patients, i.e., 60 in the 
alectinib arm and 30 in the chemotherapy arm with at least 50 overall observed PFS 
events, will provide 80% power to detect a significant improvement in the primary 
endpoint from 3 months to 7 months (HR of 0.43) for a two-sided log-rank test at an 
alpha level of 0.05. 
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0.43) 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).
If superiority for the PFS endpoints is concluded, subsequent hierarchical testing for the 
key secondary efficacy endpoint, CNS objective response rate (C-ORR) in patients with 
measurable CNS metastases at baseline, will be performed.  In ALK-positive NSCLC, 
crizotinib has been shown to exhibit impaired control of CNS metastases relative to other 
sites of systemic disease, with 46%–60% of progressions in patients treated with 
crizotinib involving the CNS (Costa et al. 2011; Chun et al. 2012; Weickhardt et al. 2012; 
Costa et al. 2015; Gainor et al. 2015).  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).  Thus, a direct 
assessment of the efficacy of alectinib in advanced ALK-positive patients who have 
failed on platinum-based therapies and crizotinib will have high clinical significance.


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3.3.6
Rationale for Pharmacokinetics Assessments
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.  To better understand the pharmacokinetics of alectinib and 
to further characterize exposure-response relationships for alectinib, this study will seek 
to better understand, identify and characterize variables that may lead to potential 
changes in exposure of alectinib in patients with advanced ALK-positive NSCLC.  
Results from these analyses will enable a more robust understanding of alectinib 
pharmacokinetics, including the identification of potential sources of variability 
influencing alectinib pharmacokinetics and/or response to alectinib therapy, and will 
inform and confirm optimal use of alectinib.
3.3.7
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.  Therefore, this 
study will collect PRO data from patients at the time points described in the Schedule of 
Assessments (Appendix 1 and 2).  The validated instruments used will include the 
European Organization for the Research and Treatment of Cancer Quality of Life 
Questionnaire—Core-30 (EORTC QLQ-C30), the European Organization for the 
Research and Treatment of Cancer Quality of Life Questionnaire—Lung Cancer-13 
(EORTC QLQ--LC13 and the EuroQoL 5 Dimension 5 level (EQ-5D-5L) (Appendix 7).  In 
addition, on an exploratory basis, this study will assess scores from two selected 
questions on the European Organization for the Research and Treatment of Cancer 
Quality of Life Questionnaire—Brain Neoplasm-20 (EORTC QLQ-BN20) (see Section 
3.3.8).  The scientific and clinical rationales for choosing these instruments are provided 
below and in the next section (Section 3.3.8).
3.3.7.1
EORTC QLQ-C30 and QLQ-LC13
The EORTC Study Group on Quality of Life has developed a modular system for 
assessing the quality of life of cancer patients in clinical trials that is composed of two 
basic elements: 1) a core quality of life questionnaire, the EORTC QLQ-C30, covering 
general aspects of health-related quality of life; and 2) additional disease- or treatment-
specific questionnaire modules (Bergman et al. 1994).  The disease-specific module 
focusing on lung cancer, the EORTC QLQ-LC13, will be used in this study.  Together, 
these two instruments can provide assessments of patient-reported quality of life related 
to cancer generally and lung cancer specifically.
Pain (chest and arm/shoulder), dyspnea, cough and fatigue have been regarded as the 
most frequent and clinically relevant disease-related symptoms experienced by patients 


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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).
3.3.7.2
EQ-5D-5L
The EQ-5D-5L questionnaire will be used in this study to assess patients’ general health 
status, as well as to assist in generating utility scores for use in pharmacoeconomic 
models for reimbursement.  The EQ-5D-5L is a generic preference-based health utility 
measure that provides a single index value for health status.  The instrument consists of 
two parts.  The first part, health-state classification, contains five dimensions of health: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  The second 
part, consisting of a visual analog scale, will not be used in this study.
The EQ-5D-5L was used previously in the PROFILE 1007 study, which compared 
crizotinib with pemetrexed or docetaxel in ALK-positive NSCLC patients who had 
progressed on a prior platinum-based chemotherapy regimen (Blackhall et al. 2014),  
#0}.  In the PROFILE 1007 study population, the overall mean health utility index scores 
(95% CI) on treatment were significantly greater (p < 0.05) for crizotinib (0.82 
[0.79−0.85]) than for chemotherapy (0.73 [0.70−0.77]; 0.74 [0.70−0.79] for pemetrexed 
and 0.66 [0.58−0.74] for docetaxel).  Within groups, a significant overall improvement 
from baseline in general health status (EQ-5D VAS) was observed for crizotinib 
compared with a significant overall deterioration for chemotherapy.  Significant overall 
deterioration from baseline was also observed for the pemetrexed and docetaxel 
subgroups.  A greater overall improvement in general health status from baseline was 
observed in the crizotinib arm compared with either pemetrexed (estimated difference 


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[95% CI]: 8.74 [4.47, 13]; p  < 0.001) or docetaxel (estimated difference [95% CI]: 14.50 
[7.82, 21.17]; p  < 0.001)
3.3.8
Rationale for Exploratory Assessments
3.3.8.1
Selected Questions From the EORTC QLQ-BN20
Approximately 46%–60% of progressions in patients treated with crizotinib involve the 
CNS (Costa et al. 2011; Chun et al. 2012; Weickhardt et al. 2012; Costa et al. 2015; 
Gainor et al. 2015).  In Phase I/II clinical trials, alectinib exhibited significant activity 
against CNS metastases (see Section 1.2).  Therefore, since significant morbidity is 
associated with CNS metastases due to the CNS involvement and to the standard forms 
of treatment (corticosteroids, surgery, and radiation), it becomes of real interest to 
determine whether the improvement in objective responses with alectinib translates into 
improvements in CNS PROs.  
To address this issue, all patients in the study will complete three questions extracted 
from the EORTC QLQ-BN20 questionnaire, a QoL instrument specific to brain 
neoplasms, at the time points indicated in the Schedule of Assessments (Appendix 1 
and 2).  The three questions are as follows:
1.
Do you have headaches?
2.
Do you have problems with coordination / balance?
3.
Did you have trouble communicating your thoughts?
Since the EORTC QLQ-LC13 will be used to assess the impact of lung cancer on patient 
quality of life in the two treatment groups, the complete EORTC QLQ-BN20 cannot also 
be included among the assessments, as the two instruments invalidate each other.  
Thus, to directly assess the quality-of-life impact of brain metastases on patients in the 
trial, which is of significant interest given that the CNS can be a sanctuary for crizotinib-
resistance, the above three questions were chosen from the EORTC QLQ-BN20.  These 
questions were selected based on information from literature searches and were agreed 
upon by the MO29750 Study Committee.  Because this approach has not been validated 
in NSCLC patients with CNS metastases, the proposed analyses will of necessity be 
conducted in an exploratory fashion.
3.3.8.2
Biomarkers
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, optional 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 may be used: 1) targeted sequencing of a panel of genes known to be 


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involved in cancer, and/or 2) unbiased genomic sequencing.  Analyses aiming to further 
characterize the molecular tumor microenvironment may be added.
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 time 
points during treatment to monitor mutations in ALK and other genes.  Similar analyses 
will be performed in tumor tissue and will be correlated with results from the analysis of 
plasma samples.
For exploratory assessments, other methods besides IHC and FISH will be used to 
determine ALK positivity (e.g., reverse transcription polymerase chain reaction, nucleic 
acids sequencing).  Information from plasma ALK assays will be used to investigate the 
use of circulating tumor nucleic acids for diagnostic purposes.  
A rationale for the RCR biomarker samples is provided in Section 4.5.11.1.
3.4
OUTCOME MEASURES 
3.4.1
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:

Progression-free survival (PFS) is defined as the time from randomization to the first 
documented disease progression, as determined using RECIST v1.1, or death from 
any cause, whichever occurs first.  Similar definitions of PFS will be used by the 
investigator (primary endpoint) and the IRC.  Patients without an event will be 
censored at the last tumor assessment.  Patients with no post-baseline 
assessments will be censored at the date of randomization.  PFS for patients with 
CNS metastasis at baseline will be defined in a  similar way, taking into account all 
lesions in the body

Overall response rate (ORR) is defined as the percentage of patients who attain 
complete response (CR) or partial response (PR), as determined using RECIST 
v1.1.  Similar definitions of ORR will be used by the investigator and the IRC.  
Patients without any post-baseline assessments will be regarded as non-responders.  
ORR for patients with CNS metastasis at baseline (C-ORR) will be defined in a 
similar way for lesions in the CNS.  (It should be noted that patients with non-
measurable disease can achieve only CR and not PR)

Disease control rate (DCR) is defined as the percentage of patients who attain 
complete response (CR), partial response (PR) or stable disease (SD) of at least 5 
weeks, as determined using RECIST v1.1.  Similar definitions of DCR will be used 
by the investigator and the IRC.  Patients without any post-baseline assessments 
will be regarded as non-responders.  CNS DCR (C-DCR) for patients with CNS 
metastasis at baseline will be defined in a similar way for lesions in the CNS.  (It 
should be noted that patients with non-measurable disease can achieve only CR or 
SD and not PR).


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
Duration of response (DOR) 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.  Similar definitions of DOR will be used by the investigator 
and the IRC.  Patients who do not progress or die after they have had a response 
are censored at the date of their last tumor measurement.  DOR for patients with 
CNS metastasis at baseline (C-DOR) will be defined in a similar way for lesions in 
the CNS, taking into account all lesions in the body

Overall survival (OS) 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

Time to CNS progression is defined as the time from randomization to the first 
documented disease progression in the CNS
3.4.2
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Serious and non-serious AEs 

Safety laboratory tests

Vital signs

ECG
Incidence, nature and severity of all adverse events will be graded according to 
NCI CTCAE v.4.0
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
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.
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


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
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, as appropriate.  The potential influence of covariates 
that contribute significantly to the between-patient differences in PK parameters 
of alectinib will also be explored and quantified, as appropriate
Additional PK parameters may be calculated as deemed appropriate.
3.4.4
Patient-Reported Outcome Measures
The PRO outcome measures for this study are as follows (see Appendix 7):

EORTC QLQ-C30 and EORTC QLQ-LC13 scores to determine the impact of 
alectinib compared with chemotherapy in the overall patient population, as well as in 
patients with CNS metastases at baseline, as measured by time to deterioration 
(TTD) in patient-reported lung cancer symptoms (e.g., cough, chest pain (single 
item) dyspnea (single item and multi-item scales], pain in chest, pain in 
arm/shoulder and fatigue)as well as measured by a composite of three symptoms 
(cough, dyspnea (multi-item subscales QLQ-LC13) and chest pain)The EORTC 
QLQ-C30 and EORTC QLQ-LC13 scores to measure PROs of HRQoL, patient 
functioning and side effects of therapy compared between patients treated with 
alectinib and those treated with chemotherapy.  The comparison will be done for the
overall patient population, as well as in patients with CNS metastases at baseline

The EuroQoL 5 Dimension (EQ-5D-5L) questionnaire score will be used for the 
overall patient population, as well as for patients with CNS metastases at baseline, 
to assess patients’ health status and generate utility scores for use in 
pharmacoeconomic models for reimbursement purposes only
3.4.5
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows (additional exploratory 
parameters may be assessed as deemed appropriate):

Scores from three specific questions extracted from the EORTC QLQ-BN20 
questionnaire, a QoL instrument specific to brain neoplasms.  The three questions 
are as follows: "Do you have headaches?"; "Do you have problems with 
coordination/balance?"; and "Did you have trouble communicating your thoughts?"  
Each of the three questions will be scored on a 4-point scale (1, Not at all; 2, A little; 
3, Quite a bit; 4, Very much), which will subsequently be linearly transformed to a 0–
100-point scale

Need and dosing for corticosteroids in case of CNS metastasis

To assess exploratory biomarkers relevant in NSCLC biology and alectinib 
mechanism of action (including but not limited to ALK genetic alterations) and their 
association with disease status, clinical outcome, efficacy and safety

To investigate molecular mechanisms of resistance to ALK inhibitors


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
To develop biomarker or diagnostic assays to detect ALK mutations/fusions in 
plasma/tumor and to establish performance characteristics of these assays
4.
MATERIALS AND METHODS 
4.1
PATIENTS
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:
1.
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.  ALK positivity must have been determined by a 
validated FISH test (recommended probe, Vysis ALK Break-Apart Probe) or a 
validated IHC test (recommended antibody, clone D5F3)
2.
Patient had received two prior systemic lines of therapy for advanced or metastatic 
disease (stage IIIB or IV), which must have included one line of platinum-based 
chemotherapy and one line of crizotinib (progression on or intolerability to crizotinib)
3.
Prior CNS or leptomeningeal metastases allowed if asymptomatic.  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 
and local treatment is indicated, patients need to complete the local treatment 
(surgery or radiotherapy).  In all cases, radiation treatment must be completed at 
least 14 days before enrollment and patients must be clinically stable 
4.
Patients with symptomatic CNS metastases for whom radiotherapy is not an option 
will be allowed to participate in this study 
5.
Measurable disease (by RECIST v1.1) prior to the administration of study treatment 
(Appendix 5)
6.
Age ≥18 years old 
7.
Life expectancy of at least 12 weeks 
8.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2 
(Appendix 6)
9.
Adequate hematologic function: 

Platelet count ≥100 x109/L 

Absolute neutrophil count (ANC) ≥1500 cells/µL

Hemoglobin ≥9.0 g/dL
10. 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 (Appendix 8)
11. 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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12. For all females of childbearing potential, a negative pregnancy test must be 
obtained prior to randomization and within 3 days before starting study treatment 
13. 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, proper use of combined oral or injected hormonal 
contraceptives, and certain intrauterine devices
14. For men: agreement to remain abstinent or use a contraceptive method that results 
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 (in addition, refer to the local label for 
pemetrexed and docetaxel).  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 
15. Able and willing to provide written informed consent prior to performing any study 
related procedures and to comply with the study protocol, including being willing and 
able to use the electronic patient-reported outcome device
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
1.
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 or in situ carcinoma of the cervix) 
2.
Patients who have received any previous ALK inhibitor other than crizotinib
3.
Any GI disorder that may affect absorption of oral medications, such as mal-
absorption syndrome or status post-major bowel resection
4.
Liver disease characterized by:

Alanine aminotransaminase (ALT) or aspartate aminotransferase (AST) > 2.5 x 
upper limit of normal (ULN) (> 5 x ULN for patients with concurrent liver 
metastases) 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 or bleeding from esophageal varices
OR

Acute viral or active autoimmune, alcoholic or other types of acute hepatitis 


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5.
NCI-CTCAE v4.0 Grade 3 or higher toxicities due to any prior therapy (excluding 
alopecia), which have not shown improvement and are strictly considered to 
interfere with current study medication
6.
Any exclusion criteria based on local label of pemetrexed or docetaxel
7.
History of organ transplant
8.
Patients with baseline QTc > 470 ms or symptomatic bradycardia
9.
Administration of strong/potent CYP3A4 inhibitors or inducers within 14 days prior to 
the first dose of study treatment and while on treatment with alectinib or docetaxel  
10. 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] or magnesium stearate) 
11. History of severe hypersensitivity reaction to pemetrexed or docetaxel or any known 
excipients of these drugs
12. Patients not eligible for treatment with docetaxel or pemetrexed according to the 
local labels
13. Pregnant or lactating women 
14. Known HIV positivity or AIDS-related illness
15. 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 
16. 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.  At least 90 
and a maximum of 120 patients (as per previous protocol version) will be randomly 
assigned in a 2:1 allocation ratio to the two treatment arms) via a block-stratified 
randomization procedure and over a planned recruitment period of approximately 
12 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) and CNS metastases at baseline 
(yes vs. no).  In addition, patients with baseline CNS metastasis will be stratified by 
history of radiotherapy (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.


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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.
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
Pemetrexed
For information on the formulation, packaging and handling of pemetrexed (Alimta®), 
refer to the local prescribing information. Pemetrexed should only be used for treatment 
of patients non-squamous NSCLC histology in this study.
4.3.1.3
Docetaxel
For information on the formulation, packaging and handling of docetaxel (Taxotere®), 
refer to the local prescribing information.
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.  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.  Treatment will continue until disease progression, 
unacceptable toxicity, withdrawal of consent or death.  
If a dose is missed, patients can make up that dose unless the next dose is due within 
6 hours.  If the time is less 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 5.1.2.1.


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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 alectinib should be recorded 
on the Adverse Event eCRF.
4.3.2.2
Pemetrexed
Pemetrexed will be administered according to the locally approved label.  The starting 
dose of pemetrexed will be 500 mg/m2 q3w.  The first dose of the study drug should be 
administered as soon as possible after randomization starting with the required 
premedication, preferably within 24 hours, and no later than 48 hours after 
randomization.  Treatment will continue until disease progression, unacceptable toxicity, 
withdrawal of consent or death.  
Premedication for Pemetrexed
All patients treated with pemetrexed must be instructed to take folic acid and vitamin B12
as a prophylactic measure to reduce treatment-related toxicity.  To reduce the incidence 
and severity of skin reactions, a corticosteroid should be given the day prior to, on the 
day of and the day after pemetrexed administration.  The premedication doses 
administered should be in compliance with the local label.
Folic Acid
Patients will obtain folic acid in one of the following forms, with preference in order from 
Option 1 to Option 3:
1.
350 to 600 µg folic acid
2.
A multivitamin containing folic acid in the range of 350 to 600 µg (acceptable only if 
Option 1 is not available)
3.
A dose of folic acid between 600 and 1000 µg (acceptable only if neither Option 1 
nor Option 2 is available)
For purposes of this trial, all patients should take oral folic acid daily according to local 
label, starting the week preceding the first infusion of pemetrexed and continuing daily 
until 21 days after discontinuation of pemetrexed.
Vitamin B12
Vitamin B12 will be prescribed by the investigator and administered as a 1000 µg 
intramuscular injection.  A vitamin B12 injection must be administered according to local 
practice for pemetrexed administration, starting the week preceding the first pemetrexed 
infusion and should be repeated approximately every 9 weeks.  Equivalent 
subcutaneous administration is permitted.
Dexamethasone
Dexamethasone 4 mg (or an equivalent corticosteroid and dose) will be given orally 
twice per day, the day before, the day of and the day after each dose of pemetrexed.


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Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.2.2.
4.3.2.3
Docetaxel
Docetaxel will be administered according to the locally approved label.  The first dose of 
docetaxel should be administered as soon as possible after randomization starting with 
the required premedication, preferably within 24 hours, and no later than 48 hours after 
randomization at a starting dose of 75 mg/m2 q3w.  Treatment will continue until disease 
progression, unacceptable toxicity, withdrawal of consent or death.  
Vital signs will be collected for docetaxel infusions according to Section 4.5.5.  For 
further details, see the local prescribing information for docetaxel.  
All patients randomized to receive docetaxel should be premedicated with 
corticosteroids according to local practice (e.g., oral dexamethasone at 16 mg per day 
[8 mg twice daily] for 3 days, starting a day prior to administration) to reduce the 
incidence and severity of fluid retention, as well as the severity of hypersensitivity 
reactions.
Anti-emetic prophylaxis may be administered at the treating physician’s discretion 
according to local practice.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.2.3.
For further details, see the local prescribing information for docetaxel.
4.3.3
Investigational Medicinal Product Accountability
All investigational medicinal products (IMPs) required for completion of this study 
(alectinib, docetaxel, pemetrexed) will be provided by the Sponsor where required by 
local health authority regulations.  The study site will acknowledge receipt of IMPs to 
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.


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4.3.4
Continued Access to Alectinib
The Sponsor will offer continued 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 completing 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 completing 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 advanced ALK-positive NSCLC

The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for advanced ALK-positive NSCLC

Provision of study drug is not permitted under the laws and regulations of the 
country in which the patient is being treated
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 therapy 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 such 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.


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4.4.1.1
Alectinib
Caution should be exercised when the following treatments or procedures are co-
administered or performed during treatment 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 signs for toxicity are carefully monitored (see 
Appendix 4)

Acetaminophen up to 2 g/day

Local therapy (e.g., stereotactic radiotherapy or surgery) may be given to patients 
who progress on alectinib with required treatment interruption as per section 4.4.2.1 
prior to continuing treatment beyond progression
4.4.1.2
Pemetrexed
For full details regarding permitted therapies with pemetrexed treatment, refer to the 
current version of the local product label.
4.4.1.3
Docetaxel
For full details regarding permitted therapies with pemetrexed treatment, refer to the 
current version of the local product label.
4.4.2
Prohibited Therapy
4.4.2.1
Alectinib
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 alectinib, unless otherwise specified below.  

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 4).

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 4)

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 
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 


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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 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 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
4.4.2.2
Pemetrexed
For full details regarding prohibited therapies with pemetrexed treatment, refer to the 
current version of the local product label.
4.4.2.3
Docetaxel
Docetaxel is a CYP3A4 substrate.  Patients randomized to receive docetaxel must avoid 
using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin and voriconazole).  There are no clinical data with a dose adjustment in 
patients receiving strong CYP3A4 inhibitors. 
In addition, concomitant treatment with CYP3A4 inducers may decrease plasma 
concentrations of docetaxel.  Therefore, concomitant medications that are CYP3A4 
inducers should be used with caution. 
Granulocyte colony-stimulating factor treatment is permitted for patients in the docetaxel 
arm.  The primary prophylaxis should be administered per the American Society of 
Clinical Oncology (ASCO), EORTC, and European Society of Medical Oncology (ESMO) 
guidelines; namely, in patients who are ≥ 60 years of age and/or with comorbidities 
(Smith et al. 2006; Crawford et al. 2009; Aapro et al. 2011). 
Anti-emetics, anti-allergic measures and other treatments for concomitant docetaxel 
toxicities may be used at the discretion of the investigator, taking into account 
precautions from local prescribing information. 
See the local prescribing information for docetaxel for all boxed warnings and 
contraindications.  


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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 alectinib because it is a potent CYP3A inhibitor and may 
increase plasma concentration of alectinib or docetaxel.
For full details regarding prohibited therapies with pemetrexed and docetaxel treatment, 
refer to the current version of the local product label.
4.5
STUDY ASSESSMENTS 
All study assessments will be carried out at the time points described in the Schedule of 
Assessments (Appendix 1 and 2) and the Schedule of Pharmacokinetic Assessments 
(Appendix 3).
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), 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
Medication Use for Control of Pain
Type, dose and frequency of medications used for the control of pain will be collected in 
this study
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.


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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.
4.5.5
Vital Signs
Vital signs will include measurements of pulse rate and systolic and diastolic blood 
pressures while the patient is in a seated position.  Other vital signs (e.g., respiratory 
rate, oxygen saturation and temperature) may be collected at the discretion of the 
investigator if clinically warranted.  Only abnormal findings will be recorded in the eCRF. 
4.5.6
ECOG Performance Status
ECOG PS will be measured using the ECOG Performance Status Scale (see 
Appendix 6).  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 (Appendix 5).  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 
(Appendix 5).  
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 (Appendix 1 and 2).  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


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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 if the soft tissue component and to meet the definition of 
measurability and so should be followed by cross-sectional imaging. 
4.5.8
Laboratory, Biomarker, and Other Biological Samples
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])

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 8]; CPK; gamma-glutamyl transferase (GGT); 
calcium; total and direct bilirubin; total protein; albumin; ALT; AST; alkaline 
phosphatase [ALP]; phosphorus;  Urinalysis (dipstick: mandatory at baseline; 
additional urinalyses if clinically indicated)

Pregnancy test (baseline).  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.  Results must be available 
prior to randomization.  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
Biomarker Assessments
The following samples will be sent to the Sponsor or a designee for analysis:

From patients who consent to undergo optional biopsy pre-treatment or at the time 
of disease progression, biopsies (formalin-fixed, paraffin-embedded) will be taken 
for exploratory research as defined in the Schedule of Assessments (Appendix 1 
and 2) 

Plasma (10 ml) obtained baseline, week 6, week 12 and every 6 weeks until disease 
progression, along with other routine laboratory or PK collection


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
Mandatory submission of residual tumor tissue (an FFPE tissue block, or 10–15 
unstained slides) from an archived tumor sample collected prior to exposure to 
crizotinib and preferably from primary tissue  
The goal of tumor collections will be to sequence ALK gene and other genes relevant in 
NSCLC biology or the tumor microenvironment to determine molecular mechanisms of 
resistance to ALK inhibitors.
These specimens will be used for research purposes to identify biomarkers useful for 
predicting and monitoring response to alectinib treatment, identifying biomarkers useful 
for predicting and monitoring alectinib safety, assessing pharmacodynamic effects of 
alectinib treatment and investigating mechanism of therapy resistance.  Additional 
markers may be measured in case a strong scientific rationale for these analyses 
develops.  Additional analyses may include but are not limited to immunohistochemistry 
and/or gene expression studies. 
Unless a patient gives specific consent for leftover specimens to be stored for optional 
exploratory research (see Section 4.5.11), these specimens will be destroyed within 5 
years after the date of final closure of the clinical database, with the following exception:

Archival tumor blocks (mandatory) will be returned at the latest by the end of the 
study, or earlier if requested by the site
Other residual tissue material (slides, extracts, etc.) will be destroyed within 5 years after 
the date of final closure of the clinical database.
For sample handling procedures, storage conditions and shipment instructions, 
see the laboratory manual.
4.5.8.3
Samples for Pharmacokinetic Assessments
PK samples will be collected in all patients on alectinib treatment as indicated in 
Appendix 1, 2 and 3 for the analysis of alectinib and its major metabolite(s) (RO5468924, 
and/or others, if applicable, appropriate and 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.
PK samples will be analyzed as needed. 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.
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 and 2).  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.
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.  Guidance for abnormal ECG results (QT prolongation) is provided in 
Table 6.
4.5.10
Patient-Reported Outcomes
PROs (EORTC QLQ-C30, QLQ-L13, EQ-5D-5L and three questions from the 
EORTC QLQ-BN20) 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 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 


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(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 this 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 Institutional Review Board or Ethics Committee (IRB/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.  Remaining tissue and plasma 
samples from study-related or non-study-related procedures that are performed during 
the study may also be stored for RCR purposes.
For all samples, dates 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 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.
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 or not 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 MO29750 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 MO29750.
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.  However, patients will not be followed for any reason after consent 
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's judgment

NSCLC disease progression, although treatment beyond PD will be allowed at the 
discretion of the patient and the investigator
See guidelines for managing adverse events and for comprehensive guidance on study 
drug discontinuation in Section 5.1.2.
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 and 2).
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment 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 
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5.
ASSESSMENT OF SAFETY 
5.1
SAFETY PLAN
Measures will be taken to ensure the safety of patients participating in this trial, including 
the use of stringent inclusion and exclusion criteria (see Sections 4.1.1 and 4.1.2) and 
close monitoring (as indicated below and in Section 4.5).  An iDMC has also been 
incorporated into the trial design to periodically review aggregate safety data (see the 
iDMC Charter for a detailed monitoring plan).
5.1.1
Risks Related to Study Drugs
5.1.1.1
Adverse Events Relating to ALK Inhibitors and Alectinib Data
Events described in this section (Section 5.1.1.1) 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.
Interstitial Lung Disease
Tyrosine kinase inhibitors (TKIs), including the ALK inhibitors crizotinib and ceritinib, 
have been associated with the occurrence of treatment-related interstitial lung disease 
(ILD) (including fatalities).
See Section 5.1.2.1 for management and follow-up.
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. 
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 with uncommon frequency in patients treated in 
alectinib clinical trials.


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In patients treated with other ALK inhibitor drugs, abnormal liver function tests and drug-
induced hepatotoxicity, including cases with fatal outcomes, have been reported.
See Section 5.1.2.1 for management and follow-up.
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 Grades 1 or 2. 
See Section 5.1.2.1 for management and follow-up.
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 the 
ALK inhibitors crizotinib and ceritinib.
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.
See Section 5.1.2.1 for management and follow-up.
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 5.1.2.1 for management and follow-up.


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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 5.1.2.1 for management and follow-up.
Edema
Most TKIs, including the ALK inhibitor crizotinib, have been associated with edema.  
Events of edema have been reported with alectinib, mostly Grade 1 or 2.
See Section 5.1.2.1 for management and follow-up.
Bradycardia
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.  Heart rate data evaluation 
(based on ECG and pulse measurements) from the pivotal 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. 
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 5.1.2.1 for management and follow-up.


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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 5.1.2.1 for management and follow-up.
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 5.1.2.1 for management and follow-up and Table 6 for guidelines for 
managing AEs.
5.1.1.2
Risks Associated With Pemetrexed
For full details regarding warnings and precaution relating to pemetrexed treatment, refer 
to the current version of the local product label.
Myelosuppression
Pemetrexed can suppress bone marrow function as manifested by neutropenia, 
thrombocytopenia and anemia (or pancytopenia).  Myelosuppression is usually the dose-
limiting toxicity (DLT).   
Skin Reactions
Skin reactions, such as rash, desquamation, alopecia and pruritus, have been reported 
in pemetrexed-treated patients not pre-treated with a corticosteroid.  
Renal Insufficiency
An insufficient number of patients has been studied with CrCl < 45 mL/min.  Therefore, 
the use of pemetrexed in patients with CrCl < 45 mL/min is not recommended. Patients 
with mild to moderate renal insufficiency (CrCl from 45 to 79 mL/min) should avoid 
taking NSAIDs such as ibuprofen, and aspirin (> 1.3 g daily) for 2 days before, on the 
day of, and 2 days following pemetrexed administration.  All patients eligible for 
pemetrexed treatment should avoid taking NSAIDs with long elimination half-lives for at 
least 5 days prior to, on the day, and at least 2 days following pemetrexed administration. 
Serious renal events, including acute renal failure, have been reported with pemetrexed 
alone or in association with other chemotherapeutic agents.  Many of the patients in 


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whom these occurred had underlying risk factors for the development of renal events 
including dehydration or pre-existing hypertension or diabetes.  
The effect of third-space fluid, such as pleural effusion or ascites, on pemetrexed is 
unknown.  In patients with clinically significant third-space fluid, consideration should be 
given to draining the effusion prior to pemetrexed administration. 
Due to the gastrointestinal toxicity of pemetrexed given in combination with cisplatin, 
severe dehydration has been observed.  Therefore, patients should receive adequate 
antiemetic treatment and appropriate hydration prior to and/or after receiving treatment. 
Cardiovascular Events
Serious cardiovascular events, including myocardial infarction and cerebrovascular 
events have been uncommonly reported during clinical studies with pemetrexed, usually 
when given in combination with another cytotoxic agent.  Most of the patients in whom 
these events have been observed had pre-existing cardiovascular risk factors. 
Immunosuppression 
An immunosuppressed status is common in cancer patients.  As a result, concomitant 
use of live attenuated vaccines (except yellow fever which is contraindicated) is not 
recommended.
5.1.1.3
Risks Associated With Docetaxel
For full details regarding warnings and precaution relating to docetaxel treatment, refer 
to the current version of the local product label.
Risks associated with docetaxel are provided in Table 6.


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Table 6
Side Effects Associated With Docetaxel
Most Common Side Effects
Less Common Side Effects 
(but may be Severe or Life Threatening)

Myelosuppression ± infection or bleeding
(may be severe)

Secondary malignancy/leukemia

Hypersensitivity reaction (may be severe)

Cardiotoxicity, arrhythmia

Fluid retention (may be severe)

Pneumonitis

Neuropathy (may be severe)

Gastrointestinal obstruction, perforation, 
hemorrhage

Cutaneous Effects (including nails, may be 
severe)

Venous thromboembolism

Alopecia

Arterial thromboembolism

Gastrointestinal (nausea, vomiting, 
stomatitis, diarrhea)

Disseminated intravascular coagulation

Fatigue

Seizures

Musculoskeletal pain

Hepatotoxicity

Lacrimation/tear duct obstruction
Due to the ethanol (also known as alcohol) content in the docetaxel formulation, some 
patients may experience intoxication during and after treatment.  Refer also to the 
warnings and precautions of the local prescribing information for docetaxel.  Other 
specific instructions can be found in Sections 4.4.1.3, 4.4.2.3 and 5.1.2.3. 
5.1.2
Management of Specific Adverse Events
5.1.2.1
Management of Specific Adverse Events with Alectinib
Management of symptomatic adverse events may require temporary interruption, dose
reduction, or treatment discontinuation of alectinib.  General dose modification advice for 
alectinib is provided in Table 7.
Table 7
Dose Reduction Schedule
Dose reduction schedule
Dose level
Starting Dose
600 mg twice daily
First dose reduction
450 mg twice daily
Second dose reduction
300 mg twice daily
Alectinib treatment should be permanently discontinued if patients are unable to tolerate 
the 300 mg twice daily dose reduction or if dose interruption exceeds 21 days. 
Guidelines for managing specific adverse events with alectinib are provided in Table 8.


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Table 8
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 5.3,5.7

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
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.


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Event
Action to Be Taken
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.
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
Abnormal kidney function 
AEs
Kidney function laboratory abnormalities are to be reported as AEs 
only if fulfilling the criteria listed in Section 5.3.5.5

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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Event
Action to Be Taken
Severe myalgia and 
CPK elevations
CPK laboratory abnormalities are to be reported as AEs only if 
fulfilling the criteria listed in Section 5.3.5.5

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 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
Other AEs (including 
bradycardia, anemia and 
CPK elevation) or
laboratory abnormalities:

Grade 3 or 4:
Temporarily interrupt alectinib for a maximum of 21 days
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).  
Third episode:  Permanently discontinue alectinib.

Grade 1:  no action required
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.


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5.1.2.2
Management of Specific Adverse Events With Pemetrexed
For full details regarding warnings and precaution relating to pemetrexed treatment, refer 
to the current version of the local product label.
Myelosuppression
Patients should be monitored for myelosuppression during treatment and pemetrexed 
should not be given to patients until ANC returns to ≥1500 cells/mm3 and platelet count 
returns to ≥100,000 cells/mm3.  Dose reductions for subsequent cycles are based on 
nadir ANC, platelet count and maximum non-hematological toxicity seen from the 
previous cycle. 
Less toxicity and reduction in grade 3/4 hematological and non-hematological toxicities 
such as neutropenia, febrile neutropenia and infection with grade 3/4 neutropenia were 
reported when pre-treatment with folic acid and vitamin B12 was administered.  Therefore 
all patients treated with pemetrexed must be instructed to take folic acid and vitamin B12
as a prophylactic measure to reduce treatment-related toxicity. 
Skin Reactions
Pre-therapy with dexamethasone (or equivalent) can reduce the incidence and severity 
of skin reactions.  A corticosteroid should be given the day prior to, on the day of and the 
day after pemetrexed administration.  The corticosteroid should be equivalent to 4 mg of 
dexamethasone administered orally twice per day, the day before, the day of, and the 
day after each dose of pemetrexed. 
Renal Insufficiency
An insufficient number of patients has been studied with CrCl < 45 mL/min.  Therefore, 
the use of pemetrexed in patients with CrCl < 45 mL/min is not recommended. Patients 
with mild to moderate renal insufficiency (CrCl from 45 to 79 mL/min) should avoid 
taking NSAIDs such as ibuprofen, and aspirin (> 1.3 g daily) for 2 days before, on the 
day of, and 2 days following pemetrexed administration.  All patients eligible for 
pemetrexed treatment should avoid taking NSAIDs with long elimination half-lives for at 
least 5 days prior to, on the day, and at least 2 days following pemetrexed administration. 
Serious renal events, including acute renal failure, have been reported with pemetrexed 
alone or in association with other chemotherapeutic agents.  Many of the patients in 
whom these occurred had underlying risk factors for the development of renal events 
including dehydration or pre-existing hypertension or diabetes.  
The effect of third-space fluid, such as pleural effusion or ascites, on pemetrexed is 
unknown.  In patients with clinically significant third-space fluid, consideration should be 
given to draining the effusion prior to pemetrexed administration. 


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Due to the gastrointestinal toxicity of pemetrexed given in combination with cisplatin, 
severe dehydration has been observed.  Therefore, patients should receive adequate 
antiemetic treatment and appropriate hydration prior to and/or after receiving treatment. 
Immunosuppression 
An immunosuppressed status is common in cancer patients.  As a result, concomitant 
use of live attenuated vaccines (except yellow fever which is contraindicated) is not 
recommended.
5.1.2.3
Management of Specific Adverse Events With Docetaxel
Guidelines for docetaxel dose modifications to manage general toxicities are shown in 
Table 9.  Guidelines for the management of hepatotoxicity for docetaxel-treated patients 
are shown in Table 10.  Guidelines for the management of edema for docetaxel-treated 
patients are shown in Table 11.  Patients who are dosed initially at 75 mg/m2 and who 
experience either febrile neutropenia, neutrophils < 500 cells/mm3 for more than 1 week, 
severe or cumulative cutaneous reactions or other Grade 3/4 nonhematological toxicities 
during docetaxel treatment should have treatment withheld until resolution of the toxicity 
and treatment then resumed at 55 mg/m2.  Patients who develop Grade ≥ 3 peripheral 
neuropathy should have docetaxel treatment discontinued entirely.
Table 9
Guidelines for Management of Specific Docetaxel-Related 
Adverse Events
Adverse Event
(Worst Grade in Previous Cycle)
Action to be Taken
Febrile neutropenia/Grade 4 AGC ≥ 7 days
Hold docetaxel until symptoms resolve a
Reduce docetaxel to 75% of previous dose
(e.g., from 75 mg/m2 to 55 mg/m2)
Grade 3 skin/neuropathy/major organ/
non-hematologic toxicity
Hold docetaxel until symptoms resolve
Reduce docetaxel to 75% of previous dose
Grade 4 skin/neuropathy/major organ/
non-hematologic toxicity
OR
Recurrence of Grade 3 toxicity after prior dose 
reduction
Discontinue docetaxel treatment
AGC = absolute granulocyte count.
a. Do not repeat until AGC ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L and toxicity ≤ Grade 2.


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Table 10 Guidelines for Management of Hepatotoxicity in Docetaxel-
Treated Patients
AST/ALT
ALP
Bilirubin
Docetaxel Dose
Mild to moderate
> 1.5 × ULN
AND
2.5 × ULN
75%
Severe
> 3.5 × ULN
AND
> 6 × ULN
OR 
> ULN
Do not treat.
Discontinue if treatment 
already started.
ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; 
ULN = upper limit of normal.
Other Specific Docetaxel Toxicities Not Requiring Dose Adjustment
Patients should be observed closely for hypersensitivity reactions, especially during the 
first and second infusions.  Severe hypersensitivity reactions characterized by 
generalized rash/erythema, hypotension and/or bronchospasm or, very rarely, fatal 
anaphylaxis have been reported in patients premedicated with 3 days of corticosteroids.  
Severe hypersensitivity reactions require immediate discontinuation of the docetaxel 
infusion and aggressive therapy.  Patients with a history of severe hypersensitivity 
reactions should not be rechallenged with docetaxel.  
Hypersensitivity reactions may occur within a few minutes following initiation of 
docetaxel infusion.  If minor reactions such as flushing or localized skin reactions occur, 
interruption of therapy is not required.
Severe fluid retention has also been reported following docetaxel therapy.  Patients 
should be premedicated with oral corticosteroids prior to each docetaxel infusion to 
reduce the incidence and severity of fluid retention (see Section 4.3.2.3).  Patients with 
preexisting effusions should be closely monitored from the first dose for the possible 
exacerbation of the effusions.  See Table 10 for the management of edema.
Table 11 Guidelines for the Management of Edema in Docetaxel-Treated 
Patients
Edema
Severity
Effusion
Asymptomatic
Mild, Grade 1
Asymptomatic, 
no intervention needed
Symptomatic
Moderate, Grade 2
Symptomatic,
may require intervention
Symptomatic, resulting in 
interruption of treatment
Severe, Grade 3
Symptomatic,
urgent intervention required


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events 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 adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event 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 or not 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), except as described in 
Section 5.3.5.10

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

Adverse events 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)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event 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 5.3.5.11)


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
Results in persistent or significant disability/incapacity (i.e., the adverse event 
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 adverse event (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 adverse event 
recorded on the eCRF.
Serious adverse events 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-serious adverse events 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).  Adverse events of special interest 
for this study include 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 5.3.5.7)

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.


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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (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 adverse event 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 adverse events at each patient contact.  All 
adverse events, 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 
serious adverse events 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 serious adverse events).
After initiation of study drug, all adverse events will be reported until 4 weeks after the 
last dose of study drug.  After this period, the investigator should report any serious 
adverse events that are believed to be related to prior 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 
adverse event 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 adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 12 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 12 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in 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:  Based on 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 oneself, 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 or 
not an adverse event 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/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis (e.g., 
"infusion-related reaction" or "anaphylactic reaction") on the Adverse Event eCRF.  If 
possible, avoid ambiguous terms such as "systemic reaction."  Associated signs and 
symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a 
patient experiences both a local and systemic reaction to the same dose of study drug, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs 
and symptoms also recorded separately on the dedicated Infusion-Related Reaction 
eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related reactions (see Section 5.3.5.1), 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 adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events 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 adverse event 
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.


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
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 adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event 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 adverse event becomes 
more severe, the most extreme severity 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 serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event 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 adverse 
events.
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 adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.


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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 adverse event.  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 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event 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 adverse event.
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 once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
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 
(as defined by Hy's law).  Therefore, investigators must report as an adverse event 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 
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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 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified adverse event 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 
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. 
5.3.5.9
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 adverse event 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").


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5.3.5.10
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 adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1 criteria (Appendix 5).  In rare cases, the 
determination of clinical progression will be based on symptomatic deterioration.  
However, every effort should be made to document progression through use of objective 
criteria.  If there is any uncertainty as to whether an event is due to disease progression, 
it should be reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
The following hospitalization scenarios are not considered to be adverse events:

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 adverse event

Hospitalization due solely to progression of the underlying cancer
5.3.5.12
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 adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event 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).
5.3.5.13
Patient-Reported Outcome Data
Adverse event 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 adverse event are identified during site review of the PRO data, 


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the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF.
5.3.5.14
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:

Serious adverse events (see Section 5.4.2 for further details)

Non-serious adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
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 serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
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. 


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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 
serious adverse events 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 the Sponsor 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, serious adverse events and non-serious adverse events 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.
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 the Sponsor 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 adverse events 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 serious adverse 
events 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.


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In the event that the EDC system is unavailable, the Clinical Trial Pregnancy Reporting 
Form provided to investigators should be completed and submitted to the Sponsor 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 (in addition, refer to the local label for 
pemetrexed and docetaxel).  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 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 a serious adverse event (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 a serious adverse event, 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 adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 


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follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (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 serious adverse events, non-serious adverse events 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.
5.6
POST-STUDY ADVERSE EVENTS
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
4 weeks after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment.  
The investigator should report these events directly to the Sponsor 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 serious adverse events and non-serious adverse 
events 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 adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Alectinib Investigator's Brochure

Local prescribing information for pemetrexed and docetaxel


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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
6.1
DETERMINATION OF SAMPLE SIZE
The sample size estimation was performed using EAST Software Version 6.0 based on 
the statistical hypotheses in Section 6.4.
Table 13 Summary of Determination of Sample Size a
Primary 
endpoint
Median Time to PFS 
(Chemo vs. Alectinib) 
months/HR
Number of 
Patients/Events
Number of Patients Per 
Treatment arm
(Chemo vs Alectinib)
PFS
3 vs. 7/0.43
90/50
30 vs. 60
Key 
Secondary 
endpoint
Response
(Chemo vs. Alectinib)
Number of Patients
C-ORR b
15% vs. 55%
24
8 vs. 16
a.
80% power, two sided alpha test at 0.05; 2:1 randomization. 
b.
Patients with measurable CNS metastases at baseline, 70% power, one-sided test at 0.05.
Assuming an accrual period of 12 months and a primary analysis with at least 50 PFS 
events planned approximately after 13 months, a sample size of 90 patients (60 patients 
in the experimental arm [alectinib] and 30 patients in the control arm [chemotherapy]) 
with at least 50 PFS events will provide 80% power to detect a significant improvement 
in the median time of the primary endpoint from 3 to 7 months (i.e., HR of 0.43), based 
on a two-sided log-rank test at an alpha level of 0.05.  In the pivotal Profile 1007 trial 
(Shaw et al. 2013), median PFS in the chemotherapy arm among 174 patients 
previously treated with one platinum-based chemotherapy regimen and treated in 
second line with either pemetrexed or docetaxel was 3 months (95% CI, 2.6–4.3).  
Hence, a median PFS of 3 months for the chemotherapy arm (control arm) has been 
assumed.
The objective response (Shaw et al. 2013) was reported in the chemotherapy group as 
20% (95% CI, 14%–26%).  Also, we expect that at least 25% of patients with 
measurable CNS metastases at baseline will be randomized in 2 treatment arms in this 
study.  Approximately 24 patients with measurable CNS metastases at baseline 


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(8 patients in control and 16 patients in experimental arm) will provide power of 70% 
(one-sided 5% alpha test) to detect clinically meaningful difference in C-ORR of 40%, 
assuming C-ORR in control arm of 15%. 
If superiority for the PFS endpoints is concluded, subsequent hierarchical testing for the 
key secondary endpoint, C-ORR in patients with measurable CNS metastases at 
baseline, will be performed.
6.2
SUMMARIES OF CONDUCT OF STUDY
All randomized patients will be summarized by treatment arms, country and investigators.  
Major protocol violations will be summarized by frequency tables.
Median follow up on treatment and study will be summarized and estimates with 
corresponding 95% confidence interval (CI) provided using the Kaplan-Meier approach.
Patients who cross over from chemotherapy to alectinib will be censored at the time of 
cross-over (additional censoring rules will be provided in the SAP).
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Formal statistical hypotheses for the primary endpoint is in Section 6.4.
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, maximum and 25th–75th quartiles.  
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 
subsequent anti-cancer therapy by treatment arms.  Previous and concurrent diseases 
and medications will also be summarized.
6.4
EFFICACY ANALYSES
6.4.1
Primary Efficacy Endpoint
The main primary endpoint is PFS, as defined in Section 3.4.1.  
The main efficacy analysis will be based on the intent-to-treat (ITT) population that 
includes all randomized patients.  The per protocol (PP) population will be defined as the 
subset of the ITT population who have received at least one dose of study medication 
with no major protocol violations (which will be defined in the statistical analysis plan 
[SAP]).


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The main analysis for investigator assessed PFS will be a stratified Cox model analysis 
that will include a treatment group variable and stratification factors, defined as:

ECOG PS (0/1 vs. 2), 

CNS metastases at baseline (yes vs. no)
In addition, patients with baseline CNS metastases will be stratified by history of 
radiotherapy (yes vs. no)
Further details for this analysis will be specified in the Statistical Analysis Plan. The un-
stratified Cox model analysis for PFS will also be provided as sensitivity analyses.
Estimates for the survivor function for PFS will be obtained by the Kaplan-Meier 
approach.  The p-value of log-rank test will be displayed together with estimated hazard 
ratios and associated 95% confidence intervals (CIs).  
Hypotheses testing for primary endpoint:

H0: the distribution of the PFS time is the same in the two treatment groups

H1: the distribution of the PFS time is different in the two treatment groups

If the hazard ratio (HR) of the investigational arm compared with the control arm 
with respect to PFS is assumed to be constant over time (λ), then the null (H0) and 
alternative hypotheses (H1) are: H0: λ=1 vs. H1: λ≠1
Unless otherwise specified, all tests will be performed at two-sided alpha of 5%.  
6.4.2
Secondary Efficacy Endpoints
The key secondary endpoint is C-ORR in patients with measurable CNS metastases at 
baseline as per IRC assessment.
If superiority for the PFS endpoints is concluded, subsequent hierarchical testing for the 
key secondary endpoint, C-ORR in patients with measurable CNS metastases at 
baseline (IRC assessment), will be performed between the two treatment groups.  The 
difference in C-ORR in patients with measurable CNS metastases at baseline per IRC 
assessment will be displayed with associated 90 and 95% CI using the Hauck-Anderson 
approach and p-value for the Chi-square test (test at a one-sided alpha level of 0.05).  
Logistic analysis will be used to assess the influence of stratification factors and baseline 
covariates in an exploratory manner.  Also, 95% Clopper-Pearson CI for each treatment 
arm will be displayed.
There will be no multiplicity adjustments for testing of other secondary endpoints.
This study is not powered for OS, so adequately powered statistical testing for this 
endpoint will not be possible.  However, Kaplan-Meier estimates and a log rank test will 
be provided in an exploratory manner to assess the difference between treatment arms 
for OS. Unless otherwise specified, other time-to-event endpoints will be analyzed in a 
similar way to PFS and OS.


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The C-ORR and ORR will be summarized by the number and proportion of responders 
and non-responders in each treatment group, together with two-sided 95% Clopper-
Pearson CI.  The difference in C-ORR (or ORR) will be displayed with associated CI 
using the Hauck-Anderson approach and p-value for the Chi-square test.  Logistic 
analysis will be used to assess the influence of stratification factors and baseline 
covariates in an exploratory manner.  Also, 95% Clopper-Pearson CI for each treatment 
arm will also be displayed. 
DCR will be summarized in a similar way to the C-ORR and ORR.
Median duration of response for each treatment arm will be estimated using the Kaplan-
Meier approach.  The hazard ratio between the two arms with associated 95% CI will 
also be estimated using Cox model analysis.  Time to response will be analyzed in a 
similar way to duration of response.
Time to CNS progression is defined as the time from randomization to the first 
documented disease progression in the CNS. 
In order to account for the competing risks inherent to the analysis of this endpoint, HR 
and corresponding 95% CI and two-sided log-rank test will be computed on the basis of 
cause-specific hazard functions to compare the risk of CNS progression between the 
alectinib and chemotherapy treatment groups.  The probability of CNS progression, non-
CNS progression and death will each be estimated using cumulative incidence functions.
These time to CNS progression analyses will be provided using all patients regardless of 
their baseline status of CNS metastases, and also when number of patients with CNS 
progression events allows, on the subgroups of patients with baseline CNS and patients 
without baseline CNS. 
Analysis methods for time-to-event endpoints, such as OS or PFS assessed by the IRC, 
are the same as those described for the primary endpoint. 
The number (percentage) of patients who received chemotherapy at the time of 
progression, and who also agreed to cross-over to receive alectinib, will be summarized.  
The following methodologies may be used as appropriate to explore the impact of cross-
over on the Overall Survival difference between treatment arms, in addition to the ITT 
analysis: censoring at time of cross-over or treatment switch, exclusion of patient 
switching treatment from the OS analysis, discount methods, or more advanced 
methods, such as for example Rank Preserving Structural Failure Time (RPSFT) 
methodology.  More details on these methodologies, different censoring rules and 
models for these types of data will be provided in the Statistical Analysis Plan (SAP).


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6.5
SAFETY ANALYSES
Safety endpoints will be analyzed for the safety population, which will include all patients 
who received at least one dose of study medication.  For analysis purposes, patients will 
be assigned to treatment groups based on actual received study medication during study 
treatment period, defined in figure 3. Safety summary for patients that cross over to 
receive alectinib upon progression on chemotherapy or who continue in treatment 
beyond progression on alectinib, will be presented separately, starting from the first day 
of alectinib treatment for patients randomized to chemotherapy and switching to Alectinib,  
and starting first day of treatment beyond progression for patients randomized to 
Alectinib and continuing Alectinib beyond progression.  
The incidence of AEs and SAEs will be summarized according to the primary system 
organ class (SOC), and within each SOC by the Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term.  AE data will be presented in frequency tables 
(overall and by intensity) by body system and treatment groups.  SAEs, AEs with NCI 
CTCAE Grade 3 or higher and AEs that cause premature discontinuation from study 
medications will be analyzed in a similar way.  Listing of deaths and cause of deaths will 
be provided.
Selected laboratory parameters will be presented in shift tables of NCI-CTCAE grade at 
baseline versus worst grade for each treatment cycle and overall, and graphically 
presented over time via box-plots split by treatment groups.
Information on study medication will also be summarized by duration on treatment, 
interruptions using descriptive statistics.
Premature withdrawal and reasons for premature withdrawal from study and study 
medication will be summarized by frequency tables.
Summaries described in this section will be also repeated for patients with CNS 
metastasis at baseline.
6.6
PHARMACOKINETIC ANALYSES
Individual and mean plasma concentrations at each sampling time point 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) will be presented, as appropriate.  Additional 
plots or summary statistics may be constructed or calculated, as appropriate.
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, as needed and if appropriate.  The PK data from this study may be pooled with 
data from other studies.  Population and individual PK parameters will be estimated and 


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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, as needed and if appropriate.
Details of the mixed-effects modeling and exploratory analyses will be reported in a 
document separate from the clinical study report.  Results of PK and/or any 
PK/pharmacodynamics analyses may be reported outside the clinical study report.
6.7
PATIENT-REPORTED OUTCOME ANALYSES
The PRO measures, EORTC QLQ-C30, EORTC QLC-LC13, EQ-5D-5L and questions 
specific to CNS metastases (a part of EORTC QLQ-BN20 questionnaire), will be 
summarized using descriptive statistics.  Selected single or multi-item subscales will be 
graphically presented and difference between two treatment groups over time will be 
explored using mixed models.
Evaluation and comparison of time to deterioration (TTD) in patient-reported lung cancer 
symptoms of cough, chest pain (single-item) dyspnea (single item and multi-item 
subscales), pain in shoulder/arm, and fatigue is a very important endpoint based on data 
collected via EORTC QLQ-C30 and EORTC QLC-LC13.  TTD in patient-reported lung 
cancer symptoms of cough, chest pain, dyspnea (single item and multiple  item), pain in 
arm/shoulder and fatigue as well as TTD for a composite of three symptoms (cough, 
dyspnea (multi-item subscales QLQ-LC13  and chest pain) will be analyzed as a time-to-
event endpoint, as described for PFS or using descriptive statistics if not recorded as a 
time-to-event endpoint.
The EQ-5D-5L 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 pharmacoeconomic 
models for reimbursement purposes only.
The Cochran-Mantel-Haenszel statistic test will be applied to take the ordinal nature of a 
variable EORTC QOQ-BN20.  More details will be specified in the statistical analyses 
plan.
More details will be specified in the SAP.
6.8
BIOMARKER ANALYSES
Descriptive analysis for biomarkers will be provided and further association between 
biomarkers and clinical endpoints (e.g., PFS, OS, ORR, etc.) will be explored using Cox 
regression model or logistic model.  More information will be provided in the SAP.


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6.9
INTERIM ANALYSES
No interim analyses for efficacy or futility are planned.  Safety review of data will be 
performed as explained in the iDMC charter.
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 through use of 
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 U.S. Food and Drug Administration (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, patient-reported outcomes, 
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.
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 


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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 U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union (E.U.) 
or European Economic Area will comply with the E.U. 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 Informed Assent Form or Home Nursing 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.


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If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative 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.
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 


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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 U.S. 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.
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, including 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 


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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
A 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.
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, 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.
An IRC will review the tumor assessments to determine the secondary endpoints.  IRC 
assessments will continue until 12 weeks after the last patient in, after which time the 
IRC assessments will be halted.
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


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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.
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).
10.
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Appendix 1
Schedule of Assessments – Alectinib Arm (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
114/Protocol MO29750, Final Version 7.1
Appendix 1
Schedule of Assessments – Alectinib Arm
Assessment
Screening
Treatment Period a
(± 7 Days for Visits; ± 3 Days for Safety Visits)
Post 
Treatment 
Visit c
Post-progression 
visits on alectinib 
treatment in case 
of TBP 
(q6w, ± 7 days) 
until PD, 
unacceptable 
toxicity or 
withdrawal
Survival 
follow-up 
and 
subsequent 
NSCLC 
treatment 
(every 3 
months)
Days
–28 
to 0
Days
–3 to 
0
Visit 
0
Baseline
Wk 0
Safety 
Visit b
Wk 2
Visit 
1
Wk  3
Safety 
Visit b
Wk 4
Visit 
2
Wk  6
Safety 
Visit b
Wk 8
Safety 
Visit b
Wk 10
Visit
3
Wk 12
All 
subsequent 
visits 
(every 
6 weeks 
until PD, 
death, or 
withdrawal 
from study 
prior to PD)
Informed consent
x
Demographics
x
Medical history
x
Pregnancy test d
x
Repeated only if necessary
Physical 
examination e
x
x
Only if clinically necessary
Vital signs 
(BP, pulse) f
x
x
x
x
x
x
x
ECOG PS
x
x
x
x
x
x
x
x
ECG g
x h
x
Week 24, 
every 12 
weeks 
thereafter
and at PD
x i
Hematology j
x
x h
x
x
x
x
x


Appendix 1
Schedule of Assessments – Alectinib Arm (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
115/Protocol MO29750, Final Version 7.1
Assessment
Screening
Treatment Period a
(± 7 Days for Visits; ± 3 Days for Safety Visits)
Post 
Treatment 
Visit c
Post-progression 
visits on alectinib 
treatment in case 
of TBP 
(q6w, ± 7 days) 
until PD, 
unacceptable 
toxicity or 
withdrawal
Survival 
follow-up 
and 
subsequent 
NSCLC 
treatment 
(every 3 
months)
Days
–28 
to 0
Days
–3 to 
0
Visit 
0
Baseline
Wk 0
Safety 
Visit b
Wk 2
Visit 
1
Wk  3
Safety 
Visit b
Wk 4
Visit 
2
Wk  6
Safety 
Visit b
Wk 8
Safety 
Visit b
Wk 10
Visit
3
Wk 12
All 
subsequent 
visits 
(every 
6 weeks 
until PD, 
death, or 
withdrawal 
from study 
prior to PD)
Biochemistry j
x
x h
x k
x
x k
x
x k
x k
x
x
x
Urinalysis
x
x h
Only if clinically necessary
x i
Concomitant 
medications
x
x
x
x
x
x
x
x
x
x
x
Optional tumor 
sample l
x
At PD
Mandatory archival 
tumor sample 
(as many as 
available) m
x
Plasma for 
detection of 
exploratory 
biomarkers, 
including ALK 
mutations 
(20 mL of blood)
x
x
x
x
Tumor 
assessment n
x o
x o
x
x
x p


Appendix 1
Schedule of Assessments – Alectinib Arm (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
116/Protocol MO29750, Final Version 7.1
Assessment
Screening
Treatment Period a
(± 7 Days for Visits; ± 3 Days for Safety Visits)
Post 
Treatment 
Visit c
Post-progression 
visits on alectinib 
treatment in case 
of TBP 
(q6w, ± 7 days) 
until PD, 
unacceptable 
toxicity or 
withdrawal
Survival 
follow-up 
and 
subsequent 
NSCLC 
treatment 
(every 3 
months)
Days
–28 
to 0
Days
–3 to 
0
Visit 
0
Baseline
Wk 0
Safety 
Visit b
Wk 2
Visit 
1
Wk  3
Safety 
Visit b
Wk 4
Visit 
2
Wk  6
Safety 
Visit b
Wk 8
Safety 
Visit b
Wk 10
Visit
3
Wk 12
All 
subsequent 
visits 
(every 
6 weeks 
until PD, 
death, or 
withdrawal 
from study 
prior to PD)
MRI scan of the 
brain
x o
x o
x
x
x p
PK samples 
(2 mL blood) q
x
x
x
PRO (EORTC 
QLQ-C30/LC13/BN
20, EQ-5D-5L) r
x
x
x
x
x
x
Alectin b s
600 mg BID
600 mg BID
Adverse events t
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Subsequent 
therapy for NSCLC
x
x
Alectin b dispensing 
(bottles to 
dispense) u 
1
1
2
3
3 bottles 
every 
12 weeks, 
starting 
from Visit 3


Appendix 1
Schedule of Assessments – Alectinib Arm (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
117/Protocol MO29750, Final Version 7.1
Assessment
Screening
Treatment Period a
(± 7 Days for Visits; ± 3 Days for Safety Visits)
Post 
Treatment 
Visit c
Post-progression 
visits on alectinib 
treatment in case 
of TBP 
(q6w, ± 7 days) 
until PD, 
unacceptable 
toxicity or 
withdrawal
Survival 
follow-up 
and 
subsequent 
NSCLC 
treatment 
(every 3 
months)
Days
–28 
to 0
Days
–3 to 
0
Visit 
0
Baseline
Wk 0
Safety 
Visit b
Wk 2
Visit 
1
Wk  3
Safety 
Visit b
Wk 4
Visit 
2
Wk  6
Safety 
Visit b
Wk 8
Safety 
Visit b
Wk 10
Visit
3
Wk 12
All 
subsequent 
visits 
(every 
6 weeks 
until PD, 
death, or 
withdrawal 
from study 
prior to PD)
Alectin b 
accountability v
x
x
x
x
Every 
12 weeks, 
starting 
from Visit 3
x
x
Blood Sample for 
Roche Clinical 
Repository (10 mL)
x
ALK anaplastic lymphoma  kinase; ECG = electrocardiogram; ECOG PS Eastern Cooperative Oncology Group Performance Status; 
EORTC QLQ-BN20 = European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire—Brain Neoplasm-20; EORTC QLQ-C30 European 
Organization for the Research and Treatment of Cancer Quality of Life Questionnaire—Core-30; 
EORTC QLQ-LC13 European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire—Lung Cancer-13; EQ-5D-5L EuroQoL 5 Dimension 5 level; 
MRI magnetic resonance imaging; NSCLC nonsmall cell lung cancer; PD progressive disease; PK pharmacokinetic; PRO patient-reported outcome; TBP, treatment beyond 
progression; Wk, Week.
a
The first dose of alectin b should be administered as soon as possible after randomization, preferably within 24 hours, and no later than 48 hours after randomization. 
b
Assessment of liver values (ALT/AST/total bilirubin/direct bilirubin/ALP every 2 weeks for the first 3 months of treatment) and CPK (every 2 weeks for the first month of treatment) 
should be performed at clinic visits.  
c
Four weeks after permanent treatment discontinuation for patients who do not receive alectinib treatment beyond progression, or at the end of randomized treatment for patients who 
enter the post progression period.
d
Screening serum pregnancy test results should be available prior to randomization.  After randomization, to be repeated as necessary (urine or serum).
e
Including an ophthalmologic examination if clinically indicated.


Appendix 1
Schedule of Assessments – Alectinib Arm (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
118/Protocol MO29750, Final Version 7.1
f
Vital signs will include measurements of pulse rate and systolic and diastolic blood pressures while the patient is in a seated position.  Other vital signs (e.g., respiratory rate, oxygen 
saturation and temperature) may be collected at the discretion of the investigator if clinically warranted.  Only abnormal findings will be recorded in the eCRF.
g
Refer to Section 4.5.9.
h
Screening assessments done within 3 days can be counted as the baseline assessment.
i
As clinically needed.
h
Screening laboratory assessment done within 3 days can be counted as the baseline assessment.
j
Refer to section 4.5.8.1
k
Blood will be drawn in the clinic to assess liver function (AST/ALT/total bilirubin/direct bilirubin/ALP on Weeks 2, 4, 8 and 10) and CPK (on Weeks 2 and 4).
l
Optional formalin-fixed, paraffin-embedded (FFPE) samples.  The baseline sample can be taken from the FFPE tumor block obtained at screening.  At progression, optional biopsy 
should be taken from the progressing lesion only.
m
Collected prior to exposure to crizotinib and preferably from primary tissue.
n
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 a kaline phosphatase 1.5 ULN) of bone metastasis should undergo radionuclide bone scan.  Post-baseline assessments are to be 
performed within 1 week for the scheduled 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.
o
Screening tumor assessment done within 28 days will be counted as the baseline assessment.
p
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. 
q
Pre-dose PK (2 mL) sampling for all patients on alectinib treatment will be performed at baseline and at specified visits during the treatment period.  The pre-dose PK samples 
should be taken immediately before (within 2 hours) intake of study medication at the specified study visits. Remind the patient not to take a daily dose at home on the day of 
scheduled study visit.  See also Appendix 3.
r
Further guidelines on PRO questionnaire administration will be provided in the study manual.
s
Refer to Section 4.3.2.1.
t
Graded according to NCI CTCAE (version 4.0).  Serious adverse events collection must start from first study-specific procedure.
u
Refer to Section 4.3.3.
v
Accurate records of all investigational medicinal products (IMPs) received at, dispensed from, returned to, and disposed of by the study site should be recorded on the Drug 
Inventory Log.  IMPs will either be disposed 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.


Appendix 2
Schedule of Assessments – Chemotherapy Arm (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
119/Protocol MO29750, Final Version 7.1
Appendix 2
Schedule of Assessments – Chemotherapy Arm
NOTE: If considered to be of clinical benefit for the patient and if there is no safety risk, patients on the chemotherapy arm can cross over to 
receive alectinib at the discretion of the patient and investigator prior to documentation of PD per RECIST v1.1.  Patients who cross over in the 
first treatment period should follow the visit schedule as in the first treatment period, i.e., tumor assessments every 6 weeks until PD, death, or 
withdrawal from study prior to PD.
Assessment
Screening
Treatment Period a
(Patients should report to the hospital every 3 weeks ± 3 days for chemotherapy administration) b
(For Chemo Cycle Only administration beyond Wk 12, which will occur every 3 weeks, refer to the Wk 9 
column for required assessments. Every 6 weeks, a visit will occur for assessments according to Wk 12)
Post 
Treatment 
Visit e
Post-
progression 
visits on 
alectinib 
treatment in 
case of cross 
over 
(q6w, ± 7 days) 
until PD, 
unacceptable 
toxicity or 
withdrawal f
Survival 
follow-up 
and 
subsequent 
NSCLC 
treatment 
(every 3 
months)
Days
–28 
to 0
Days
–3 to 
0
Chemo 
Cycle &
Visit 
0
Baseline
Wk 0
Safety
Call c
Wk 
2
Chemo 
Cycle 
& 
Visit 1
Wk 
3
Safety 
Call c
Wk
4
Chemo 
Cycle 
&
Visit 2
Wk 
6
Safety 
Call c
Wk
8
Chemo
Cycle 
Only d
Wk
9
Safety 
Call c
Wk
10
Chemo
Cycle
&
Visit 3
Wk 
12
All 
subsequent 
visits 
Every 
6 weeks 
thereafter 
until PD, 
death, or 
withdrawal 
from study 
prior to PD)
Informed consent
x
Demographics
x
Medical history
x
Pregnancy test g
x
Repeated only if necessary
Physical examination h
x
x
Only if clinically necessary
Vital signs 
(BP, pulse) i
x
x
x
x
x
x
x
ECOG PS
x
x
x
x
x
x
x
x


Appendix 2
Schedule of Assessments – Chemotherapy Arm (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
120/Protocol MO29750, Final Version 7.1
Assessment
Screening
Treatment Period a
(Patients should report to the hospital every 3 weeks ± 3 days for chemotherapy administration) b
(For Chemo Cycle Only administration beyond Wk 12, which will occur every 3 weeks, refer to the Wk 9 
column for required assessments. Every 6 weeks, a visit will occur for assessments according to Wk 12)
Post 
Treatment 
Visit e
Post-
progression 
visits on 
alectinib 
treatment in 
case of cross 
over 
(q6w, ± 7 days) 
until PD, 
unacceptable 
toxicity or 
withdrawal f
Survival 
follow-up 
and 
subsequent 
NSCLC 
treatment 
(every 3 
months)
Days
–28 
to 0
Days
–3 to 
0
Chemo 
Cycle &
Visit 
0
Baseline
Wk 0
Safety
Call c
Wk 
2
Chemo 
Cycle 
& 
Visit 1
Wk 
3
Safety 
Call c
Wk
4
Chemo 
Cycle 
&
Visit 2
Wk 
6
Safety 
Call c
Wk
8
Chemo
Cycle 
Only d
Wk
9
Safety 
Call c
Wk
10
Chemo
Cycle
&
Visit 3
Wk 
12
All 
subsequent 
visits 
Every 
6 weeks 
thereafter 
until PD, 
death, or 
withdrawal 
from study 
prior to PD)
ECG i
x k
x
Week 24, 
every 12 
weeks 
thereafter
and at PD
x l
Hematology m
x
x k
x
x
x
x
x
Biochemistry m
x
x k
x
x
x
x
x
Urinalysis
x
x k
Only if clinically necessary
x l
Concomitant 
medications
x
x
x
x
x
x
x
x
x
x
x
x
Optional tumor 
sample n
x
At PD
Mandatory archival 
tumor sample 
(as many as 
available) o
x


Appendix 2
Schedule of Assessments – Chemotherapy Arm (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
121/Protocol MO29750, Final Version 7.1
Assessment
Screening
Treatment Period a
(Patients should report to the hospital every 3 weeks ± 3 days for chemotherapy administration) b
(For Chemo Cycle Only administration beyond Wk 12, which will occur every 3 weeks, refer to the Wk 9 
column for required assessments. Every 6 weeks, a visit will occur for assessments according to Wk 12)
Post 
Treatment 
Visit e
Post-
progression 
visits on 
alectinib 
treatment in 
case of cross 
over 
(q6w, ± 7 days) 
until PD, 
unacceptable 
toxicity or 
withdrawal f
Survival 
follow-up 
and 
subsequent 
NSCLC 
treatment 
(every 3 
months)
Days
–28 
to 0
Days
–3 to 
0
Chemo 
Cycle &
Visit 
0
Baseline
Wk 0
Safety
Call c
Wk 
2
Chemo 
Cycle 
& 
Visit 1
Wk 
3
Safety 
Call c
Wk
4
Chemo 
Cycle 
&
Visit 2
Wk 
6
Safety 
Call c
Wk
8
Chemo
Cycle 
Only d
Wk
9
Safety 
Call c
Wk
10
Chemo
Cycle
&
Visit 3
Wk 
12
All 
subsequent 
visits 
Every 
6 weeks 
thereafter 
until PD, 
death, or 
withdrawal 
from study 
prior to PD)
Plasma for detection 
of exploratory 
biomarkers, including 
ALK mutations 
(20 mL of blood)
x
x
x
x
Tumor assessment p
x q
x q
x
x
x r
MRI scan of the brain
x q
x q
x
x
x r
PRO (EORTC 
QLQ-C30/LC13/BN20, 
EQ-5D-5L) s
x
x
x
x
x
x
Adverse events t
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Subsequent therapy 
for NSCLC
x
x
Chemotherapy 
dispensing and 
accountability u
x
x
x
x
x
x v


Appendix 2
Schedule of Assessments – Chemotherapy Arm (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
122/Protocol MO29750, Final Version 7.1
Assessment
Screening
Treatment Period a
(Patients should report to the hospital every 3 weeks ± 3 days for chemotherapy administration) b
(For Chemo Cycle Only administration beyond Wk 12, which will occur every 3 weeks, refer to the Wk 9 
column for required assessments. Every 6 weeks, a visit will occur for assessments according to Wk 12)
Post 
Treatment 
Visit e
Post-
progression 
visits on 
alectinib 
treatment in 
case of cross 
over 
(q6w, ± 7 days) 
until PD, 
unacceptable 
toxicity or 
withdrawal f
Survival 
follow-up 
and 
subsequent 
NSCLC 
treatment 
(every 3 
months)
Days
–28 
to 0
Days
–3 to 
0
Chemo 
Cycle &
Visit 
0
Baseline
Wk 0
Safety
Call c
Wk 
2
Chemo 
Cycle 
& 
Visit 1
Wk 
3
Safety 
Call c
Wk
4
Chemo 
Cycle 
&
Visit 2
Wk 
6
Safety 
Call c
Wk
8
Chemo
Cycle 
Only d
Wk
9
Safety 
Call c
Wk
10
Chemo
Cycle
&
Visit 3
Wk 
12
All 
subsequent 
visits 
Every 
6 weeks 
thereafter 
until PD, 
death, or 
withdrawal 
from study 
prior to PD)
Blood Sample for 
Roche Clinical 
Repository (10 mL)
x
ALK anaplastic lymphoma kinase; ECG = electrocardiogram; ECOG PS Eastern Cooperative Oncology Group Performance Status; 
EORTC QLQ-BN20 = European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire—Brain Neoplasm-20; EORTC QLQ-C30 European 
Organization for the Research and Treatment of Cancer Quality of Life Questionnaire—Core-30; 
EORTC QLQ-LC13 European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire—Lung Cancer-13; EQ-5D-5L EuroQoL 5 Dimension 5 level; 
MRI magnetic resonance imaging; NSCLC nonsmall cell lung cancer; PD progressive disease; PK pharmacokinetic; PRO patient-reported outcome; TBP, treatment beyond 
progression; Wk, Week.
a
The first dose of the study drug (and the required premedication, when applicable) should be administered as soon as possible after randomization, preferably within 24 hours, and 
no later than 48 hours after randomization.  
b
The chemotherapy cycle should always occur every 21 ± 3 days.  Thus, if there is a delay in chemotherapy administration (e.g., for an AE), the next chemotherapy administration 
should occur every 21 ± 3 days thereafter, even if this administration schedule does not align with the prespecified study assessment visits.  In other words, Investigators should not 
shorten the chemotherapy cycle in order to re-align with the assessment schedule.  
c
New AEs and new treatment(s) since last visit, by phone interview. 
d
Specific eCRFs will be available at the chemo-only visits.  
e
Four weeks after permanent treatment discontinuation for patients who do not cross over to alectinib.


Appendix 2
Schedule of Assessments – Chemotherapy Arm (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
123/Protocol MO29750, Final Version 7.1
f
Refer to Appendix 1 for the Schedule of Assessments for patients who cross over to alectinib therapy, including drug dispensation, accountability and safety visits.  Please note that 
the first full assessment visit and re-supply of study drug for patients who cross over will be after 6 weeks (and not at 3 weeks, as with patients who are randomized to the alectin b 
study arm).
g
Screening serum pregnancy test results should be available prior to randomization.  After randomization, to be repeated as necessary (urine or serum).
h
Including an ophthalmologic examination if clinically indicated.
i
Vital signs will include measurements of pulse rate and systolic and diastolic blood pressures while the patient is in a seated position.  Other vital signs (e.g., respiratory rate, oxygen 
saturation and temperature) may be collected at the discretion of the investigator if clinically warranted.  Only abnormal findings will be recorded in the eCRF.
j
Refer to Section 4.5.9. 
k
Screening assessments done within 3 days can be counted as the baseline assessment.
l
As clinically needed
m
Refer to section 4.5.8.1
n
Optional formalin-fixed, paraffin-embedded (FFPE) samples.  The baseline sample can be taken from the FFPE tumor block obtained at screening.  At progression, optional biopsy 
should be taken from the progressing lesion only.
o
Collected prior to exposure to crizotinib and preferably from primary tissue.
p
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 a kaline phosphatase 1.5 ULN) of bone metastasis should undergo radionuclide bone scan.  Post-baseline assessments are to be 
performed within 1 week for the scheduled 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.
q
Screening tumor assessment done within 28 days will be counted as the baseline assessment.
r
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. 
s
Further guidelines on PRO questionnaire administration will be provided in the study manual.
t 
Graded according to NCI CTCAE (version 4.0).  Serious adverse events collection must start from first study-specific procedure.
u
Refer to Section 4.3.3.  Note that only information related to drug supply will be captured in the interactive web-based response system.  Any new AEs or concomitant medications at 
chemotherapy cycle visits should be captured on the eCRF.
v
Chemotherapy will be re-supplied every 3 weeks. 


Appendix 2
Schedule of Pharmacodynamic and Pharmacokinetic 
Assessments (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
124/Protocol MO29750, Final Version 7.1
Appendix 3
Schedule of Pharmacokinetic Assessments
Visit
Timepoint
Visit 0 (baseline) a
Pre-dose (within 2 hours before intake of alectinib)
Visit 1 (Week 3)
Pre-dose (within 2 hours before intake of alectinib)
Visit 2 (Week 6)
Pre-dose (within 2 hours before intake of alectinib)
PK = pharmacokinetics
a. Before the first dose of alectinib.


Appendix 4
List of Substrates, Inhibitors, and Inducers of 
Drug-Metabolizing Enzymes and Transporters (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
125/Protocol MO29750, Final Version 7.1
Appendix 4
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
This information in this appendix is adapted from Levien and Baker 20032, Zhang 20103, 
and FDA Guidance on Drug-Drug Interactions.
Also see:

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dr
ugInteractionsLabeling/ucm080499.htm 
                                           
2
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.
3
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.


Appendix 4
List of Substrates, Inhibitors, and Inducers of 
Drug-Metabolizing Enzymes and Transporters (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
126/Protocol MO29750, Final Version 7.1

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.


Appendix 5
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
127/Protocol MO29750, Final Version 7.1
Appendix 5
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 
                                           
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.


Appendix 5
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
128/Protocol MO29750, Final Version 7.1
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.
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.


Appendix 5
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
129/Protocol MO29750, Final Version 7.1
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.
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


Appendix 5
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
130/Protocol MO29750, Final Version 7.1
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.
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.


Appendix 5
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
131/Protocol MO29750, Final Version 7.1
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 
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.


Appendix 5
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
132/Protocol MO29750, Final Version 7.1

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 
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.


Appendix 5
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
133/Protocol MO29750, Final Version 7.1
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.
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 


Appendix 5
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
134/Protocol MO29750, Final Version 7.1
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.
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.


Appendix 5
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
135/Protocol MO29750, Final Version 7.1
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 
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 


Appendix 5
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
136/Protocol MO29750, Final Version 7.1
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.


Appendix 5
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
137/Protocol MO29750, Final Version 7.1
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.


Appendix 5
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
138/Protocol MO29750, Final Version 7.1
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.


Appendix 5
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1: Excerpt from Original Publication (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
139/Protocol MO29750, Final Version 7.1
Appendix 6
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


Appendix 7
EORTC QLQ-C30/LC13 and EQ-5D-5L Questionnaires (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
140/Protocol MO29750, Final Version 7.1
Appendix 7
EORTC QLQ-C30/LC13 and EQ-5D-5L Questionnaires


Appendix 7
EORTC QLQ-C30/LC13 and EQ-5D-5L Questionnaires (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
141/Protocol MO29750, Final Version 7.1


Appendix 7
EORTC QLQ-C30/LC13 and EQ-5D-5L Questionnaires (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
142/Protocol MO29750, Final Version 7.1




Appendix 7
EORTC QLQ-C30/LC13 and EQ-5D-5L Questionnaires (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
144/Protocol MO29750, Final Version 7.1


Alectinib—F. Hoffmann-La Roche Ltd
145/Protocol MO29750, Final Version 7.1
Appendix 8
Modification of Diet in Renal Disease (MDRD) Formula
The estimated 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
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.

SAP_003.pdf: 
 
Official Title: 
 
RANDOMIZED, MULTICENTER, PHASE III, OPEN-LABEL 
STUDY OF ALECTINIB VERSUS PEMETREXED OR DOCETAXEL 
IN ANAPLASTIC LYMPHOMA KINASE-POSITIVE ADVANCED 
NON-SMALL CELL LUNG CANCER PATIENTS PREVIOUSLY 
TREATED WITH PLATINUM-BASED CHEMOTHERAPY AND 
CRIZOTINIB 
NCT Number: NCT02604342 
Document Date: SAP Version 3.0: 21-Aug-2018 
 
 


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`LSfahMLKMaScULKM_SKNo~aO`aNNar_`q`ahO~_haK~_`LgTKaLP_OKMSMpoMPPp_
O_SNa`_fLKK~_KMh_aqO`aNNar_`f_qMS_fLNK~_qM`NKfLTaqLP_OKMSMpMSKL_qaPPaoMSi
O~_haK~_`LgTc
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ecXcXcd
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qaPPaoMSif_qMSMKMaSc
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}~_p_NKar_`LPP`_NgaSN_qa`LNp_OKMNf_qMS_fLNK~_haNKqLra`LpP_aKOah_]
LOOa`fMSiKamkJ}rdcdO`MK_`ML]LKLSTrMNMKLqK_``LSfahMLKMaSLSfLqK_`qM`NK
K`_LKh_SKfLK_NLSfgKaK~_fLKLOKaqqa`K~_qM`NKfMN_LN_g`ai`_NNMaS]o~MO~_r_`
aOO`NqM`NKc
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}~_aKOah_NL`_a`f_`_fp_Paoq`ahhaNKKaP_LNKqLra`LpP_
 mahgP_K__NgaSN_jmn
 UL`KMLP_NgaSN_jUn
 JKLpP_lMN_LN_jJln
 U`ai`_NNMr_lMN_LN_jUln
 aSrLPLpP_jn
_NgaSN_NaqaSmaSUlL`_K`_LK_fLNJlc

a`MSr_NKMiLKa`LNN_NNh_SKN]K~_p_NKar_`LPP`_NgaSN_oMPPp_f_`Mr_f
g`ai`LhhLKMOLPPT]LOOa`fMSiKamkJ}rdcd]pLN_faSK~_MSr_NKMiLKa`ar_`LPP
Np_OK`_NgaSN_g_`rMNMKOaPP_OK_faSK~__mc}~_MSr_NKMiLKa`ar_`LPPNp_OK
`_NgaSN_g_`KMh_gaMSKoMPPSaKp_`_f_`Mr_fg`ai`LhhLKMOLPPTc_NKar_`LPP`_NgaSN_
MNK~_qM`NKaOO``_SO_aqK~_haNKqLra`LpP_aKOah_]LNf_KLMP_fLpar_cRp_NK
`_NgaSN_aqma`UOLSSaKp_LNN_NN_fSP_NNMKMNOaSqM`h_f]Sa_L`PM_`K~LSqa`
jeno__NjXfLTNnq`ahK~_KMh_L`_NgaSN_aqma`UMNqM`NKNNg_OK_fcUP_LN_
`_q_`KaK~_p_PaoKLpP_MqK~_gLKM_SK_g_`M_SO_fLKP_LNKaS_ar_`LPP`_NgaSN_aq
mahgP_K__NgaSN_jmn]UL`KMLP_NgaSN_jUna`aKrLPLpP_jnLKLSTKMh_
aSK`_LKh_SK]K~_qaPPaoMSiOaSr_SKMaSNoMPPp_N_fKaf_`Mr_K~_OaSqM`h_fp_NK
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We_`LPPf_NgaSN_LK
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LzrLofMNK`kPTj_KLKKu_rM`NKKMj_gaMSK]LSTqMN_LN_N__SLKLNklN_mk_SKKMj_gaMSK]_e_S
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qk`LKMaSra`JpsLNj_Kc}as_e_`]Naj_KMj_NofjLTl_OPLMj_qsu_SNklN_mk_SKNOLSN
Nkyy_NKNjLPPP_NMaSNs_`_PM~_PTNKMPPg`_N_SKLSqMSrLOKKu_gLKM_SKuLqUf]SaKof]LKKu_
rM`NKKMj_gaMSKcSq_`Ku_N_OM`OkjNKLSO_N]Ku_a`MyMSLPofNuakPql_OuLSy_qKaUfLSqKu_
l_NK`_NgaSN_MNUfc
zrLNkl_OK_g_`M_SO_qaSPTofvwof]nWfsMPPl_ofc
zrLNkl_OK_g_`M_SO_qaSPTUfvwUf]nWfsMPPl_Ufc
zrLNkl_OK_g_`M_SO_qaSPTUfJpUf]nWfsMPPl_Jpc
zrLNkl_OKuLqaSPTaS_Kkja`LNN_NNj_SKgaNKlLN_PMS_sMKuLSae_`LPP`_NgaSN_arvw]
Ku_SKu_ae_`LPP`_NgaSN_sMPPl_N_KKajMNNMSy
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RjMSMjkjMSK_`eLPar[s__~N{b[qLTN|sMPPl_OaSNMq_`_qra`JKLlP_pMN_LN_{Jp|
Kal_LNNMyS_qLNl_NKae_`LPP`_NgaSN_]Mc_cMSKu_OLN_Ku_NMSyP_`_NgaSN_MNJp]
Ufa`of]KuMNNMSyP_`_NgaSN_jkNKuLe_l__SLNN_NN_qSaP_NNKuLS[s__~N{LK
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zrKu_Nkl_OKuLNjMNNMSylLN_PMS_Kkja`LNN_NNj_SKLSqa`SaaSK`_LKj_SKKkja`
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rk_s_NKal_`LPP`_NgaSN_LNg_`nftia`gLKM_SKNuMKktvJj_KLNKLNMNLKsLN_PMS_
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rk_s_NKal_`LPP`_NgaSN_LNg_`nftia`gLKM_SKNuMKkj_LNy`LsP_tvJj_KLNKLNMN
LKsLN_PMS_mtwxWfquMPPs_LNN_NN_paSPTsTnftLSpuMPPs_p_iMS_pMSLNMjMPL`uLT
sTOaSNMp_`MSoaSPTP_NMaSNMSKk_tvJc
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uLTLNia`UJLNN_NN_psTMSl_NKMoLKa`c
 UJLNg_`nftia`gLKM_SKNuMKktvJj_KLNKLNMNLKsLN_PMS_uMPPs_p_iMS_p
MSLNMjMPL`uLT]KLhMSoMSKaLOOaySKLPPP_NMaSNMSKk_sapTc
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p_iMS_pMSLNMjMPL`uLT]KLhMSoMSKaLOOaySKLPPP_NMaSNMSKk_sapTc
zcXcXcb
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Kk_g_`O_SKLo_aigLKM_SKNukaLKKLMSOajgP_K_`_NgaSN_mtfqa`gL`KMLP
`_NgaSN_mUfq]LNp_K_`jMS_pyNMSoftnJrldcdcULKM_SKNuMKkayKLSTgaNKw
sLN_PMS_LNN_NNj_SKNuMPPs_LNNMoS_pKaKk_vaSwlLPyLsP_mvqOLK_oa`T
LSp`_oL`p_pLNSaSw`_NgaSp_`NcnKNkayPps_SaK_pKkLKgLKM_SKNuMKkSaSw
j_LNy`LsP_pMN_LN_OLSLOkM_l_aSPTtfLSpSaKUfc
 WffLNg_`nftia`LPPgLKM_SKNMNp_iMS_pyNMSoKk_NLj_p_iMSMKMaSLNia`
WffLNg_`MSl_NKMoLKa`c
 WffLNg_`nftia`gLKM_SKNuMKktvJj_KLNKLNMNLKsLN_PMS_mtwWffqMN
p_iMS_pMSLNMjMPL`uLTia`P_NMaSNMSKk_tvJc
 WffLNg_`nftia`LPPgLKM_SKNuMKkj_LNy`LsP_tvJj_KLNKLNMNLKsLN_PMS_
mtwWffqMNp_iMS_pMSLNMjMPL`uLTia`P_NMaSNMSKk_tvJc
zcXcXcz
9~6D~6A:8|A5GD86
 MN_LN_OaSK`aP`LK_mtfqLNg_`MSl_NKMoLKa`ia`LPPgLKM_SKNMNp_iMS_pLN
Kk_g_`O_SKLo_aigLKM_SKNuMKkLs_NKal_`LPP`_NgaSN_aitf]Ufa`J
ukMOkPLNK_pia`Lpy`LKMaSaiLKP_LNK[u__hNc
 tfLNg_`nftia`LPPgLKM_SKNMNp_iMS_pyNMSoKk_NLj_p_iMSMKMaSLNtf
LNg_`MSl_NKMoLKa`c
 tvJtfmtwtfqLNg_`nftia`gLKM_SKNuMKktvJj_KLNKLNMNLKsLN_PMS_
MNp_iMS_pMSLNMjMPL`uLTia`P_NMaSNMSKk_tvJc
 twtfLNg_`nftia`gLKM_SKNuMKkj_LNy`LsP_tvJj_KLNKLNMNLKsLN_PMS_
MNp_iMS_pMSLNMjMPL`uLTia`P_NMaSNMSKk_tvJc
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Kk_KMj_i`ajuk_S`_NgaSN_mtfa`UfquLNiM`NKpaOyj_SK_pKaiM`NK
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l_kMS_lMSLNMpMPL`rLTka`P_NMaSNMSKo_jsJc
e fWgLNh_`igjka`hLKM_SKNrMKop_LNm`LtP_jsJp_KLNKLNMNLKtLN_PMS_ujv
fWgwMNl_kMS_lMSLNMpMPL`rLTka`P_NMaSNMSKo_jsJc
xcXcXcy
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Wq_`LPPNm`qMqLPuWJwMNl_kMS_lLNKo_KMp_k`ap`LSlapMLKMaSKal_LKok`apLST
OLmN_cULKM_SKNrMKoamKLS_q_SKrMPPt_O_SNa`_lLKKo_PLNKlLK_SarSKat_LPMq_c
ULKM_SKNrMKoamKLSTkaPParvmhMSka`pLKMaSrMPPt_O_SNa`_lLKKo_lLK_ak
`LSlapMLKMaSc
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e LPPhLKM_SKN
e hLKM_SKrMKojsJp_KLNKLNMNLKtLN_PMS_
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`LlMan`LhoMO_qMl_SO_akjsJh`an`_NNMaScULKM_SKNroalM_la`roa_h_`M_SO_
SaSvjsJh`an`_NNMaSrMPPt_O_SNa`_lLKKo_aOOm``_SO_lLK_akKo_Oa``_NhaSlMSn
_q_SKcULKM_SKNroalMlSK_h_`M_SO_LSTakKo_kaPParMSn_q_SKNjsJh`an`_NNMaS]
SaSvjsJh`an`_NNMaSa`l_LKorMPPt_O_SNa`_lLKKo_M`PLNKKmpa`LNN_NNp_SKlLK_c
jsJh`an`_NNMaSMNl_kMS_lLNh`an`_NNMaSlm_KaS_rPTl_q_Pah_ljsJP_NMaSN
LSla`h`an`_NNMaSakh`__MNKMSntLN_PMS_jsJP_NMaSNcWSKo_tLNMNakgjiJqdcd]
KoMNMNl_kMS_lLNLS_rhaNKvtLN_PMS_jsJt`LMSP_NMaSuNwLSla`LSMSO`_LN_akX\
MSKo_NmpakPaSn_NKlMLp_K_`NakKo_p_LNm`LtP_tLN_PMS_jsJP_NMaSNOaphL`_l
KaSLlM`LSla`mS_mMqaOLPh`an`_NNMaSakSaSvp_LNm`LtP_tLN_PMS_jsJP_NMaSNc
saSvjsJh`an`_NNMaSMNl_kMS_lLNh_`igj`LlMan`LhoMO_qMl_SO_akh`an`_NNMaS
roMOoMNSaKLjsJh`an`_NNMaSc
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e MSLPPhLKM_SKN`_nL`lP_NNakKo_M`tLN_PMS_NKLKmNakjsJp_KLNKLN_Nc
e MShLKM_SKNrMKotLN_PMS_jsJp_KLNKLN_N
e MShLKM_SKNrMKoamKtLN_PMS_jsJp_KLNKLN_N
xcXcb
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e Mp_Ka`_NhaSN_ugwLNh_`MSq_NKMnLKa`ka`LPPhLKM_SKNMNl_kMS_lLNKo_
KMp_k`ap`LSlapMLKMaSKaKo_kM`NKlaOmp_SK_lat_OKMq_`_NhaSN_uMc_cjg
a`UgwcoMNrMPPaSPTt_OLPOmPLK_lka`hLKM_SKNroaoLq_Lt_NKaq_`LPP
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rLKLLSrOLSwL_`_Oaww_SrLKMaSNKaK_JsaSNa`KaNKasa`Lw_SrK_NK}rTaS
K_{LNMNa~NL~_KT~MSrMS|Nc_~`_}_SOTa~K_N_`_uM_vNMNs`auMr_rMSN_OKMaScc
aNKassMS|~a`_L`PTs`aa~a~_~~MOLOTvMPP`_N}PK~`awLSTa~K_N_`_|}PL``_uM_vNc
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_PMNKa~KL{P_NLSr~M|}`_NKa{_s`auMr_r~a`{aKas_SLSrOPaN_rN_NNMaSL`_
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RN_K]`_~_``_rLNas_S`_sa`KNvMPP{_s`_N_SK_rr}`MS|K_MVyas_SN_NNMaSNc
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_LOOLK_|a`TxvMKLOLK_|a`T~a`wMNNMS|rLKLza~K_sL`Lw_K_`vMPP{_s`_N_SK_rc
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Kd_fM`NKK`_LKk_SKeLTafLP_OKMSMjj_TaSeg`ai`_NNMaSa`j_TaSe
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Nsj_OKNKdLKOaSKMSs_eLP_OKMSMjj_TaSeg`ai`_NNMaS
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