Conditions: Neoplasms Colorectal Neoplasms Melanoma Pancreatic Neoplasms Sarcoma Ovarian Neoplasms Brain Neoplasms Thyroid Neoplasms Neuroendocrine Tumors Cholangiocarcinoma Salivary Gland Neoplasms Head and Neck Neoplasms Thyroid Cancer, Papillary Lymphoma, Large-Cell, Anaplastic Neoplasms by Site Respiratory Tract Neoplasms Thoracic Neoplasms Respiratory Tract Diseases Carcinoma, Bronchogenic Bronchial Neoplasms Intestinal Neoplasms Gastrointestinal Neoplasms Digestive System Neoplasms Digestive System Diseases Gastrointestinal Diseases Colonic Diseases Intestinal Diseases Central Nervous System
Keywords: agnostic ALK+ Alk-positive ALK positive ALK mutation GI breast sarcoma neuroendocrine female reproductive ALK ALK fusions ALK gene rearrangements colorectal cancer entrectinib basket study salivary gland cancers primary brain tumors melanoma sarcomas papillary thyroid cancer renal cell cancer pancreatic cancer breast cancer cholangiocarcinoma head & neck cancers ovarian cancer anaplastic lymphoma kinase positive solid tumors ALK+ solid tumors
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy and safety of alectinib in participants with Anaplastic Lymphoma Kinase (ALK)-positive locally advanced or metastatic solid tumors other than lung cancer.

Detailed description:

Arms:
arm 1: Participants with locally advanced or metastatic ALK-positive tumors will receive alectinib twice daily (BID) until disease progression, unacceptable toxicity, death, or withdrawal from the study for any reason.

Interventions: intervention 1: Alectinib
Intervention descriptions: intervention 1: Participants will receive 600 mg oral alectinib BID until disease progression, unacceptable toxicity, withdrawal from treatment, or death.

Protocol document:
Prot_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Alectinib—F. Hoffmann-La Roche Ltd
Protocol BO41929, Version 4
PROTOCOL
TITLE:
A PHASE II, OPEN-LABEL, SINGLE-ARM
DECENTRALIZED HOME-BASED APPROACH
STUDY TO EVALUATE THE EFFICACY AND
SAFETY OF ALECTINIB IN LOCALLY ADVANCED
OR METASTATIC ALK-POSITIVE SOLID TUMORS
PROTOCOL NUMBER:
BO41929
VERSION NUMBER:
4
EUDRACT NUMBER:
2021-002352-36
IND NUMBER:
111,723
NCT NUMBER:
04644315
TEST PRODUCT:
Alectinib (RO5424802)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below.
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
24-Nov-2021 23:50:48


Alectinib—F. Hoffmann-La Roche Ltd
2/Protocol BO41929, Version 4
PROTOCOL HISTORY
Protocol
Version
Date Final
4
See electronic date stamp on title page
3
17 August 2021
2
9 June 2021
1
2 October 2020


Alectinib—F. Hoffmann-La Roche Ltd
3/Protocol BO41929, Version 4
PROTOCOL AMENDMENT, VERSION 4:
RATIONALE
Protocol BO41929 has been amended primarily to update information related to the risk 
of anemia associated with alectinib and to introduce management guidance related to 
hemolytic anemia, in line with the Dear Investigator Letter on hemolytic anemia dated 
28 October 2021 Additional changes have been made to clarify language in the protocol 
and to align process between the two possible operational approaches that can be 
employed to conduct the study (i.e., Virtual site and/or Physical site approach). The 
changes to the protocol, along with a rationale for each change, are summarized below:
Safety-related changes 

Benefit-risk assessment of COVID-19 vaccine and efficacy of alectinib has been
moved to Section 1.4.2.1.

Additional information has been included regarding hemolytic anemia 
(Section 5.1.1.3) and dose modification guidance for the management of hemolytic 
anemia adverse reaction with alectinib (Section 5.1.2.3, Table 1) in line with the 
Dear Investigator Letter on hemolytic anemia dated 28 October 2021.
Clarifications and process-related changes

Information related to Alectinib approval status and associated clinical practice have 
been removed in section 1.4.1 since it was redundant with information presented 
earlier in the section.

Language has been simplified regarding patient ALKtumors identification in 
Section 3.3.1.

Language on Investigator Oversight of Study Personnel has been adjusted to clearly 
specify in which country virtual and/or physical site operational approach can be 
used and clarify reason of offering the two approaches. (Section 3.3.1 and
Appendix 9).

The data collection approach for virtual sites was adjusted to enable entry of eCRF 
data through EDC (RAVE) directly instead of Science 37 platform to be transferred 
in RAVE, and align with data entry approach for Physical site as well as to add 
clarification to indicate that, in addition to virtual site, the approach with physical 
study sites (e.g., hospital, clinic, or oncology institution) can be used in the 
United States (Sections 3.3.1, 4.6.6, 7.1, 7.2, 7.3.1, Appendix 9).

Language has been adjusted for inclusion criteria regarding prior treatment to clarify 
that alectinib as second line is acceptable once Standard of Care (SoC) fails. There 
is no need to exhaust all SoC alternatives before initiating alectinib (Section 4.1.1).

The responsibilities of the Principal Investigator and the role of the Medical Monitor 
in determining patient eligibility and during study conduct have been clarified 
(Sections 4.5.3,4.6.6, 5.1.2.2).


Alectinib—F. Hoffmann-La Roche Ltd
4/Protocol BO41929, Version 4

For clarity, language has been adjusted regarding when physical examinations are 
performed in patient homes (Sections 5.1 and 5.3.1.1).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Alectinib—F. Hoffmann-La Roche Ltd
5/Protocol BO41929, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 24
1.1
Background on ALK-Positive Solid Tumors........................... 24
1.1.1
Background on ALK-Oncogene and ALK-Inhibitor 
Development ......................................................................... 24
1.2
Background on Alectinib........................................................ 25
1.2.1
Background on Tumor-Agnostic Drug 
Development ......................................................................... 25
1.2.2
Alectinib................................................................................. 26
1.3
Background on the Decentralized Study Model..................... 27
1.4
Study Rationale and BenefitRisk Assessment..................... 28
1.4.1
Trial-Specific Risk Assessment ............................................. 29
1.4.2
COVID-19 BenefitRisk Assessment..................................... 30
1.4.2.1
COVID-19 Vaccines .............................................................. 31
2.
OBJECTIVES AND ENDPOINTS ............................................................... 31
2.1
Efficacy Objectives ................................................................ 32
2.1.1
Primary Efficacy Objective..................................................... 32
2.1.2
Secondary Efficacy Objective................................................ 32
2.1.3
Exploratory Efficacy Objective............................................... 33
2.2
Safety Objectives................................................................... 33
2.3
Pharmacokinetic Objective .................................................... 34
2.4
Exploratory Biomarker Objectives ......................................... 34
2.5
Health Status Utility Objective ............................................... 34
3.
STUDY DESIGN......................................................................................... 34
3.1
Description of the Study......................................................... 34
3.1.1
Internal Monitoring Committee............................................... 37
3.2
End of Study and Length of Study......................................... 37
3.3
Rationale for Study Design.................................................... 37
3.3.1
Rationale for Single-Arm Decentralized Design..................... 37
3.3.2
Rationale for Alectinib Dose and Schedule............................ 39


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3.3.3
Rationale for Patient Population and Analysis 
Groups................................................................................... 40
3.3.4
Rationale for Biomarker Assessments................................... 40
3.3.5
Rationale for Pharmacokinetic Sample Collection................. 41
3.3.6
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 41
4.
MATERIALS AND METHODS .................................................................... 41
4.1
Patients.................................................................................. 41
4.1.1
Inclusion Criteria.................................................................... 42
4.1.2
Exclusion Criteria................................................................... 44
4.2
Screen Failures ..................................................................... 45
4.3
Method of Treatment Assignment.......................................... 45
4.4
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 46
4.4.1
Study Treatment Formulation and Packaging........................ 46
4.4.1.1
Alectinib................................................................................. 46
4.4.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 46
4.4.3
Investigational Medicinal Product Handling and 
Accountability ........................................................................ 47
4.4.4
Continued Access to Alectinib ............................................... 48
4.5
Concomitant Therapy ............................................................ 48
4.5.1
Permitted Therapy................................................................. 49
4.5.2
Cautionary Therapy ............................................................... 49
4.5.3
Prohibited Therapy ................................................................ 49
4.6
Study Assessments............................................................... 50
4.6.1
Informed Consent Forms and Screening Log........................ 52
4.6.2
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 53
4.6.3
Physical Examinations........................................................... 53
4.6.4
Vital Signs.............................................................................. 54
4.6.5
Tumor and Response Evaluations......................................... 54
4.6.5.1
Non-Primary CNS Tumors Assessments............................... 56
4.6.5.2
Primary CNS Tumors Assessments ...................................... 57


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4.6.5.3
Corticosteroid Use for Primary CNS tumors .......................... 57
4.6.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 57
4.6.7
Electrocardiograms................................................................ 60
4.6.8
Clinical Outcome Assessments ............................................. 61
4.6.8.1
Data Collection Methods for Clinical Outcome 
Assessments ......................................................................... 61
4.6.8.2
Description of Clinical Outcome Assessment 
Instruments............................................................................ 61
4.6.9
Optional Samples for Research Biosample 
Repository ............................................................................. 62
4.6.9.1
Overview of the Research Biosample Repository.................. 62
4.6.9.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 62
4.6.9.3
Sample Collection.................................................................. 63
4.6.9.4
Confidentiality........................................................................ 63
4.6.9.5
Consent to Participate in the Research 
Biosample Repository............................................................ 64
4.6.9.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 64
4.6.9.7
Monitoring and Oversight....................................................... 65
4.7
Treatment, Patient, and Study Discontinuation...................... 65
4.7.1
Study Treatment Discontinuation........................................... 65
4.7.2
Patient Discontinuation from the Study.................................. 66
4.7.3
Study Discontinuation............................................................ 67
4.7.4
Site Discontinuation............................................................... 67
5.
ASSESSMENT OF SAFETY....................................................................... 67
5.1
Safety Plan ............................................................................ 67
5.1.1
Risks Associated with Alectinib ............................................. 68
5.1.1.1
Interstitial Lung Disease and Pneumonitis............................. 68
5.1.1.2
Hepatotoxicity........................................................................ 68
5.1.1.3
Anemia, Including Hemolytic Anemia .................................... 69
5.1.1.4
Gastrointestinal Disorders ..................................................... 69
5.1.1.5
Skin Disorders ....................................................................... 69
5.1.1.6
Vision Disorders .................................................................... 69


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5.1.1.7
Edema ................................................................................... 70
5.1.1.8
Bradycardia ........................................................................... 70
5.1.1.9
Abnormal Renal Function (Serum Creatinine 
Increased, Acute Kidney Injury)............................................. 71
5.1.1.10
Severe Myalgia and CPK Elevations..................................... 71
5.1.1.11
Dysgeusia.............................................................................. 71
5.1.1.12
Alkaline Phosphatase Increase ............................................. 71
5.1.2
Management of Patients Who Experience 
Adverse Events ..................................................................... 72
5.1.2.1
Dose Modifications ................................................................ 72
5.1.2.2
Treatment Interruption ........................................................... 72
5.1.2.3
Management Guidelines........................................................ 73
5.2
Safety Parameters and Definitions ........................................ 76
5.2.1
Adverse Events ..................................................................... 77
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 77
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 78
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 78
5.3.1
Adverse Event Reporting Period ........................................... 79
5.3.1.1
Special Considerations Related to Decentralized 
Study Design ......................................................................... 79
5.3.2
Eliciting Adverse Event Information....................................... 80
5.3.3
Assessment of Severity of Adverse Events ........................... 80
5.3.4
Assessment of Causality of Adverse Events ......................... 81
5.3.5
Procedures for Recording Adverse Events............................ 82
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 82
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 82
5.3.5.3
Persistent or Recurrent Adverse Events................................ 83
5.3.5.4
Abnormal Laboratory Values ................................................. 83
5.3.5.5
Abnormal Vital Sign Values ................................................... 84
5.3.5.6
Abnormal Liver Function Tests.............................................. 84
5.3.5.7
Deaths ................................................................................... 85


Alectinib—F. Hoffmann-La Roche Ltd
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5.3.5.8
Preexisting Medical Conditions.............................................. 85
5.3.5.9
Lack of Efficacy or Worsening of ALK-Positive 
Tumor .................................................................................... 86
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 86
5.3.5.11
Cases of Overdose, Medication Error, Drug 
Abuse, or Drug Misuse .......................................................... 86
5.3.5.12
Patient-Reported Outcome Data ........................................... 88
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 89
5.4.1
Medical Monitors and Emergency Medical 
Contacts ................................................................................ 89
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 90
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 90
5.4.2.2
Events That Occur after Study Drug Initiation........................ 90
5.4.3
Reporting Requirements for Pregnancies.............................. 90
5.4.3.1
Pregnancies in Female Patients............................................ 90
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 91
5.4.3.3
Abortions ............................................................................... 91
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 91
5.5
Follow-Up of Patients after Adverse Events .......................... 92
5.5.1
Investigator Follow-Up........................................................... 92
5.5.2
Sponsor Follow-Up ................................................................ 92
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 92
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 92
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 93
6.1
Determination of Sample Size ............................................... 94
6.2
Summaries of Conduct of Study............................................ 94
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 95
6.4
Efficacy Analyses .................................................................. 95
6.4.1
Primary Efficacy Endpoint...................................................... 95


Alectinib—F. Hoffmann-La Roche Ltd
10/Protocol BO41929, Version 4
6.4.2
Secondary Efficacy Endpoints............................................... 95
6.4.2.1
Secondary Endpoint Definitions............................................. 95
6.4.3
Exploratory Biomarker Endpoints .......................................... 97
6.5
Safety Analyses..................................................................... 97
6.6
Pharmacokinetic Analyses..................................................... 98
6.7
Biomarker Analyses............................................................... 98
6.8
Health Status Utility Analyses................................................ 99
6.9
Interim Analysis ................................................................... 100
7.
DATA COLLECTION AND MANAGEMENT ............................................. 100
7.1
Data Quality Assurance....................................................... 100
7.2
Electronic Case Report Forms............................................. 101
7.3
Source Data Documentation................................................ 101
7.3.1
Virtual Study Sites ............................................................... 101
7.3.2
Physical Study Sites ............................................................ 102
7.4
Use of Computerized Systems ............................................ 103
7.5
Retention of Records........................................................... 103
8.
ETHICAL CONSIDERATIONS.................................................................. 103
8.1
Compliance with Laws and Regulations .............................. 103
8.2
Informed Consent................................................................ 103
8.3
Institutional Review Board or Ethics Committee.................. 105
8.4
Confidentiality...................................................................... 105
8.5
Financial Disclosure ............................................................ 106
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 106
9.1
Study Documentation .......................................................... 106
9.2
Protocol Deviations.............................................................. 106
9.3
Management of Study Quality ............................................. 106
9.4
Inspections .......................................................................... 107
9.5
Administrative Structure....................................................... 107
9.6
Dissemination of Data and Protection of 
Trade Secrets...................................................................... 108
9.7
Protocol Amendments ......................................................... 109


Alectinib—F. Hoffmann-La Roche Ltd
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10. REFERENCES ......................................................................................... 110
LIST OF TABLES
Table 1
Guidelines for Management of Risks, Adverse Events, and 
Selected Laboratory Abnormalities with Alectinib ....................... 73
Table 2
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 81
Table 3
Causal Attribution Guidance ....................................................... 82
Table 4
ORR Scenarios with Associated 95% CI .................................... 94
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 37
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 115
Appendix 2
Schedule of Pharmacokinetic and Biomarker Samples ............ 119
Appendix 3
ECOG Performance Status Scale............................................. 121
Appendix 4
List of P-gp Substrates.............................................................. 122
Appendix 5
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 123
Appendix 6
Response Assessment in Neuro-Oncology (RANO) Criteria .... 133
Appendix 7
EQ-5D-5L.................................................................................. 142
Appendix 8
European Organisation for the Research and Treatment of 
Cancer QLQ-C30...................................................................... 145
Appendix 9
Investigator Oversight of Study Personnel................................ 147


Alectinib—F. Hoffmann-La Roche Ltd
12/Protocol BO41929, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE II, OPEN-LABEL, SINGLE-ARM
DECENTRALIZED HOME-BASED APPROACH
STUDY TO EVALUATE THE EFFICACY AND
SAFETY OF ALECTINIB IN LOCALLY ADVANCED
OR METASTATIC ALK-POSITIVE SOLID TUMORS
PROTOCOL NUMBER:
BO41929
VERSION NUMBER:
4
EUDRACT NUMBER:
2021-002352-36
IND NUMBER:
111,723
NCT NUMBER:
04644315
TEST PRODUCT:
Alectinib (RO5424802)
MEDICAL MONITOR:
, M.D.
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 of the signed form to the Sponsor.


Alectinib—F. Hoffmann-La Roche Ltd
13/Protocol BO41929, Version 4
PROTOCOL SYNOPSIS
TITLE:
A PHASE II, OPEN-LABEL, SINGLE-ARM DECENTRALIZED
HOME-BASED APPROACH STUDY TO EVALUATE THE
EFFICACY AND SAFETY OF ALECTINIB IN LOCALLY ADVANCED
OR METASTATIC ALK-POSITIVE SOLID TUMORS
PROTOCOL NUMBER:
BO41929
VERSION NUMBER:
4
EUDRACT NUMBER:
2021-002352-36
IND NUMBER:
111,723
NCT NUMBER:
04644315
TEST PRODUCT:
Alectinib (RO5424802)
PHASE:
Phase II
INDICATION:
Anaplastic lymphoma kinasepositive solid tumors
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy and safety of alectinib in patients with anaplastic 
lymphoma kinase (ALK)-positive locally advanced or metastatic solid tumors other than 
lung cancer.  Specific objectives and corresponding endpoints for the study are outlined 
below.
Primary Efficacy Objective
The primary efficacy objective is to demonstrate a clinically relevant response to 
experimental treatment on the basis of the following endpoint:

Confirmed objective response rate (ORR) (defined as the proportion of patients with a 
complete response [CR] or a partial response [PR]) 28 days after initial response, in 
patients with solid tumors as determined by the investigator according to Response 
Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
The primary efficacy objective of the trial is to evaluate alectinib at the dose of 600 mg BID
until disease progression, death, or withdrawal for any other reasons in patients with ALK 
fusion solid tumors (excluding enrolled patients with cancer of unknown primary (CUP) site
and central nervous system [CNS] primary tumors) with measurable disease at baseline 
who have a baseline tumor assessment per the investigator according to RECIST v1.1 and 
receive at least one dose of alectinib (response-evaluable population).
The primary evaluation will be made regardless of whether patients withdraw from 
treatment, withdraw consent, or receive additional or alternative therapy.
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of alectinib in 
patients with ALK-positive solid tumors in the response-evaluable population, defined 
according to the investigator or by blinded independent center review (BICR), depending 
on who is assessing the endpoint, on the basis of the following endpoints:

Confirmed ORR, defined as the proportion of patients with a CR or PR 28 days after 
initial response by BICR according to RECIST v1.1


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
Duration of response (DOR), defined as the time from the first occurrence of a 
documented objective response to disease progression or death from any cause 
(whichever occurs first), as determined by both the investigator and by BICR according 
to RECIST v1.1

Progression-free survival (PFS), defined as the time from first dose of alectinib 
treatment to disease progression or death from any cause, as determined by both the 
investigator and BICR according to RECIST v1

CNS ORR, defined as objective tumor response rate (a CR or a PR) of CNS lesions in 
patients with measurable CNS metastases at baseline by BICR according to 
RECIST v1.1

CNS DOR, defined as the time from the first observation of CNS response until the first 
observation of CNS progression or death from any cause by BICR according to 
RECIST v1.1

Overall survival (OS), defined as the time from first dose of study drug to death from 
any cause
For patients with primary CNS tumors with measurable disease at baseline who have a 
baseline tumor assessment per the investigator according to Response Assessment in 
Neuro-Oncology (RANO) criteria and receive at least one dose of alectinib:

ORR, DOR, and PFS in all ALK fusionpositive patients who have measurable disease 
at baseline as determined by both the investigator and BICR

OS
For patients with solid tumors without ALK fusions, harboring defined ALK mutations 
(R1275Q, F1245C, F1174X, with X being any other amino acid) and receive at least one 
dose of alectinib:

ORR, DOR, and PFS as determined by the investigator and by BICR according to 
RECIST v1.1

CNS ORR and DOR in patients with CNS metastases at baseline by BICR according 
to RECIST v1.1

OS
For patients with CUP who receive at least one dose of alectinib:

ORR, DOR, and PFS as determined by both the investigator and BICR according to 
RECIST v1.1

CNS ORR and DOR in patients with CNS metastases at baseline, as determined by 
BICR according to RECIST v1.1

OS
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of alectinib in 
patients with ALK-positive CUP and non-CUP solid tumors who receive at least one dose 
of alectinib on the basis of the following endpoints:

ORR, DOR, and PFS, as determined by the investigator and by BICR according to 
RECIST v1.1

CNS ORR and DOR in patients with CNS metastases at baseline by BICR according 
to RECIST v1.1

OS


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Safety Objectives
The safety objective for this study is to evaluate the safety of alectinib in all dosed patients 
on the basis of the following endpoints:

Incidence and severity of adverse events, including serious adverse events, with 
severity determined according to National Cancer Institute Common Terminology 
Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0)

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is to characterize the alectinib PK profile 
on the basis of the following endpoint:

Plasma concentrations of alectinib and its metabolite(s) as applicable at 
specified timepoints
Exploratory Biomarker Objectives
The exploratory biomarker objectives for this study are as follows:

To identify and/or evaluate biomarkers that are associated with primary or acquired 
resistance to alectinib in the biomarker-evaluable population by analyzing the 
relationship between biomarkers found in circulating DNA in blood and tumor tissue, 
with efficacy endpoints

To assess relationship between levels of circulating free DNA (cfDNA) at baseline, and 
changes in levels of cfDNA at different timepoints during treatment, with efficacy 
endpoints
Health Status Utility Objective
The exploratory health status utility objective for this study is to evaluate health status utility 
scores of patients treated with alectinib on the basis of the following endpoint:

Change from baseline in QLQ-C30 scores during study treatment

Change from baseline in EQ-5D-5L index-based and Visual Analog Scale scores 
during study treatment
Study Design
Description of Study
This Phase II, open-label, single-arm study is designed to investigate the efficacy and 
safety of alectinib in patients with locally advanced or metastatic solid tumors (excluding 
lung cancer) that are determined to be ALK-positive per the Foundation Medicine Inc. 
(FMI) next-generation sequencing (NGS) test on tissue or blood (FoundationOne CDx 
[F1CDx] or FoundationOne Liquid CDx [F1LCDx] or FoundationOneHeme [F1HEME]). 
ALK positivity determined per local accredited laboratory NGS-validated testing on tissue 
or blood may be accepted.
Patients can be identified by means of one of the two following enrollment pathways:
1.
The Precision Enrollment approach offered by FMI.  Briefly, when nonlung cancer
samples are determined by FMI central testing to be positive for ALK, an FMI medical 
oncologist will contact the ordering physician (local oncologist) and provide information 
about the trial.  If this is of interest to both the physician and the patient, enrollment 
procedures will begin.
2.
Patients with ALK-positive NGS test results obtained outside FMI’S Precision 
Enrollment approach may be identified and the local ALK NGS test report will be made 
available and will be assessed by the investigator for eligibility.  The study team and 
Medical Monitor are to be consulted.  If ALK positivity is not accepted per the criteria, 
prospective FMI testing is required and the patient may be enrolled if assessed to be 
ALK-positive by FMI.


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For eligible and enrolled patients, the tumor tissue sample must be submitted for 
retrospective analysis by FMI using the F1CDx assay.
The nature of the approach makes it impossible to predict at which clinical sites these 
patients will be identified.  Therefore, a decentralized, home-based approach will be 
implemented using mHCPs that have professional qualifications as per local requirements.  
The mHCPs will attend to the patient at home, and the investigator will interact with the 
patient using telemedicine.  This approach minimizes the need for on-site visits for 
patients, thus making clinical trials more accessible to patients regardless of location.  
Patients with both ALK-fusion and selected ALK mutations will be enrolled in the study.  
Enrollment will end once approximately 50 patients with ALK fusion solid tumors evaluable 
by RECIST v1.1 have been recruited, regardless of the number of enrolled patients with 
primary CNS tumors (evaluable according to RANO criteria), with CUP or ALK mutations.  
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity (for a total of up to two screenings per participant) 
at the investigator's discretion.  Patients must re-sign the Informed Consent Form prior to 
re-screening.  The investigator will record reasons for screen failure in the screening log.
Replacement of patients with ALK fusion solid tumors assessed according to 
RECIST v1.1 who discontinue their participation in the study will be allowed if enrolled 
patients have not received any dose of alectinib.
The primary endpoint will be based on the response-evaluable population with ALK fusion 
solid tumors that are assessed according to RECIST v1.1.
The primary objective of the study is confirmed ORR as per investigator assessment in 
solid tumors assessed according to RECIST v1.1.  Secondary endpoints include ORR by 
BICR, DOR, and PFS as per investigator assessment and BICR, CNS ORR, and DOR as 
per BICR, OS, and for patients with primary CNS tumor, the ORR, DOR and PFS as per 
investigator assessment and BICR according to RANO criteria.  BICR procedures will be 
detailed in the BICR Charter.
The efficacy in patients with solid tumors harboring ALK mutations, with CUP, or with 
primary CNS tumors evaluable according to RANO criteria will be assessed as secondary 
endpoints.
An interim, non-binding analysis will be performed once the first 15 RECIST v1.1 
investigator-assessed response-evaluable patients with ALK fusions (excluding patients 
with primary CNS tumors and patients with CUP) have a response evaluation at 8 weeks 
available (unless they progressed or discontinued earlier from the study).  If the analysis 
result shows that the response rate does not achieve at least 25% (4 responders), the 
study may be terminated due to futility.
Patients will receive alectinib at the dose of 600 mg BID, taken with food, until disease 
progression, death, or withdrawal for any other reasons.  Treatment beyond radiological 
progression is possible in the event of isolated lesion progression if, in the investigator’s 
opinion, there is evidence of ongoing clinical benefit.
All enrolled patients will undergo regular, scheduled visits until disease progression, death, 
withdrawal from the study, or study termination, whichever occurs first.  For patients 
receiving alectinib beyond radiological progression, scheduled visits (including tumor 
assessments), will continue to be performed until treatment permanently discontinues.
For the first 12 weeks (3 months), regular safety assessments will be scheduled at 
baseline and every 2 weeks to allow for more frequent liver function and CPK assessments 
as per alectinib label.  After Week 12, patients will undergo regular safety visits every 
4 weeks.
Tumor assessments will be performed during screening and every 8 weeks (calculated 
from baseline) during study conduct and will consist of computed tomography (CT) and 
brain magnetic resonance imaging (MRI) scans (or brain CT scans if MRI is not feasible).  
Brain scans will be mandatory at baseline and during study conduct for patients with 
primary CNS tumors or brain metastases at baseline.  For patients without brain 
metastases at baseline, brain scans will be performed as clinically indicated during study 
conduct.  A safety follow-up will occur during the treatment discontinuation visit 28 days 
(4 weeks) after the final dose of alectinib.


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Plasma samples will be obtained for biomarker analysis at baseline, Week 8, Week 36, 
and upon disease progression, and for PK analysis at baseline and every 4 weeks at 
scheduled visits during the treatment period.
Internal Monitoring Committee
An internal monitoring committee (IMC) will monitor patient safety throughout the study, 
focusing on death cases and interim futility analysis.  The IMC will include Sponsor’s 
representatives from Clinical Science, Clinical Safety, and Biostatistics.  The IMC will 
review all necessary cumulative data at regular intervals during the study.  At the time of 
each review, the IMC will make appropriate recommendations (e.g., the study should 
continue as planned, the protocol should be amended, enrollment should be held pending 
further safety evaluations).  Decisions will be made in consideration of the totality of the 
available data.  Ad-hoc meetings may be called in addition to scheduled meetings, as 
necessary, to provide recommendations on management of any new safety issues.  
Specific operational details such as the Committee's composition, frequency and timing of 
meetings, and members' roles and responsibilities are provided in the IMC Charter.
Number of Patients
Approximately 50 patients with ALK-fusion solid tumors will be enrolled in this study.
Patients with both ALK-fusion and selected ALK mutations will be enrolled in the study.  
Enrollment will end once around 50 patients with ALK-fusions solid tumors evaluable 
according to RECIST v1.1 have been recruited (regardless of the number of enrolled 
patients with primary CNS tumors, CUP, or harboring selected ALK mutations.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Histologically confirmed locally advanced or metastatic solid tumor excluding lung 
cancer

ALK-positive tumor per FMI NGS (NGS F1CDx, F1LCDx, or F1HEME) or per local 
accredited laboratory using validated NGS testing of tumor tissue or peripheral blood:

ALK fusion

The following ALK-activating mutations:  R1275Q, F1245C, or F1174X

Local ALK test report (only for cases with local ALK testing)

Disease progression on prior treatment, or previously untreated disease with no 
available acceptable treatment

Other prior cancer therapies are allowed, including investigational drugs, if any 
treatment-related toxicities (excluding alopecia) have resolved to Grade 1 or better and 
laboratory values as defined in inclusion criteria, and meet the following washout 
criteria prior to first dose of alectinib:

At least 4 weeks must have elapsed since the last dose of the prior cytotoxic 
chemotherapy or antibody-directed therapy.

At least 7 days must have elapsed since prior tyrosine kinase inhibitor therapy.

At least 14 days must have elapsed since prior radiotherapy.

Measurable disease at baseline, as assessed by investigator (by RECIST v1.1, or 
according to RANO criteria for patients with primary CNS tumors)
For primary CNS tumors, only MRI scans will be accepted.  If the local radiology 
facility cannot perform MRI, the patient will be excluded from the study.

Life expectancy of at least 12 weeks in the opinion of the investigator

Eastern Cooperative Oncology Group Performance Status of 02

Adequate hematologic function:

Platelet count 100109/L


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
Absolute neutrophil count 1500/L

Hemoglobin 9 g/dL

Adequate hepatic function:

ALT (SGPT) and AST (SGOT) 2.5 upper limit of normal (ULN) (5 ULN for 
patients with concurrent liver metastasis)

Bilirubin 2 mg/dL

Adequate renal function:

Serum creatinine 2 ULN

Calculated creatinine clearance of 60 mL/min (Cockroft-Gault formula)

Patients with primary CNS tumors are eligible

Patients with CUP tumors are eligible

Patient with brain or leptomeningeal metastasis are allowed in the study if 
asymptomatic and if they meet the following criteria:

No neurological signs and clinically stable for at least 2 weeks without 
corticosteroid treatment for brain metastasis prior to first dose of alectinib

If previously treated with whole-brain radiotherapy or gamma-knife radiosurgery, 
treatment must have been completed at least 2 weeks prior to first dose of 
alectinib

Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests and other study procedures

Willingness to comply with home-based approach and visits by mHCPs

Ability to swallow alectinib capsules intact (without chewing, crushing, or opening)

Women of childbearing potential must have a negative serum pregnancy test result 
during screening and a negative urine pregnancy test at baseline before first dose of 
study drug is administered (unless a negative serum test was obtained within 10 days 
of first dose of study drug, in which case the urine pregnancy test is not required)

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 1% per 
year during the treatment period and for at least 90 days after the last dose of alectinib.  
Women must refrain from donating eggs during this same period.
Women must remain abstinent or use contraceptive methods with a failure rate of 
1% per year during the treatment period and at least 90 days after the final dose 
of alectinib.  Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarchal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with 
no identified cause other than menopause), and is not permanently infertile due to 
surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.  
Hormonal contraceptive methods must be supplemented by a barrier method.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not adequate methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive methods, and agreement to refrain from donating sperm, as defined 
below:


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With a female partner of childbearing potential who is not pregnant, men who are 
not surgically sterile must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of 1% per year during 
the treatment period and for least 90 days after the final dose of alectinib.  Men 
must refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for at least 90 days after the final dose of alectinib to avoid
exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and 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.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
3 months after the final dose of alectinib

Lung cancer

Patients with one of the following ALK point mutations:  I1171X, G1202R, V1180L

Prior therapy with an ALK inhibitor

Liver disease characterized by any of the following:

Impaired excretory function or synthetic function or other conditions of 
decompensated liver disease such as coagulopathy, hepatic encephalopathy, 
hypoalbuminemia, ascites, or bleeding from esophageal varices

Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis:
Active viral hepatitis B is defined as having positive hepatitis B surface antigen 
(HBsAg).  Patients with past hepatitis B virus (HBV) infection or resolved HBV 
infection (hepatitis B core antibody [HBcAb]HBcAb positive, but negative 
HBsAg) are eligible only if the HBV DNA test is negative.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA.

Known HIV infection

Patients with symptomatic bradycardia

Patients with symptomatic or unstable brain metastasis
Patients with primary CNS tumors are allowed.

Malabsorption syndrome or any other condition that would interfere with 
enteral absorption

Incomplete recovery from any surgery prior to treatment

Any other malignancies within 5 years prior to enrollment, except the following:

Curative treated basal cell carcinoma of the skin, early gastrointestinal cancer by 
endoscopic resection, in situ carcinoma of the cervix, ductal carcinoma in situ, 
papillary thyroid cancer

Any cured cancer that is considered to have no impact on PFS or OS for the 
current ALK-positive solid tumor

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion of 
the study

History of hypersensitivity to alectinib or any of its excipients
This includes, but is not limited to, patients with galactose intolerance, a congenital 
lactase deficiency, or glucose-galactose malabsorption


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End of Study
The end of this study is defined as the date when the last patient, last visit, occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is 
received from the last patient, whichever occurs later.
Length of Study
The end of the study is expected to occur approximately in the year 2026.
In addition, the Sponsor may decide to terminate the study at any time.
The length of the study is expected to be approximately 5 years.
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal product (IMP) for this study is alectinib.
Alectinib will be supplied by the Sponsor as a capsule dosage form containing the active 
ingredient 9-ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-6,11-dihydro-
5Hbenzo[b]carbazole-3-carbonitrile hydrochloride.
Each capsule contains 150 mg of alectinib (as free base) along with lactose monohydrate, 
carboxymethylcellulose calcium, hydroxypropyl cellulose, sodium lauryl sulfate, and 
magnesium stearate as excipients.
Alectinib will be supplied by the Sponsor as capsules in bottles.  Alectinib capsules should 
be stored in accordance with the storage instructions on the label.
Alectinib 600 mg (four 150-mg capsules) is to be administered orally BID with food.  The 
capsules should not be opened and the contents of capsules should not be dissolved.
A missed dose can be taken within 6 hours of the scheduled time.  If the time since the 
missed dose is greater than 6 hours, or if the patient vomits, the patient should wait until 
the next schedule time and take the next scheduled dose.  Patients should not take two 
doses at the same time to make up a missed dose.
Patient will be treated until disease progression, unacceptable toxicity, withdrawal from 
treatment, or death.  Treatment beyond radiological progression is possible in the event of 
isolated lesion progression if, in the Investigator’s opinion, there is evidence of ongoing 
clinical benefit.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Cases of accidental overdose or medication error, overdose, medication error, drug abuse, 
or drug misuse, along with any associated adverse events, should be reported as 
described in the protocol.
Statistical Methods
Primary Analysis
The primary efficacy endpoint is ORR as assessed by investigator per RECIST v1.1, 
defined as the proportion of patients with an objective response.  An objective response is 
defined as a CR or a PR per RECIST v1.1.  Confirmation of objective response is required 
(confirmed 28 days apart in two separate tumor assessments).  Patients not meeting this 
criterion (including patients without a post-baseline tumor assessment) will be considered 
as non-responders.
An estimate of the ORR and its 95% CI using the Clopper-Pearson method will be 
calculated.
The primary efficacy analysis population consists of all patients with ALK fusionpositive 
solid tumors (excluding patients with CUP and primary CNS tumors) with measurable 
disease at baseline who have a baseline tumor assessment per the investigator according 
to RECIST v1.1 and have received at least one dose of study treatment.
The primary analysis will take place once all patients have been followed for a minimum of 
24 weeks (i.e., three tumor assessments) to allow confirmation of any observed CR or PR, 
unless they progressed or withdrew from sooner from the study.


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Determination of Sample Size
Patients with both ALK-fusion and selected ALK mutations will be enrolled in the study.  
Enrollment will end once around 50 patients with ALK fusions solid tumors evaluable 
according to RECIST v1.1 have been recruited, regardless of the number of enrolled 
patients with primary CNS tumors (evaluable according to RANO criteria), with CUP, or
ALK mutations).
This sample size has been chosen so that for the primary analysis the lower limit of the 
two-sided 95% CI (using an exact Clopper-Pearson CI) around the point estimate of the 
confirmed ORR according to RECIST v1.1 will represent a clinically relevant response.  
With a sample size of 50 patients, an observed response rate of 46% (23 of 50 responses) 
would have a lower limit of the two-sided 95% CI of 31.8%, which is considered to be 
clinically relevant in this tissue-agnostic, biomarker-defined population with no available 
treatment options.  With 50 patients, there is 70% power to detect a 16% increase in ORR 
from clinically relevant 30% to 46% at the 5% two-sided significance level.
Different ORR scenarios with their associated 95% CI are presented the following table.
ORR Scenarios with Associated 95% CIs
Expected ORR
Expected Number of Patients 
with a Response
95% CI for ORR a
46%
23
(31.81, 60.68)
48%
24
(33.66, 62.58)
50%
25
(35.53, 64.47)
ORRobjective response rate.
a Using the Clopper-Pearson method and given a sample size of 50 patients.
With a sample size of 50 patients, an ORR of 46% will have an associated 95% CI of 
31.81% to 60.68%.
Interim Analysis
A non-binding interim analysis will be performed after 15 RECIST v1.1 
investigator-assessed response-evaluable patients with ALK fusions tumors (excluding 
patients with primary CNS tumors and patients with solid tumors of CUP) have at least a 
response evaluation available at 8 weeks (unless they progressed or discontinued earlier 
from the study).  During the period waiting for a response evaluation of these first 
15 patients, the study will continue to enroll.  If the analysis result shows that the response 
rate does not achieve at least 25% (4 responders), the study may be terminated due to 
futility.
Further details regarding the rules and guidelines of data review will be provided in the IMC 
Charter.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ALK
anaplastic lymphoma kinase
BID
twice a day
BICR
blinded independent center review
CDx
companion diagnostic
cfDNA
circulating free DNA
COVID-19
coronavirus disease 2019
CR
complete response
CRC
clinical research coordinator
CT
computed tomography (scan)
CTCAE
Common Terminology Criteria for Adverse Events
CUP
cancer of unknown primary (site)
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
EORTC
European Organisation for the Research and Treatment 
of Cancer
DOR
duration of response
F1CDx
FoundationOne CDx
F1LCDx
FoundationOne Liquid CDx
FDA
(U.S.) Food and Drug Administration
FMI
Foundation Medicine, Inc.
GI
gastrointestinal
HBcAb
hepatitis B core antibody 
HBsAg
hepatitis B surface antigen 
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IMT
inflammatory myofibroplastic tumors
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
mHCP
mobile health care professional


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Abbreviation
Definition
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NGS
next-generation sequencing
NSCLC
non–small cell lung cancer
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PET
positron emission tomography
PFS
progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetic
PR
partial response
PRO
patient-reported outcome
QTcF
QT interval corrected through use of Fridericia's formula
RANO
Response Assessment in Neuro-Oncology
RBR
Research Biosample Repository
RECIST v1.1
Response Evaluation Criteria in Solid Tumors, Version 1.1
SLS
sodium lauryl sulfate
TKI
tyrosine kinase inhibitor
ULN
upper limit of normal
VAS
Visual Analog Scale


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1.
BACKGROUND
1.1
BACKGROUND ON ALK-POSITIVE SOLID TUMORS
1.1.1
Background on ALK-Oncogene and ALK-Inhibitor 
Development
Anaplastic lymphoma kinase (ALK) is a cytoplasmatic membrane tyrosine kinase 
receptor protein encoded by the ALK gene.  While wild-type ALK is expressed at very 
low levels in most normal human tissues, and its physiological expression is limited to 
neuronal cells (glial cells, neurons, endothelial cell, and pericytes) (Pulford et al. 1997), 
the ALK gene has been found to be rearranged, mutated, or amplified in a series of 
tumors (Ardini et al. 2010).  In particular, chromosomal rearrangements result in ALK
fusion proteins that have been shown to be constitutively active leading to increased 
signaling of pathways that drive uncontrolled cell growth, survival, and ultimately 
tumorigenesis.
Expression of these ALK fusion genes in mouse 3T3 fibroblasts cause cell 
transformation and enhanced proliferation.  Inhibition of ALK activity in Ba/F3 cells 
transfected with the EML4-ALK fusion protein resulted in inhibition of cell growth 
(Ou et al. 2012).  In addition, inhibition of ALK signaling demonstrated anti-tumor efficacy 
in two xenograft models in athymic mice, namely, the H3122 non–small cell lung cancer
(NSCLC) and Karpas299 anaplastic large cell lymphoma models harboring the 
EML4-ALK and nucleophosmin ALK fusion proteins, respectively (Koivunen et al. 2008; 
Webb et al. 2009).
In NSCLC, ALK fusions are observed with a frequency of approximately 5%.  In solid 
tumors other than NSCLC, many different ALK-fusion partners have been identified in a 
variety of malignancies, including, but not limited to, Spitz tumors, inflammatory 
myofibroplastic tumors (IMTs), thyroid cancer, digestive tract cancer, ovarian cancer,
and renal cell carcinoma (Hallberg and Palmer 2013; Cao et al. 2019).  However, 
outside of NSCLC, the frequency of ALK rearrangements in solid tumors is extremely 
low and estimated at about 0.2% (Ross et al. 2017).  In addition to ALK fusion proteins, 
activating mutations in the ALK kinase domain have been found in different tumor types, 
including familial and sporadic cases of neuroblastoma (Lamant et al. 2000; Mossé et al. 
2008; Wood et al. 2009).
Given the relatively high prevalence of ALK alterations in NSCLC, ALK inhibitor 
development in solid tumors has been largely limited to this indication, and to date 
several ALK inhibitors have been approved for advanced or metastatic ALK-positive 
NSCLC (Serritella and Bestvina 2020).  Crizotinib (Xalkori; Pfizer, Inc.) was the first 
ALK inhibitor approved and registered for the treatment of advanced and metastatic 
ALK-positive NSCLC (Sahu et al. 2013; Shaw et al. 2013).  Crizotinib was granted 
approval for first-line treatment of patients with ALK-positive NSCLC with advanced or 
metastatic disease based on the results of the Phase III PROFILE 1014 study, which 
showed a significantly longer progression-free survival (PFS) for patients treated with 


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crizotinib compared with platinum-based chemotherapy (median PFS: 10.9 vs. 
7.0 months) in patients with previously untreated ALK-positive NSCLC (Solomon et al.
2014).  Since then, next-generation ALK inhibitors, such as alectinib, ceritinib, and 
brigatinib, have been granted market authorization as first- or second-line treatment for 
advanced and metastatic ALK-positive NSCLC (Serritella and Bestvina 2020).
Studies of patients who had progression with crizotinib treatment revealed two main 
reasons for treatment failure: development of resistance because of secondary 
mutations predominantly in ALK or occasionally in other genes, such as EGFR or KRAS 
(Katayama et al. 2011; Doebele et al. 2012; Kim et al. 2013), and CNS relapse or 
progression. The CNS is the primary site of initial treatment failure in approximately 
46% of patients with ALK-positive NSCLC treated with crizotinib due to its poor CNS 
penetration (Costa et al. 2011; Chun et al. 2012; Weickhardt et al. 2012).  Significant 
morbidity is associated with brain metastases as a direct consequence of the 
pathophysiology of brain metastases and as a result of the side effects of treatment 
required to control CNS disease, such as corticosteroids, surgery, and radiation.
1.2
BACKGROUND ON ALECTINIB
1.2.1
Background on Tumor-Agnostic Drug Development
In recent years, there has been a shift in cancer treatment practices based on improved 
understanding of oncogenic signaling processes, as opposed to an “all-comers”
approach (Gambardella et al. 2020).  Molecular alterations in specific kinases often 
result in constitutive activation of cell proliferation and survival pathways, which can drive 
the initiation and progression of malignancy.  This is particularly evident in NSCLC, for 
which numerous targeted therapies have been approved and adopted in clinical practice 
for specific molecularly defined populations, such as patients with NSCLC harboring 
EGFR-activating mutations, ALK fusions, and ROS1 rearrangements (National 
Comprehensive Cancer Network [NCCN] 2020).
More recently, this biomarker-driven treatment paradigm has gone beyond the confines 
of histologically defined tumors to be applied more broadly, regardless of tumors site of 
origin, in the so-called tumor-agnostic setting.  This approach considers treatment based 
on known oncogenic drivers/genomic alterations to be more relevant than histology for 
the purpose of defining treatment strategies.
The tumor-agnostic setting has been recently validated by the U.S. Food and Drug 
Administration’s (FDA’s) approvals of NTRK inhibitors, such as larotrectinib and 
entrectinib in metastatic solid tumors expressing the TRK fusion oncogene, regardless of 
tumor’s primary origin and histology.  The efficacy of larotrectinib was investigated in 
55 adult and pediatric patients across 17 unique TRK fusionpositive tumor types 
(Drilon et al. 2018).  The response rate across multiple tumor types was 75% (95% CI: 
61% to 85%) by independent review and 80% (95% CI: 67% to 90%) by investigator
assessment (Drilon et al. 2018).  Entrectinib was investigated in 54 patients across 


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10 different tumor types and 19 different histologies (Doebele et al. 2020).  The 
response rate across tumor types was 57% (95% CI: 43% to 71%), and median duration 
of response (DOR) was 10 months (95% CI: 7.1 months to not estimable).
In addition, pembrolizumab, a PD-1 inhibitor, has received FDA approval in the 
tumor-agnostic setting in microsatellite instabilityhigh or mismatch repairdeficient 
metastatic solid tumors.  The efficacy of pembrolizumab was investigated across 
five single-arm clinical trials in 149 patients with 15 different solid tumor types that were 
microsatellite instability high or mismatch repair deficient positive (Marcus et al. 2019).  
The overall objective response rate (ORR) was 39.6% (95% CI: 32% to 48%), with DOR
ranging from 1.6 months to 22.7 months.
These approvals demonstrate that therapies aimed at well-characterized oncogenic 
markers can deliver significant benefit and represent promising personalized treatment 
option regardless of tumor’s site of origin and histological type.
1.2.2
Alectinib
Alectinib (also referred to as RO5424802 or CH5424802) is an oral small molecule, 
highly selective and potent next-generation ALK inhibitor with benzo[b]carbazole 
scaffold. In enzyme inhibition assays performed in vitro, this compound has been shown 
to selectively inhibit ALK and RET. Alectinib also shows in vitro and in vivo anti-tumor 
activity against tumor cell lines harboring ALK translocations, ALK alterations, and 
neuroblastoma lines harboring ALK-activating mutations. Alectinib is not a substrate of 
efflux transporters (such as P-glycoprotein [P-gp]) in the bloodbrain barrier and is 
therefore able to distribute into and be retained within the CNS leading to high levels of 
CNS drug exposure.
Alectinib was approved in the United States, Canada, the European Union, and several 
other countries at a dose of 600 mg twice a day (BID) for the treatment of patients with 
ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.  
This indication was approved by the FDA on the basis of the ORR and DOR observed in 
two single-arm pivotal studies (NP28761 and NP28673), demonstrating a combined 
ORR of 51% in this crizotinib-failed population and median DOR of 14.9 months 
(Yang et al. 2017).  Efficacy in the CNS was also assessed in these trials, with a 
combined CNS response rate of 64% observed in patients with measurable CNS 
disease at baseline (Gadgeel et al. 2016).  The most common adverse events (occurring 
in 20% of patients) observed in the combined analysis were constipation (38%), fatigue 
(34%), peripheral edema (28%), myalgia (25%), nausea (23%), cough (21%) and 
headache (21%).  Reported adverse events were mostly of Grade 1 or Grade 2 severity, 
and no Grade 3 adverse event occurred with a frequency of more than 5%, the most 
common being increased blood CPK (4%), dyspnea (4%), increased ALT (3%), and 
increased AST (3%).  Adverse events leading to dose modification or interruptions 
occurred in 33% of patients, whereas adverse events leading to treatment withdrawal 
were reported in 6% of patients (Yang et al. 2017).


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Alectinib has also been approved in the first-line setting on the basis of the data 
observed in BO28984 (ALEX), a randomized, open-label Phase III study of alectinib 
versus crizotinib in treatment-naive patients with ALK-positive NSCLC. The study 
showed a clinically meaningful and statistically significant improvement in 
investigator-assessed PFS of alectinib compared with crizotinib. At the updated data 
cutoff (1 December 2017), the PFS stratified hazard ratio was 0.43 (95% CI: 0.32 to
0.58) and median PFS with alectinib was 34.8 months (95% CI: 17.7 months to not 
evaluable) versus 10.9 months (95% CI: 9.1 to 12.9 months) with crizotinib (Camidge et 
al. 2019). Alectinib has also shown considerable activity in the CNS, with CNS response 
rates of 81% in patients with measurable CNS disease at baseline (Peters et al. 2017), 
and a median PFS in patients with CNS metastases at baseline of 27.7 versus 
7.4 months for crizotinib (hazard ratio0.35; 95% CI: 0.22 to 0.56) (Camidge et al. 2019).
The safety profile of alectinib was consistent with that previously observed in trials 
conducted in patients who had previously received treatment with crizotinib. At the 
primary analysis, despite the longer treatment duration in the alectinib arm compared
with the crizotinib arm (17.9 months and 10.7 months, respectively), alectinib appeared 
to be better tolerated than crizotinib, as shown by the lower incidence of patients with 
adverse events that were Grade 3 in severity (41% vs. 50%), leading to treatment 
interruptions (19% vs. 25%) and dose reductions (16% vs. 21%) (Peters et al. 2017).
Refer to the Alectinib Investigator's Brochure for details on nonclinical and clinical 
studies.
1.3
BACKGROUND ON THE DECENTRALIZED STUDY MODEL
Clinical trials have made rapid advances in terms of digitalization and decentralization
(Laegemiddelstyrelsen 2021).  Digital tools have reduced the need for patients to attend 
appointments at a hospital or similar clinical setting.  Such tools enable digital consent 
and electronic consultations, and can include electronic data collection systems, 
wearables, and other medical devices.  These advances make it possible to conduct 
decentralized clinical trials that promote health service equality, allowing patients to 
participate in clinical trials, regardless of their mobility or proximity to hospitals.  This 
ensures a wider representation of trial participants, which is likely to facilitate the 
recruitment and retention of patients in clinical trials.
The benefit of a decentralized study model is that patients can be treated at home.  This 
eliminates the need for them to travel long distances for clinic visits and provides an 
opportunity for patients with rare diseases to participate in a clinical trial.  In this model, 
the investigator can treat and monitor the patient remotely (via telemedicine) in the 
physical presence of a mobile health care professional (mHCP).  Protocol assessments 
can be conducted at the patient’s home by the mHCP with the investigator present via 
telemedicine.  In this model, the mHCP can collect and prepare all samples for shipment 
to the analytical lab, with imaging investigations being conducted at a facility identified 
and set up for the study close to the patient’s home.  The investigator can make referrals 


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to a specialist if additional investigations are needed to ensure patient safety, as in the 
traditional clinical trial model.  The logistics of conducting a decentralized study may 
differ according to local requirements and investigator preference.
In the context of the current study, ALK positivity may be determined using local or 
centralized testing results, making it is impossible to predict where identified patients will 
be located.  Therefore, given the targeted population, the rarity of ALK positivity, and the 
approach used to identify patients, a decentralized approach has been chosen for this 
study.
1.4
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
This trial will assess the efficacy and safety of alectinib in ALK-positive solid tumors 
other than lung cancer. For the purposes of this study, ALK positivity is defined as ALK
fusions or the selected ALK-activating mutations R1275Q, F1245C, F1174X (with X 
being any other amino acid).  Patients enrolled in this study will represent a population 
with a high-unmet medical need because patients will be eligible only if they have either 
exhausted or are unsuitable to receive the standard-of-care treatment for their 
diagnosed malignancy.
Alterations in ALK have been shown to be an important mechanism of oncogene
addiction in many tumor types (Hallberg and Palmer 2013; Ross et al. 2017), and 
although these alterations are rare in non-NSCLC tumors, evidence of clinical benefit 
from ALK inhibitors in a variety of ALK-driven malignancies exists.  Efficacy of ALK
inhibitors have been reported in nonclinical models of neuroblastoma harboring 
ALK-activating mutations, such as F1174L, F1245C, and R1275Q (Trigg and Turner
2018).  In addition, clinical benefit has been described with alectinib in a patient with 
small cell carcinoma of the prostate harboring the F1174C ALK mutation (Carneiro et al. 
2018).
Clinical benefit has also been reported with ALK inhibitors in patients with various solid 
tumors harboring ALK fusions, such as cancer of unknown primary (CUP) site, IMT, 
colorectal cancer, and thyroid cancer (Amatu et al. 2015; Godbert et al. 2015; Yakirevich 
et al. 2016; Gambacorti-Passerini et al. 2018), and with alectinib in papillary renal cell 
carcinoma (Pal et al. 2018), metastatic IMT (Saiki et al. 2017; Honda et al. 2019) and 
large cell neuroendocrine carcinoma (Shimizu et al. 2019). Of note, while most of the 
efficacy data for alectinib, particularly in the clinical setting, are based on inhibition of the 
EML4-ALK fusion protein (the most abundant fusion protein observed in NSCLC), 
evidence of alectinib activity in other types of ALK fusion proteins exist.  In the ALEX trial 
of alectinib versus crizotinib in treatment-naive patients with ALK-positive NSCLC, 
11 patients enrolled in the alectinib arm were identified to harbor fusion partners other 
than EML4 (KLC1, BCL11A, FTO, KIF5B, BRE, MAP4K3 LM07, and ORC5).  Of these, 
10 patients achieved a best overall response of a partial response (PR), and 
one experienced stable disease (Roche data on file).


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In patients with ALK-positive NSCLC, alectinib has proven to be a potent, well tolerated, 
brain-penetrant ALK inhibitor at the approved dosage of 600 mg BID, and there is no 
reasonable expectation that the safety profile observed with alectinib in patients with
ALK-positive NSCLC should differ significantly when administered to patients with other 
solid tumors. Therefore, it is expected that alectinib in the population enrolled in this 
study will show a favorable benefitrisk profile.
Identified and potential risks associated with alectinib treatment will be closely monitored 
throughout the clinical program.  Patients' safety during the study is optimized by 
targeting the most appropriate patient population through inclusion and exclusion 
criteria, stringent safety monitoring by the Sponsor, and protocol-specified study drug 
modification criteria (see Section 5.1.2).
The role of ALK alterations in different tumor types, combined with the promising clinical 
activity described above in non-NSCLC tumors, supports further investigation of alectinib 
in the tumor-agnostic setting for patients with solid tumors harboring ALK fusions or 
selected ALK-activating mutations (such as the one described in neuroblastoma), for 
whom no alternative standard therapy is suitable.
1.4.1
Trial-Specific Risk Assessment
Alectinib is an approved drug in NSCLC.  In this setting, it is prescribed by oncologists 
and taken by patients at home BID.  If this was a traditional study rather than a 
decentralized study, patients would be asked to take alectinib at home as per 
investigator instructions.  Moreover, the safety assessments to be completed at the 
patient’s home in this study are the same as those that would be completed at an 
in-clinic visit. More frequent safety visits are scheduled during the first 3 months in order 
to closely monitor initial patient exposure to alectinib. In addition, patients will be 
instructed to take the first dose in the presence of an mHCP.
This study allows both virtual and physical study sites (see Appendix 9 and 
Section 3.3.1).
The following elements are associated with the decentralized nature of the study:

Telemedicine
–
The investigator and clinical research coordinator (CRC) will be in remote 
contact with the patient.
–
An mHCP will perform protocol-mandated assessments and will collect and 
prepare all samples for shipment to an analytical laboratory.
–
A smartphone will be provided to the patients with an application that facilitates 
connection with the investigator and CRC.

Electronic ICF

At-home investigational medicinal product (IMP) delivery

Local imaging center close to the patient’s home


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Overall, based on the expected favorable benefitrisk profile of alectinib in this study, the 
decentralization elements stated above, the patient population to be enrolled, the 
well-characterized and tolerated safety profile of alectinib and its route of administration 
along with the standard practice, the risks associated with decentralization are expected 
to be similar to those in a traditional study.
In this decentralized study, all included elements have been designed to enable 
operating as close as possible to the level of a non-decentralized study.

Investigator and Sponsor have exactly the same responsibilities, as outlined in the 
International Council for Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH; E6R2).

Safety management performed remotely will follow the same approach as 
management for a non-decentralized trial.
–
There will be more frequent safety visits during the first 3 months in order to 
closely monitor initial patient exposure to alectinib.
–
Patients will be instructed to take the first dose in the presence of an mHCP.
–
The investigator will make arrangements for referrals to a specialist if additional 
investigations to the study protocol are needed to ensure patient safety.

All drug shipments will be temperature controlled and bottles pre-labelled for clinical 
trial use. The mHCP will check bottle integrity and label and provide instruction to 
patient on how to take the medicine.

The mHCP will be a trained, experienced, and qualified healthcare professional. 
Assessments and supervision of the mobile healthcare professional will be 
performed in the remote presence of the investigator.
1.4.2
COVID-19 BenefitRisk Assessment
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are a more vulnerable population, with the 
potential for more severe clinical outcomes from COVID-19.  However, it is unclear 
whether or how cancer therapies such as chemotherapy and targeted therapy impact 
the incidence or severity of COVID-19.  Based on its safety profile and mechanism 
of action, it is not anticipated that the treatment used in this study will increase the risk of 
infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).  Clinical 
trials with the treatment in this study have been ongoing during this pandemic and, 
although the study numbers are small, enrolled patients have not shown any increased 
risk of developing COVID-19 symptoms.
Study BO41929 is home based, utilizing mHCPs, who would continue to observe the 
applicable epidemiologic/public health and hygiene measures, and telemedicine visits
with the investigator.


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1.4.2.1
COVID-19 Vaccines
Based on a specific benefitrisk assessment, taking into account the available relevant 
information, the approved non-live COVID-19 vaccines may and should be administered 
in patients who are in the study, as long as there is no other contraindication 
(e.g., known hypersensitivity to a vaccine component).
Although there is no specific requirement regarding the timing of vaccine administration, 
the vaccination should ideally be at least commenced before study enrollment and 
initiation of study drug, whenever possible.
Details of any COVID-19 vaccination received before study enrollment should be 
captured in the medical history section, at screening, whereas details regarding the 
COVID-19 vaccine received during the study should be recorded in the concomitant 
medication section.
Investigators should share with patients' primary healthcare providers relevant 
information regarding any potential effect of respective study drugs on the response to 
COVID-19 vaccination, as applicable.  Also, patients should contact the investigators or 
site staff, when they are invited to receive a COVID-19 vaccine deployed in their region.  
The decision to vaccinate a patient should be based on a patient’s SARS-CoV-2 
infection/complication risk, general health condition, severity of underlying malignancy, 
and regional epidemiology of COVID-19.  COVID-19 vaccines should be administered in 
accordance with their respective prescribing information and applicable immunization 
guidelines.
After COVID-19 vaccination, one should continue to observe the applicable 
epidemiologic/public health and hygiene measures during the pandemic, along with per 
protocol safety measures and assessments in order to minimize the risk and to 
appropriately identify and assess potential adverse reactions (e.g., nausea, diarrhea, 
myalgia) possibly shared by vaccines and study drugs.
Based on the published mechanism of action of the COVID-19 vaccines and the known 
mechanism of action of alectinib, there is no scientific rationale to expect that 
COVID-19 vaccines will affect the efficacy of alectinib.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy and safety of alectinib in patients with ALK-positive 
locally advanced or metastatic solid tumors other than lung cancer.  Specific objectives 
and corresponding endpoints for the study are outlined below.


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2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective is to demonstrate a clinically relevant response to 
experimental treatment on the basis of the following endpoint:

Confirmed ORR, defined as the proportion of patients with a complete response 
[CR] or a PR 28 days after initial response in patients with solid tumors, as 
determined by the investigator according to Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST v1.1)
The primary efficacy objective of the trial is to evaluate alectinib at the dose of 600 mg 
BID until disease progression, death, or withdrawal for any other reasons in patients with 
ALK fusion solid tumors (excluding enrolled patients with CUP and CNS primary tumors) 
with measurable disease at baseline who have a baseline tumor assessment per the 
investigator according to RECIST v1.1 and receive at least one dose of alectinib 
(response-evaluable population).
The primary evaluation will be made regardless of whether patients withdraw from 
treatment, withdraw consent, or receive additional or alternative therapy.
2.1.2
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of alectinib in 
patients with ALK-positive solid tumors in the response-evaluable population, defined 
according to the investigator or by blinded independent center review (BICR), depending 
on who is assessing the endpoint, on the basis of the following endpoints:

Confirmed ORR, defined as the proportion of patients with a CR or PR 28 days 
after initial response by BICR according to RECIST v1.1

Duration of response (DOR), defined as the time from the first occurrence of a 
documented objective response to disease progression or death from any cause 
(whichever occurs first), as determined by both the investigator and by BICR
according to RECIST v1.1

Progression-free survival (PFS), defined as the time from first dose of alectinib 
treatment to disease progression or death from any cause, as determined by both 
the investigator and BICR according to RECIST v1

CNS ORR, defined as objective tumor response rate (a CR or a PR) of CNS lesions 
in patients with measurable CNS metastases at baseline by BICR according to 
RECIST v1.1

CNS DOR, defined as the time from the first observation of CNS response until the 
first observation of CNS progression or death from any cause by BICR according to 
RECIST v1.1

Overall survival (OS), defined as the time from first dose of study drug to death from 
any cause


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For patients with primary CNS tumors with measurable disease at baseline who have a 
baseline tumor assessment per the investigator according to Response Assessment in 
Neuro-Oncology (RANO) criteria and receive at least one dose of alectinib:

ORR, DOR, and PFS in all ALK fusionpositive patients who have measurable 
disease at baseline as determined by both the investigator and BICR

OS
For patients with solid tumors without ALK fusions, harboring defined ALK mutations 
(R1275Q, F1245C, F1174X, with X being any other amino acid) and receive at least 
one dose of alectinib:

ORR, DOR, and PFS as determined by the investigator and by BICR according to 
RECIST v1.1

CNS ORR and DOR in patients with CNS metastases at baseline by BICR
according to RECIST v1.1

OS
For patients with CUP who receive at least one dose of alectinib:

ORR, DOR, and PFS as determined by both the investigator and BICR according to 
RECIST v1.1

CNS ORR and DOR in patients with CNS metastases at baseline, as determined by 
BICR according to RECIST v1.1

OS
2.1.3
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of alectinib in 
patients with ALK-positive CUP and non-CUP solid tumors who receive at least 
one dose of alectinib on the basis of the following endpoints:

ORR, DOR, and PFS, as determined by the investigator and by BICR according to 
RECIST v1.1

CNS ORR and DOR in patients with CNS metastases at baseline, as determined by 
BICR according to RECIST v1.1

OS
2.2
SAFETY OBJECTIVES
The safety objective for this study is to evaluate the safety of alectinib in all dosed 
patients on the basis of the following endpoints:

Incidence and severity of adverse events, including serious adverse events, with 
severity determined according to National Cancer Institute Common Terminology 
Criteria for Adverse Events Version 5.0 (NCI CTCAE)

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results


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2.3
PHARMACOKINETIC OBJECTIVE
The pharmacokinetic (PK) objective for this study is to characterize the alectinib PK 
profile on the basis of the following endpoint:

Plasma concentrations of alectinib and its metabolite(s) as applicable at 
specified time points
2.4
EXPLORATORY BIOMARKER OBJECTIVES
The exploratory biomarker objectives for this study are as follows:

To identify and/or evaluate biomarkers that are associated with primary or acquired 
resistance to alectinib in the biomarker-evaluable population by analyzing the 
relationship between biomarkers found in circulating DNA in blood and tumor tissue, 
with efficacy endpoints

To assess relationship between levels of circulating free DNA (cfDNA) at baseline
and changes in levels of cfDNA at different timepoints during treatment with efficacy 
endpoints
2.5
HEALTH STATUS UTILITY OBJECTIVE
The exploratory health status utility objective for this study is to evaluate health status 
utility scores of patients treated with alectinib on the basis of the following endpoint:

Change from baseline in QLQ-C30 scores during study treatment

Change from baseline in EQ-5D-5L index-based and Visual Analog Scale (VAS)
scores during study treatment
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This Phase II, open-label, single-arm study is designed to investigate the efficacy and 
safety of alectinib in patients with locally advanced or metastatic solid tumors (excluding 
lung cancer) that are determined to be ALK-positive per the Foundation Medicine Inc.
(FMI) next-generation sequencing (NGS) test on tissue or blood (FoundationOne CDx 
[F1CDx] or FoundationOne Liquid CDx [F1LCDx] or FoundationOneHeme [F1HEME]).
ALK positivity determined per local accredited laboratory NGS-validated testing on tissue 
or blood may be accepted.
Patients can be identified by means of one of the two following enrollment pathways:
1.
The Precision Enrollment approach offered by FMI.  Briefly, when nonlung cancer 
samples are determined by FMI central testing to be positive for ALK, an FMI 
medical oncologist will contact the ordering physician (local oncologist) and provide 
information about the trial.  If this is of interest to both the physician and the patient, 
enrollment procedures will begin.
2.
Patients with ALK-positive NGS test results obtained outside FMI’S Precision 
Enrollment approach may be identified and the local ALK NGS test report will be 


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made available (see Section 4.6.6) and will be assessed by the investigator for 
eligibility. The study team and Medical Monitor are to be consulted. If ALK positivity
is not accepted per the criteria, prospective FMI testing is required and the patient 
may be enrolled if assessed to be ALK-positive by FMI.
For sample requirements, see Section 4.6.6 and Appendix 2, Table 3.
For eligible and enrolled patients, the tumor tissue sample must be submitted 
(see Section 4.6.6 and Appendix 2, Table 3) for retrospective analysis by FMI using the
F1CDx assay.
The nature of the approach makes it impossible to predict at which clinical sites these 
patients will be identified.  Therefore, a decentralized, home-based approach will be
implemented using mHCPs that have professional qualifications as per local
requirements.  The mHCPs will attend to the patient at home, and the investigator will 
interact with the patient using telemedicine. This approach minimizes the need for
on-site visits for patients, thus making clinical trials more accessible to patients 
regardless of location. Patients with both ALK-fusion and selected ALK mutations will be 
enrolled in the study. Enrollment will end once approximately 50 patients with ALK
fusion solid tumors evaluable by RECIST v1.1 have been recruited, regardless of the 
number of enrolled patients with primary CNS tumors (evaluable according to RANO 
criteria), with CUP or ALK mutations. Patients who do not meet the criteria for 
participation in this study (screen failure) may qualify for one re-screening opportunity 
(for a total of up to two screenings per participant) at the investigator's discretion.  
Patients must re-sign the Informed Consent Form prior to re-screening.  The investigator 
will record reasons for screen failure in the screening log (see Section 4.6.1).
Replacement of patients with ALK fusion solid tumors assessed according to 
RECIST v1.1 who discontinue their participation in the study will be allowed if enrolled 
patients have not received any dose of alectinib.
The primary endpoint will be based on the response-evaluable population with ALK 
fusion solid tumors that are assessed according to RECIST v1.1.
The primary objective of the study is confirmed ORR as per investigator assessment in 
solid tumors assessed according to RECIST v1.1 (see Appendix 5).  Secondary 
endpoints include ORR by BICR, DOR, and PFS as per investigator assessment and by 
BICR, CNS ORR, and DOR as per BICR, OS, and for patients with primary CNS tumor, 
the ORR, DOR and PFS as per investigator assessment and BICR according to RANO 
criteria.  BICR procedures will be detailed in the BICR Charter.
The efficacy in patients with solid tumors harboring ALK mutations, with CUP, or with 
primary CNS tumors evaluable according to RANO criteria will be assessed as 
secondary endpoints.


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An interim, non-binding analysis will be performed once the first 15 RECIST v1.1 
investigator-assessed response-evaluable patients with ALK fusions (excluding patients 
with primary CNS tumors and patients with CUP) have a response evaluation at 8 weeks 
available (unless they progressed or discontinued earlier from the study).  If the analysis 
result shows that the response rate does not achieve at least 25% (4 responders), the 
study may be terminated due to futility.
Patients will receive alectinib at the dose of 600 mg BID, taken with food, until disease 
progression, death, or withdrawal for any other reasons.  Treatment beyond radiological 
progression is possible in the event of isolated lesion progression if, in the investigator’s 
opinion, there is evidence of ongoing clinical benefit.
All enrolled patients will undergo regular, scheduled visits until disease progression, 
death, withdrawal from the study, or study termination, whichever occurs first.  For 
patients receiving alectinib beyond radiological progression, scheduled visits (including 
tumor assessments), will continue to be performed until treatment permanently 
discontinues.
For the first 12 weeks (3 months), regular safety assessments will be scheduled at 
baseline and every 2 weeks to allow for more frequent liver function and CPK 
assessments as per alectinib label.  After Week 12, patients will undergo regular safety 
visits every 4 weeks. See Appendix 1 for the schedule of activities.
Tumor assessments will be performed during screening and every 8 weeks (calculated 
from baseline) during study conduct and will consist of computed tomography (CT) and 
brain magnetic resonance imaging (MRI) scans (or brain CT scans if MRI is not 
feasible).  Brain scans will be mandatory at baseline and during study conduct for 
patients with primary CNS tumors or brain metastases at baseline.  For patients without 
brain metastases at baseline, brain scans will be performed as clinically indicated during 
study conduct.  A safety follow-up will occur during the treatment discontinuation visit 
28 days (4 weeks) after the final dose of alectinib.
Plasma samples will be obtained for biomarker analysis at baseline, Week 8, Week 36, 
and upon disease progression, and for PK analysis at baseline and every 4 weeks at 
scheduled visits during the treatment period.
Figure 1 presents an overview of the study design.  The schedule of activities is provided 
in Appendix 1.


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Figure 1
Study Schema
ALKanaplastic lymphoma kinase; BIDtwice a day; ECOG Eastern Cooperative Oncology 
Group; F/Ufollow-up; RECIST v1.1Response Evaluation Criteria in Solid Tumors,
Version 1.1.
3.1.1
Internal Monitoring Committee
An internal monitoring committee (IMC) will monitor patient safety throughout the study, 
focusing on death cases and interim futility analysis.  The IMC will include Sponsor’s 
representatives from Clinical Science, Clinical Safety, and Biostatistics.  The IMC will 
review all necessary cumulative data at regular intervals during the study.  At the time of 
each review, the IMC will make appropriate recommendations (e.g., the study should 
continue as planned, the protocol should be amended, enrollment should be held 
pending further safety evaluations).  Decisions will be made in consideration of the 
totality of the available data.  Ad-hoc meetings may be called in addition to scheduled 
meetings, as necessary, to provide recommendations on management of any new safety 
issues. Specific operational details such as the Committee's composition, frequency and 
timing of meetings, and members' roles and responsibilities are provided in the IMC 
Charter.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit, occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is 
received from the last patient, whichever occurs later.  The end of the study is expected 
to occur approximately in the year 2026.
In addition, the Sponsor may decide to terminate the study at any time.
The length of the study is expected to be approximately 5 years.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Single-Arm Decentralized Design
This study will be a single-arm trial with ORR as the primary endpoint.  The choice of a 
single-arm design is driven by the extremely low frequency of the target population 
(estimated at around 0.2%) (Ross et al. 2017).  Having a matched control would be 
difficult in this tumor-agnostic population, as it is impossible to predict which tumor types 
will be enrolled, and in what proportion relative to the overall number of patients 
recruited. Adding to the complexity of finding a suitable control arm is the requirement 


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for enrolled patients to have exhausted standard therapy or to be unsuitable to receive 
the standard of care for their diagnosed malignancy. This will mean that patients 
included in this trial will receive alectinib in different lines of therapy, further increasing 
the difficulty of finding a matched control group.
The low prevalence of ALK-positive patients in solid tumors other than NSCLC (Ross 
et al. 2017) does not lend itself to traditional recruitment approaches. It is estimated that 
more than 25,000 patients would need to be screened in order to identify 50 potentially 
eligible patients.
Patients can be identified by means of one of the two following enrollment pathways:
1.
The Precision Enrollment approach offered by FMI.  Briefly, when nonlung cancer 
samples are determined by FMI central testing to be positive for ALK, an FMI 
medical oncologist will contact the ordering physician (local oncologist) and provide 
information about the trial.  If this is of interest to both the physician and the patient, 
enrollment procedures will begin.
2.
Patients with ALK-positive NGS test results obtained outside FMI’S Precision 
Enrollment may be identified and the local ALK NGS test report will be made 
available (see Section 4.6.6) and will be assessed by the investigator for eligibility.  
The study team and Medical Monitor are to be consulted.  If ALK positivity is not 
accepted per the criteria, prospective FMI testing is required and the patient may be 
enrolled if assessed to be ALK-positive by FMI.
For sample requirements, see Section 4.6.6 and Appendix 2, Table 3.
For eligible and enrolled patients, the tumor tissue sample must be submitted 
(see Section 4.6.6 and Appendix 2, Table 3) for retrospective analysis by FMI using the 
F1CDx assay.
For more information, see Section 4.6.6.
Site activation following patient identification is not a viable approach since this would 
take several weeks to be completed, resulting in significant delays to the start of 
treatment. For these reasons, a decentralized design will be adopted using 
telemedicine. The infrastructure platform for this particular approach will be provided if it 
is not yet available for the investigator.
Patient visits will be home-based, conducted by a mHCP and remotely by the 
investigator via telemedicine. Visit assessments will be conducted by the mHCP with
remote supervision from the investigator whenever required. The mHCP must be 
licensed to perform the assessments according to country regulations. Study materials 
(including study drug) will be shipped either to the patient’s home or brought to the 
patient’s home via an alternative process (e.g., via the mHCP).  See the country-specific 
operations manual for details.  For tests that cannot be performed at home (such as 


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scans for tumor assessments), arrangements will be made for patients to visit the 
nearest local facility that can perform the required tests.
In this decentralized study, the patient’s care is provided by the mHCP and investigator.  
As in any clinical trial, the relevant patient health care providers will be kept informed 
about the patient to ensure continuity of care outside the study. The investigator will 
participate in all scheduled, home-based visits via telemedicine. The responsibilities of 
the investigator in the oversight of study personnel are described in Appendix 9.
In order to allow flexibility to participate in the study there are two operational 
approaches that can be used for study conduct as outlined below:

Investigators who are associated with a physical study site (e.g., hospital, clinic, or 
oncology institution) that is involved in the study conduct

Investigators who are not associated with a physical study site
A third-party vendor, such as Science 37, will be involved in the study conduct 
(virtual study site).
Implementation of the elements cited above will depend on local requirements as well as 
the site scheme foreseen in the country where the study is being conducted.  The 
investigators will be informed about the approach used in their country.  Please refer to 
the country-specific operations manual (see Appendix 9 for further details).
3.3.2
Rationale for Alectinib Dose and Schedule
The 600-mg BID dosing regimen of alectinib was established as the recommended 
Phase 2 dose based on safety (Section 1.4), tolerability, PK, and anti-tumor activity from 
the dose-escalation part of Phase I/II Study NP28761 (Gadgeel et al. 2014).  This dosing 
regimen was then approved in the ALK-positive, crizotinib refractory or intolerant
advanced NSCLC on the basis of the positive benefitrisk profile observed in the pivotal 
Phase II Studies NP28761 and NP28673.  In addition, the 600-mg BID dosing regimen 
has also been approved in the ALK-positive, treatment-naive, advanced NSCLC 
population on the basis of the efficacy and safety results reported in the ALEX trial 
(Peters et al. 2017), as well as the cumulative PK, exposureresponse and 
exposure-safety data observed with alectinib (Morcos et al. 2018; Smart et al. 2019).
Tumors driven by a particular oncogene tend to become addicted to that pathway and 
can greatly benefit from its targeted inhibition (Pagliarini et al. 2015).  As shown in 
ALK-positive NSCLC, alectinib is a potent and well-tolerated brain-penetrant 
ALK-inhibitor, and case reports exist describing its efficacy in the treatment of patients 
with ALK-positive solid tumors other than NSCLC when dosed at 600 mg BID (see
Section 1.2).  In addition, there is no reasonable expectation that the safety profile 
observed with alectinib in ALK-positive NSCLC at this dose should differ significantly 
when administered to patients with other solid tumors.  Therefore, it is expected that 


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600-mg BID dose of alectinib in this population will demonstrate a favorable benefitrisk 
profile.
3.3.3
Rationale for Patient Population and Analysis Groups
The study population consists of patients with ALK-positive locally advanced or 
metastatic solid tumors other than lung cancer who have either exhausted or are 
unsuitable to receive the standard of care for their diagnosed malignancy.  
See Section 1.1 for details on ALK fusions and ALK alterations and Section 1.4 for more
information about the study population.
The primary analysis will be performed on ALK fusion solid tumors (excluding patients 
with CUP and CNS primary tumors) that are measurable at baseline, as assessed by the 
investigator according to Response Evaluation Criteria in Solid Tumors Version 1.1 
(RECIST), which is expected to be the main population recruited in the study.
Patients with CUP are also allowed in the study, and data will be analyzed separately 
from the data in the primary analysis.  This will be done to preserve the primary analysis 
population of patients with ALK fusion solid tumors. Analyzing patients with CUP as a 
part of the primary analysis population would lead to increased risk of enrolling patients 
with misdiagnosed ALK-positive lung cancer.
Patients with primary CNS tumors are allowed in the study, and data will be analyzed 
separately as their disease is assessed using a different set of criteria (i.e., the RANO 
criteria).
Patients with tumors harboring selected ALK-activating mutations are also allowed in the 
study.  However, data will be analyzed separately from data in the primary analysis
because evidence of benefit with ALK inhibitors in these tumors is less robust than for
ALK fusiondriven malignancies and is primarily limited to neuroblastoma.
3.3.4
Rationale for Biomarker Assessments
Cancer is a heterogeneous disease, and ALK-positive tumors as defined in this study 
can occur in different forms, depending on the type of ALK fusion partner or 
ALK-activating mutation driving the malignancy (Hallberg and Palmer 2013). ALK fusion 
partners, ALK fusion variants, and ALK mutations, or mutations in tumor-related genes 
occurring before or during alectinib treatment may influence treatment efficacy. ALK 
mutations and mutations in cancer-related genes can appear as a result of biologic 
selection pressure on tumor cells induced by the treatment.  Therefore, patients enrolled 
in the study may not be equally likely to benefit from treatment with alectinib.  Biomarker 
samples collected prior to dosing will be assessed in an effort to identify those patients 
most likely to respond to alectinib.  Biomarker samples collected during study conduct 
will be assessed to investigate possible correlation between levels of cfDNA with activity 
of alectinib or progression during treatment, and samples collected at progression will be 
analyzed in an effort to identify acquired resistance mechanisms to alectinib.


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Validated and approved diagnostic tests are required to identify patients with 
ALK-positive tumors who are eligible for alectinib treatment across tumor types.  
Currently available companion diagnostic tests for alectinib are approved only for 
NSCLC.  Therefore, approved tissue and plasma NGS assays to detect ALK-positive 
patients for alectinib treatment across tumor types are needed.  Patients may not have 
enough tumor tissue available to be tested for rare biomarkers such as ALK by tissue.  
Plasma ALK assays that analyze circulating tumor nucleic acids will enable more 
patients to be tested for ALK positivity.  Data generated in this study may support a 
possible registration of tissue and plasma NGS assays as CDx for alectinib across tumor 
types.
3.3.5
Rationale for Pharmacokinetic Sample Collection
To date, the pharmacokinetics of alectinib have been characterized in ALK-positive 
NSCLC patients.  The data collected from this study will enable the understanding of 
alectinib pharmacokinetics in this tumor-agnostic population and will allow researchers to 
investigate potential sources of variability influencing alectinib and/or response to 
alectinib therapy.
3.3.6
Rationale for Patient-Reported Outcome Assessments
The benefits associated with alectinib treatment in this patient population must be 
weighed with its potential impact on patients' health-related quality of life and function.
Patient-reported outcomes (PROs) provide a unique understanding of patients’ 
experience with the disease and associated treatment.  Therefore, the aim of the PRO 
endpoints in this study is to complement traditional efficacy and safety endpoints to 
inform the benefitrisk profile of alectinib in the tumor-agnostic setting.
The focus will be on capturing patients’ experience with symptoms commonly 
experienced as result of treatment intake or clinical progression.  Data will be collected 
using the European Organisation for the Research and Treatment of Cancer (EORTC)
QLQ-C30 (Aaronson et al. 1993).  In addition, in order to inform pharmacoeconomic 
modeling, health status utility scores will be collected using the EQ-5D-5L Questionnaire 
will be used (EuroQol Group 1990; Herdman et al. 2011; Janssen et al. 2013; Devlin and 
Brooks 2017).
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 50 patients with ALK-fusion solid tumors will be enrolled. In addition, 
patients with CUP, CNS primary tumor, and tumors harboring ALK mutations will be 
allowed in this study.


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4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age18 years at time of signing Informed Consent Form

Histologically confirmed locally advanced or metastatic solid tumor excluding lung 
cancer

ALK-positive tumor per FMI NGS (NGS F1CDx, F1LCDx, or F1HEME) or per local 
accredited laboratory using validated NGS testing of tumor tissue or peripheral 
blood:
– ALK fusion
– The following ALK-activating mutations:  R1275Q, F1245C, or F1174X
– Local ALK test report (only for cases with local ALK testing; see Section 4.6.5.3)

Disease progression on prior treatment, or previously untreated disease with no 
available acceptable treatment

Other prior cancer therapies are allowed, including investigational drugs, if any 
treatment-related toxicities (excluding alopecia) have resolved to Grade 1 or better
and laboratory values as defined in inclusion criteria, and meet the following 
washout criteria prior to first dose of alectinib:
– At least 4 weeks must have elapsed since the last dose of the prior cytotoxic 
chemotherapy or antibody-directed therapy.
– At least 7 days must have elapsed since prior tyrosine kinase inhibitor (TKI)
therapy.
– At least 14 days must have elapsed since prior radiotherapy.

Measurable disease at baseline, as assessed by investigator (by RECIST v1.1, or 
according to RANO criteria for patients with primary CNS tumors)
For primary CNS tumors, only MRI scans will be accepted.  If the local radiology 
facility cannot perform MRI, the patient will be excluded from the study.

Life expectancy of at least 12 weeks in the opinion of the investigator

Eastern Cooperative Oncology Group (ECOG) Performance Status of 02
(see Appendix 3)

Adequate hematologic function:
–
Platelet count 100 109/L
–
Absolute neutrophil count 1500/L
–
Hemoglobin 9 g/dL

Adequate hepatic function:
–
ALT (SGPT) and AST (SGOT) 2.5upper limit of normal (ULN) (5ULN for 
patients with concurrent liver metastasis)
–
Bilirubin 2 mg/dL


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
Adequate renal function:
–
Serum creatinine 2 ULN
–
Calculated creatinine clearance of 60 mL/min (Cockcroft-Gault formula)

Patients with primary CNS tumors are eligible

Patients with CUP tumors are eligible

Patient with brain or leptomeningeal metastasis are allowed in the study if 
asymptomatic and if they meet the following criteria:
–
No neurological signs and clinically stable for at least 2 weeks without 
corticosteroid treatment for brain metastasis prior to first dose of alectinib
–
If previously treated with whole-brain radiotherapy or gamma-knife 
radiosurgery, treatment must have been completed at least 2 weeks prior to 
first dose of alectinib

Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests and other study procedures

Willingness to comply with home-based approach and visits by mHCPs

Ability to swallow alectinib capsules intact (without chewing, crushing, or opening)

Women of childbearing potential must have a negative serum pregnancy test result 
during screening and a negative urine pregnancy test at baseline before first dose of 
study drug is administered (unless a negative serum test was obtained within 
10 days of first dose of study drug, in which case the urine pregnancy test is not 
required)

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for at least 90 days after the last dose of 
alectinib.  Women must refrain from donating eggs during this same period.
Women must remain abstinent or use contraceptive methods with a failure rate of 
1% per year during the treatment period and at least 90 days after the final 
dose of alectinib.  Women must refrain from donating eggs during this same 
period.
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state (12 continuous months of amenorrhea 
with no identified cause other than menopause), and is not permanently infertile 
due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another 
cause as determined by the investigator (e.g., Müllerian agenesis).  The 
definition of childbearing potential may be adapted for alignment with local 
guidelines or regulations.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. Hormonal contraceptive methods must be supplemented by a barrier 
method.


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The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not adequate methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive methods, and agreement to refrain from donating sperm, as 
defined below:
With a female partner of childbearing potential who is not pregnant, men who are 
not surgically sterile must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of 1% per year during 
the treatment period and for least 90 days after the final dose of alectinib.  Men 
must refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for at least 90 days after the final dose of 
alectinib to avoid exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and 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.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 3 months after the final dose of alectinib

Lung cancer

Patients with one of the following ALK point mutations:  I1171X, G1202R, V1180L

Prior therapy with an ALK inhibitor

Liver disease characterized by any of the following:
–
Impaired excretory function or synthetic function or other conditions of 
decompensated liver disease such as coagulopathy, hepatic encephalopathy, 
hypoalbuminemia, ascites, or bleeding from esophageal varices
–
Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis:
Active viral hepatitis B is defined as having positive hepatitis B surface 
antigen (HBsAg).  Patients with past hepatitis B virus (HBV) infection or 
resolved HBV infection (hepatitis B core antibody [HBcAb]HBcAb positive, 
but negative HBsAg) are eligible only if the HBV DNA test is negative.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction (PCR) is negative for HCV RNA.

Known HIV infection

Patients with symptomatic bradycardia


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
Patients with symptomatic or unstable brain metastasis

Patients with primary CNS tumors are allowed

Malabsorption syndrome or any other condition that would interfere with 
enteral absorption

Incomplete recovery from any surgery prior to treatment

Any other malignancies within 5 years prior to enrollment, except the following:
–
Curative treated basal cell carcinoma of the skin, early gastrointestinal (GI) 
cancer by endoscopic resection, in situ carcinoma of the cervix, ductal 
carcinoma in situ, papillary thyroid cancer
–
Any cured cancer that is considered to have no impact on PFS or OS for the 
current ALK-positive solid tumor

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion 
of the study

History of hypersensitivity to alectinib or any of its excipients
This includes, but is not limited to, patients with galactose intolerance, a 
congenital lactase deficiency, or glucose-galactose malabsorption
4.2
SCREEN FAILURES
Individuals who do not meet the criteria for participation in this study (screen failure) may 
qualify for one screening opportunities (for a total of two screenings per individual) at the 
investigator's discretion.  The investigator will maintain a record of reasons for screen 
failure (see Section 4.6.1).
4.3
METHOD OF TREATMENT ASSIGNMENT
This is a Phase II, open-label, single-arm study.  Patients with both ALK fusion and 
selected ALK mutations will be enrolled in the study.
The decentralized study design minimizes the need for on-site visits for patients, thus 
making clinical trials more accessible to patients regardless of location.
Patients can be identified by means of one of the two following enrollment pathways:
1. The Precision Enrollment approach offered by FMI.  Briefly, when nonlung cancer 
samples are determined by FMI central testing to be positive for ALK, an FMI 
medical oncologist will contact the ordering physician (local oncologist) and provide 
information about the trial.  If this is of interest to both the physician and the patient, 
enrollment procedures will begin.
2. Patients with ALK-positive NGS test results obtained outside FMI’S Precision 
Enrollment may be identified and the local ALK NGS test report will be made 
available (see Section 4.6.6) and will be assessed by the investigator for eligibility.  
The study team and Medical Monitor are to be consulted.  If ALK positivity is not 


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accepted per the criteria, prospective FMI testing is required and the patient may be 
enrolled if assessed to be ALK-positive by FMI.
For sample requirements, see Section 4.6.6 and Appendix 2, Table 3.
For eligible and enrolled patients, the tumor tissue sample must be submitted (see 
Section 4.6.6 and Appendix 2, Table 3) for retrospective analysis by FMI using the
F1CDx assay.
Replacement of patients with ALK-fusion solid tumors assessed according to 
RECIST v1.1 will be allowed for enrolled patients that have not taken any dose of
alectinib.
4.4
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The IMP for this study is alectinib.
4.4.1
Study Treatment Formulation and Packaging
4.4.1.1
Alectinib
Alectinib will be supplied by the Sponsor as a capsule dosage form containing the active 
ingredient 9-ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-6,
11-dihydro-5Hbenzo[b]carbazole-3-carbonitrile hydrochloride.
Each capsule contains 150 mg of alectinib (as a free base) along with lactose 
monohydrate, carboxymethylcellulose calcium, hydroxypropyl cellulose, sodium lauryl 
sulfate, and magnesium stearate as excipients.
Alectinib will be supplied by the Sponsor as capsules in bottles.  Alectinib capsules 
should be stored in accordance with the storage instructions on the label.
For more information on the formulation and handling of alectinib, see the latest Alectinib 
Investigator's Brochure.
4.4.2
Study Treatment Dosage, Administration, and Compliance
Alectinib 600 mg (four 150-mg capsules) is to be administered orally BID with food. The 
capsules should not be opened, and the contents of capsules should not be dissolved.
A missed dose can be taken within 6 hours of the scheduled time. If the time since the 
missed dose is greater than 6 hours, or if the patient vomits, the patient should wait until 
the next schedule time and take the next scheduled dose. Patients should not take 
two doses at the same time to make up a missed dose.
Patient will be treated until disease progression, unacceptable toxicity, withdrawal from 
treatment, or death. Treatment beyond radiological progression is possible in the event 


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of isolated lesion progression if, in the investigator’s opinion, there is evidence of 
ongoing clinical benefit.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Cases of accidental 
overdose or medication error, overdose, medication error, drug abuse, or drug misuse, 
along with any associated adverse events, should be reported as described in 
Section 5.3.5.11.
Guidelines for dose modification and treatment interruption or permanent discontinuation 
for patients who experience adverse events are provided in Section 5.1.2.
4.4.3
Investigational Medicinal Product Handling and Accountability
The IMP required for completion of this study will be provided by the Sponsor. The 
study site (i.e., investigator or other authorized personnel [e.g., pharmacist or mHCP]) is 
responsible for maintaining records of IMP delivery, IMP inventory, IMP use by each 
patient, and disposition or return of unused IMP, thus enabling reconciliation of all IMP 
received. See the country-specific operations manual for additional details.
In order to ensure patient anonymization, the Sponsor will ship the IMP to a licensed 
pharmacy, which could be an independent vendor or the central site pharmacy.  The 
licensed pharmacy will dispense the IMP after investigator’s prescription and manage 
the IMP and associated shipments to the patient’s home; the process will be detailed in 
the country-specific operations manual as per local requirements.
The study site should follow all instructions included with each shipment of IMP.  The 
licensed pharmacy used for the study will acknowledge receipt of IMPs supplied by the 
Sponsor by returning the appropriate documentation form to confirm the shipment 
condition and content.  Any damaged shipments will be replaced.  The depot must 
confirm that appropriate temperature conditions have been maintained during transit, 
either by time monitoring (shipment arrival date and time) or temperature monitoring of 
the IMP. The IMP must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions, with 
access limited to authorized staff.
Investigator or delegate will be responsible for coordinating the shipment of IMP to the 
patient’s home prior to the date and time of the visit. Upon delivery, a telemedicine visit 
with the patient or patient caregiver will be conducted by the investigator or delegate to 
confirm that appropriate temperature conditions have been maintained during transit and 
that the IMP was received in good condition (i.e., no damage and unopened) according 
to the process described in the country-specific operations manual.


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Appropriate packaging will be delivered to patients’ homes, or as per local regulations, in 
order to return unused IMP after IMP accountability is performed by an mHCP or at the 
site, whichever is in agreement with the local requirements. The returned IMP will be 
stored at the depot until final disposition is confirmed by the study monitor or Sponsor.
4.4.4
Continued Access to Alectinib
The Sponsor will offer continued access to Roche IMP (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 Roche IMP (alectinib) 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 Roche IMP 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 Roche IMP (alectinib) after completing the study if
any of the following conditions are met:

The Roche IMP 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 wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the IMP or data suggest that the IMP
is not effective for the indication explored in this study

The Sponsor has reasonable safety concerns regarding the IMP as treatment for the 
indication explored in this study

Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.5
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 14 days 
prior to initiation of study drug to the treatment discontinuation visit occurring 28 days 
after last dose of study drug.  All such medications should be reported to the investigator
and recorded on the Concomitant Medications eCRF. Details about the product and the 


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number of doses will be reported for COVID-19 vaccines and for COVID-19 infection 
mitigation.
4.5.1
Permitted Therapy
The medications and/or treatments below are permitted:

Premedication with analgesics and/or anti-emetics may be administered at the 
discretion of the investigator.

Local therapy (e.g., stereotactic radiotherapy or surgery) may be given in patients 
with isolated asymptomatic CNS progression (e.g., new CNS oligometastases) after 
consultation with the Sponsor.

In certain instances, palliative radiotherapy to bone lesions and for purposes of pain 
control may be permitted, provided it does not interfere with the assessment of 
tumor target/non-target lesions, and is considered to be medically necessary by the 
investigator.  The sponsor must be notified if palliative radiotherapy is started.

If palliative radiation is indicated, palliative radiation may start within 24 hours of the 
last dose of alectinib, unless, in the judgment of the investigator, patient safety will 
require a longer washout period prior to palliative therapy.  Dosing of alectinib may 
resume with the resolution of any radiation toxicity to Grade 1 or better.

Inactivated vaccines are allowed.
4.5.2
Cautionary Therapy
Caution should be exercised when the following are co-administered with alectinib:

For medications that are substrates of P-gp transported or breast cancer resistance 
protein transporter, the investigator should carefully assess the risks against 
benefits when considering concomitant use of alectinib.  Alectinib has been shown 
to have potential for inhibition of those transporters.  Substrates with a narrow 
therapeutic index (e.g., methotrexate, digoxin) should be avoided.  If 
co-administration cannot be avoided, it is recommended that drug levels and/or 
signs for toxicity are carefully monitored (see Appendix 4).
4.5.3
Prohibited Therapy
Use of the following concomitant therapies (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, and nutritional supplements) is prohibited during 
the study except during follow-up period and for at least 14 days prior to initiation of 
alectinib treatment, unless otherwise specified.  Exceptions to restrictions of the 
therapies listed below may be made if the rationale is discussed and documented 
between the investigator and Sponsor’s clinical pharmacologist:

Systemic immunosuppressive drugs, cytotoxic or chemotherapeutic agents
Note: The use of systemic corticosteroids for the management of CNS 
metastases may be permitted after discussion with the Medical Monitor.

Additional investigational drug (excluding post-progression during survival follow-up)


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
Radiotherapy/radionuclide therapy, except for palliative radiotherapy to bone lesions 
or for pain control

If palliative radiation is indicated, alectinib should be interrupted for at least 24 hours 
before start of radiation treatment
Dosing of alectinib may resume with the resolution of any radiation toxicity to 
Grade 1 or better.
The list of medication provided above is not necessarily comprehensive.  If in doubt, the 
investigator may consult with the Medical Monitor when prescribing concomitant 
medications.
4.6
STUDY ASSESSMENTS
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.
In this decentralized model, all scheduled study activities, from signing of informed 
consent to scheduled safety visits and study closeout, will be executed remotely
whenever possible. Home-based visits and assessments will be performed by the 
investigator via telemedicine sessions, facilitated by mHCPs attending to the patient’s 
home. Investigator will be responsible for ensuring that all mHCPs are licensed, 
qualified, in good standing per applicable country-specific regulations and requirements, 
and that appropriate background checks have been performed. The responsibilities of 
the investigator in the oversight of study personnel are described in Appendix 9.
During scheduled visits, the mHCP will perform study assessments as directed remotely 
by the investigator.  In addition, as per schedule of activities (see Appendix 1), blood 
samples for hematological and chemistry laboratory assessments, as well as plasma 
samples for biomarker and PK analysis, will be obtained, processed, and sent to one or 
several laboratories or to the Sponsor or a designee for analysis.  The mHCP will also 
perform a dipstick urinalysis at the patient’s home.  The mHCP will document results as 
per local requirements.
Remote visits may be facilitated by the CRC. For virtual sites, the CRC will be the 
Science 37 CRC, while for physical sites, the investigator may delegate the CRC 
responsibilities to the mHCP or site personnel.  The CRC will be responsible for 
scheduling the home-based visits.
For tests that cannot be performed at home (such as scans for tumor assessments), 
arrangements will be made by the investigator, mHCP, or CRC for patients to visit a 
local facility that can perform the required tests.
All source data relevant to the study, including efficacy and safety parameters, will be 
kept at the site or captured using a validated platform (i.e., the Science 37 Platform) (see 
Section 7 for additional details).  The study data entered will be available in the eCRF 


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database (RAVE) to allow the Sponsor’s study team to perform data management and 
medical review, and generate queries accordingly.  Queries will be answered by the 
investigator or designee. Details related to source data, data capture, and cleaning can 
be found in the country-specific operations manual.
On-Study Visits:  Assessments and Procedures
Study visits will be performed at patients’ homes according to the schedule of activities 
as outlined in Appendix 1.
All necessary study supplies, including the study drug, will be shipped by secure courier 
to the patient’s home (or, alternatively, see Section 4.4.3) ahead of the scheduled study 
visits.  Return labels will be included so patients can return supplies to vendor once 
study participation is completed or upon discontinuation.
The CRC will schedule visits taking into consideration the patients’ availability and the 
allowed visit windows and will notify the investigator and mHCP, as applicable.  The 
coordinating responsible will set up the appointment for the investigator to perform the 
telemedicine remote visits and remind the patient of upcoming visits and procedures that 
will take place during the visit.  In addition, the coordinating responsible will provide 
remote coordination and technical assistance during all visits. The patient will be 
provided with a mobile device for the duration of the study to facilitate interactions with 
the investigator, the mHCP, and the coordinating responsible. See the country-specific 
operations manual for more details.
For tests that cannot be performed at home (such as scans for tumor assessments),
arrangements will be made for patients to visit a local facility that can perform the 
required tests.
Unscheduled visits will also be performed at patients’ homes if possible.  However, it 
may be necessary that patients visit a local laboratory/specialist or the local oncologist 
for safety reasons, as needed.  Records generated from these visits will be obtained and
sent to investigator or uploaded into the relevant data capture system for documentation 
and the investigator’s review.
For details on procedures and assessments to be performed at each visit, see the 
schedule of activities in Appendix 1.
The local oncologist or current treating physician will be informed in writing according to 
local requirements of all clinically relevant updates to the status of the patient by the 
CRC, in addition to communication between the investigator and the local oncologist or 
current treating physician when necessary.  This is to ensure continuity of care should 
the investigator require that the patient visits the local oncologist for safety reasons.


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If the investigator determines that the patient requires an in-person consultation with a 
medical provider (e.g., there is a new symptom or an adverse event that warrants an 
in-person evaluation), the patient will be referred to his or her oncologist or relevant 
specialist for an in-person examination.  With the patient’s medical records release 
authorization, designated study personnel will contact the facility that performed the 
in-person examination to obtain the resulting medical records and transcribe them on the 
eCRF for the investigator to review.
In the event that a scheduled home-based visit cannot be performed within the allowed 
window (see Appendix 1), the visit should be-rescheduled as soon as possible.  Should 
this not be feasible, the patient may be asked to visit his or her local oncologist to 
perform the necessary procedures (including laboratory tests) to ensure continuity of 
care.
4.6.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained by the site.  This study may use an electronic informed consent 
process if allowed by local regulations as described below.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a detailed record of 
all patients screened and document eligibility or record reasons for screening failure, as 
applicable.
This log will be maintained as described above.
Informed Consent Process
Patients will be asked to provide informed consent to allow screening procedures to 
begin.  Electronic signature or wet ink signature is acceptable as per local requirements.  
Electronic signature details can be found in the country-specific operations manual.
The potential study patient will review the documents (paper or electronic) and discuss 
them with the investigator via a telemedicine visit, during which all their questions about 
the study will be answered and all elements of the informed consent process will be 
covered.  Study coordinators will also facilitate the review of the inform consent with the 
patients.  During this discussion, the investigator will be able to evaluate the potential 
patient’s understanding by querying them about the objectives of the study, risks of 
participation, expectations, and other information present in the informed consent.  The 
investigator will provide clarifications and further explanation as needed.
After this discussion, the patient will be given the opportunity to independently consider 
participation in the study.  If willing to participate, the patient will provide a handwritten


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signature directly recorded electronically in the designated signature block using a 
computer mouse, touchscreen, or stylus depending on the capability of his or her device
or wet ink signature, as per local regulations.  The investigator will countersign in the 
same manner, also as per local regulations and in a timely manner.  The patient will be 
provided with a copy (electronic or paper) of the fully executed informed consent 
documents, and the informed consent process will be documented and maintained at the
site as part of source documentation as required per regulation.
In addition, if consented patients are located in the United States, the patient will sign the 
Authorization to Use and Disclose Protected Health Information and, for patients in 
California, an Experimental Research Subject Bill of Rights document. An equivalent 
document may apply to other countries and will be used accordingly (see the 
country-specific operations manual for details).
A screening visit will be scheduled after inform consent is obtained.  The CRC will 
register the patient in the Sponsor-provided system.  A mHCP will complete screening 
procedures at the patient’s home, with the investigator participating via a telemedicine
and a coordinating responsible providing remote coordination and technical assistance 
during the visit if applicable and required (see country-specific operations manual for 
details).  Various procedures may be completed on different days to accommodate the 
patient’s and mHCP’s schedules, as long as they are completed within the screening 
visit window.  Specific screening procedures and assessments are outlined in the 
schedule of activities (see Appendix 1).
The investigator, mHCP, and the CRC will enter data collected during screening on the 
eCRF, and the investigator will review the data to confirm the patient’s eligibility 
according to the inclusion and exclusion criteria (see Section 4.1).
4.6.2
Medical History, Baseline Conditions, Concomitant Medication,
and Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), female reproductive status, and 
smoking history, will be recorded at baseline.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 14 days prior to initiation of 
study treatment will be recorded.  At the time of each follow-up physical examination, an 
interval medical history should be obtained and any changes in medications and 
allergies should be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.6.3
Physical Examinations
A complete physical examination, performed during screening, should include an 
evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 


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dermatologic, musculoskeletal, respiratory, GI, genitourinary, and neurologic systems.  
Any abnormality identified as baseline condition should be recorded on the General 
Medical History and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations should be performed at specified 
baseline and post-baseline visits and as clinically indicated.  Changes from baseline 
abnormalities should be recorded in patient notes.  New or worsened clinically significant 
abnormalities should be recorded as adverse events on the eCRF.
For patients with primary CNS tumors, a neurological examination must be performed at 
each tumor assessment visit and compared to the neurological examination performed 
at the time of the previous disease assessment.  This will allow the evaluation of 
responses in these patients according to RANO criteria.  Definition of clear neurological 
worsening is difficult to describe because progression in the CNS can present in 
numerous ways.  Accordingly, evaluation of neurological function at each disease 
assessment will be based purely on the mHCP’s and investigator’s assessment of the 
patient’s neurological state compared with the neurological function at the time of the 
previous disease assessment.  Neurological status will be recorded as “stable or 
improved” or “worsened” on the RANO response pages.
Telemedicine Physical Examinations (if applicable)
Physical examinations for this study will be conducted via telemedicine, which is 
permitted in the recruitment countries/states selected for this study.  The investigator,
assisted by a mHCP, will conduct physical examinations of study patients via 
telemedicine during a videoconference session.
As part of this examination, under the direction of the investigator present over 
telemedicine, a mHCP will assist in performing the physical examination required per 
protocol at the patient’s home.
4.6.4
Vital Signs
Vital signs will be reported on the eCRF and will include measurements of respiratory 
rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated 
position, weight, and temperature. New or worsened clinically significant abnormalities 
will be reported as adverse events on the eCRF.
Vital sign measurement will be performed by an mHCP professional.
4.6.5
Tumor and Response Evaluations
All known and suspected sites of disease must be assessed and documented at 
screening and re-assessed at each subsequent tumor evaluation according to the 
schedule of activities (see Appendix 1) until investigator-assessed radiographic disease 
progression (or loss of clinical benefit in case treatment continues beyond disease


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progression), withdrawal of consent, study termination by the Sponsor, or death, 
whichever occurs first.
Tumor assessments will be performed during screening and every 8 weeks (calculated 
from baseline) during study conduct and will consist of CT and brain MRI scans (or brain 
CT scans if MRI is not feasible).
Because imaging scans cannot be performed at home, arrangements will be made for 
patients to visit a local imaging facility that can perform the required tests. Patients will 
use the same imaging facility for the duration of their participation in the study. The CRC 
will coordinate with the patient and imaging facility to schedule imaging procedures
according to the schedule of activities (see Appendix 1). The local imaging facilities will 
be instructed regarding and if required, trained on the methodology required for disease 
assessments to be performed according to RECIST v1.1 or RANO criteria, as 
applicable.
Methods:

CT scans:  CT scans should be performed with oral or IV contrast unless 
contraindicated and have a maximum slices thickness of 5 mm

MRI scans, with minimum sequences consisting of the following:
–
Pre-contrast T1, T2/fluid-attenuated inversion recovery
–
Post-contrast T1, with two orthogonal planes (or a volume acquisition) 
recommended

Recommended slice thickness:  5 mm with no gap
Imaging facilities should perform scans according to requirements specified above and 
should apply the same radiographic procedure used to define measurable disease at 
screening throughout the study for consistency. The scans and radiology report will be 
submitted to Science 37 and the investigator as soon as possible to allow treatment 
decisions in a timely manner.
Response will be assessed by the investigator on the basis of the CT and MRI scans 
according to RECIST v1.1 (see Appendix 5) or, for patients with primary CNS tumors, 
RANO criteria, which include neurological examination and corticosteroid use (see 
Appendix 6).
In addition, scans will be sent for BICR for assessment of responses according to 
RECIST v1.1 and, for patients with primary CNS tumors, according to RANO criteria.
Assessments performed by BICR will not be shared with the investigator and will have 
no impact on the management of the patient.


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Tumor assessments performed as standard-of-care prior to obtaining informed consent 
and within 28 days prior to the first dose may be considered as baseline assessment if 
they satisfy the protocol criteria.
Scheduled tumor assessments should be kept according to the original scheduled based 
on the date of first dose administration, regardless of clinical visits delays and drug 
interruptions. At the investigator’s discretion, tumor assessment may be repeated at any 
time if progressive disease is suspected (for example, in case of symptomatic 
deterioration).
An objective response should be confirmed by repeat assessments at least 4 weeks 
after initial documentation.  No additional assessment is planned for 4 weeks after the 
initial response, but every effort should be made to obtain confirmation of response, 
even if a patient who has initially responded is withdrawn from study treatment for any 
reasons other than progression or death.
Patients who discontinue study treatment for any reason other than progression of 
disease or death should continue to have regular disease assessments every 8 weeks 
per the schedule of assessments (see Appendix 1) until progression.
4.6.5.1
Non-Primary CNS Tumors Assessments
Screening assessments for non-primary CNS tumors should include CT scans (with oral
or IV contrast unless contraindicated) of the chest, abdomen, and pelvis (if applicable), 
and be consistent with standard imaging required for the malignancy under 
consideration. An MRI scan of the head must be performed at screening to assess CNS 
metastases.  Patients with known or suspected bone metastases should undergo 
radionuclide bone scan at screening. Bone scans, positron emission tomography (PET)
scans, 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 meets the definition of measurability.
In the event that a CT PET/CT scanner is used for tumor assessments, the CT portion of 
the PET/CT scan must meet the criteria for diagnostic quality.
In the event that the local imaging facility cannot perform MRI, CT scans of the head 
may be performed instead.
Patients without brain or bone disease at baseline do not need brain or bone scans at 
subsequent tumor assessments unless clinically warranted.


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4.6.5.2
Primary CNS Tumors Assessments
For patients with primary CNS tumors, all assessments must be performed by MRI.  If 
the local radiology facility cannot perform MRI, the patient cannot be enrolled in the 
study.
4.6.5.3
Corticosteroid Use for Primary CNS tumors
For patients with primary CNS tumors, corticosteroid intake should be captured at all
tumor assessment visits and compared with corticosteroid intake at the time of the 
previous tumor assessment.  The changes will be recorded as “stable or decreased” or 
“increased” on the RANO response pages.  Increases and decreases in corticosteroid 
intake should be clinically justified.  Increases in corticosteroid dose for reasons other 
than for CNS disease control do not need to be taken into consideration when making 
this comparison.
4.6.6
Laboratory, Biomarker, and Other Biological Samples
The following laboratory tests will be performed centrally or locally (refer to the 
country-specific operations manual):

Hematology: hemoglobin, hematocrit, platelet count, RBC count, WBC count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, and lymphocytes)

Coagulation: PT or INR, and aPTT or PTT

Chemistry panel: Sodium, potassium, chloride, glucose, creatinine, creatinine 
clearance (according to Cockcroft and Gault method), gamma-glutamyl transferase, 
total protein, albumin, phosphorus magnesium, calcium, total and direct bilirubin, 
ALP, CPK, ALT, AST, uric acid, and BUN or urea

Pregnancy test
All women of childbearing potential will have a serum pregnancy test at 
screening. A urine pregnancy test must also be obtained at baseline before 
first dose of study drug is administered (unless a negative serum test was 
obtained within 10 days of first dose of study drug, in which case the urine 
pregnancy test is not required). Urine pregnancy tests will be performed at 
specified subsequent visits as per the schedule of activities (see Appendix 1).  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy 
test.

Urinalysis, using dipstick (pH, specific gravity, glucose, protein, ketones, blood)
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis:

Plasma sample for PK analysis
PK plasma samples will be taken during screening or before the first dose.
At subsequent visits, the time of sample draw and the time of the last dose 
must be captured in the eCRF. For each sample, approximately 2 mL of 
venous blood will be collected for alectinib PK analysis at the timepoints 
specified in the PK schedule in Appendix 2. Patients who permanently 


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discontinue alectinib will also discontinue from all PK sampling and 
assessments. Plasma concentrations of alectinib and its metabolite(s), as 
applicable, will be measured by a specific, validated liquid 
chromatography-tandem mass spectrometry assay.
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.

Plasma samples for exploratory research on biomarkers
Biomarker plasma sampling and tissue collection will be in accordance with the 
Institutional Review Board/Ethics Committee (IRB/EC)-approved Informed 
Consent Form and applicable laws (e.g., health authority requirements).
Plasma samples, including those collected from patients who do not enroll in 
the study, may be used for future research and/or development of 
disease-related tests or tools. Blood will be collected to prepare for cfDNA 
analysis at the required timepoints (see Appendix 2).

Tumor tissue sample from patients with F1LCDx and F1HEME results will be 
analyzed retrospectively by F1CDx tissue NGS (see Appendix 2, Table 3).

Tumor tissue sample from patients enrolled with local ALK-positive NGS testing will 
be analyzed retrospectively by F1CDx tissue NGS. Plasma may be accepted in 
absence of tissue for the analyses.  The Medical Monitor is available to advise as 
needed. Information about the local laboratory report (laboratory name, sample type, 
date, test type, result) will be collected (see Appendix 2, Table 3).

Tumor tissue for the prospective determination of the ALK status in case of an 
unacceptable per protocol criteria local ALK test result
The tumor samples must be formalin-fixed, paraffin-embedded (FFPE) tissue blocks with 
greater than 20% tumor content. Blocks are preferred. If blocks cannot be sent, 
11 slides cut at 45um thick may be submitted.  The Medical Monitor is available to 
advise as needed.
Tumor tissue should be of good quality based on total and viable tumor content.  
Samples must contain a minimum of 50 viable tumor cells that preserve cellular context 
and tissue architecture regardless of needle gauge or retrieval method. Samples 
collected by means of resection, core-needle biopsy (at least three cores, embedded in 
a single paraffin block), or excisional, incisional, punch, or forceps biopsy are 
acceptable.  Tumor tissue from bone metastases that have been decalcified is not 
acceptable.
NGS may be performed by Foundation Medicine if local ALK testing is not under the 
protocol criteria (i.e., by immunohistochemistry).  If performed by means of prospective 
testing by Foundation Medicine, the investigator may obtain an NGS report through 
Foundation Medicine's web portal.  If allowed by local laws, the investigator may share 


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and discuss the results with the patient, unless the patient chooses otherwise.  The NGS 
report is generated for research purposes and is not provided for the purposes of guiding 
future treatment decisions.  Results will not be available for samples that do not meet 
criteria for testing.
Using FMI for retrospective analysis of tissue, the CDx program will be performed 
according to local regulations.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.6.9), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exceptions:

Plasma samples collected for PK analysis will be destroyed no later than 5 years 
after the final Clinical Study Report has been completed.

Tumor and plasma samples (and their derivatives) collected for biomarker research 
will be destroyed no later than 5 years after the final Clinical Study Report has been 
completed.

For enrolled patients, remaining archival tissue blocks will be returned upon request 
or no later than the time of final closure of the study database, whichever occurs 
first.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
Given the complexity and nature of exploratory biomarker analyses, data derived from 
these analyses will generally not be provided to investigators or patients unless required 
by law.  The aggregate results of any conducted research will be available in accordance 
with the effective Sponsor policy on study data publication.
Special Considerations for Blood Sampling
An mHCP, who may be a phlebotomist, will draw blood and process samples at the 
patient’s home per laboratory manual using the laboratory kits provided by the central 
laboratory (at scheduled or unscheduled home visits).  Samples will be centrifuged as 
necessary and shipped to the central laboratory for analysis, along with the original 


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completed laboratory transmittal form (a copy of the form will be sent to Science 37, and 
a photograph of the original will be uploaded into the Science 37 Platform).
Sharps and used tubes will be placed into sharps containers and shipped by the mHCP
for appropriate destruction.  Results reported by the central laboratory will be uploaded 
into the eCRF for review, assessment, and documentation by the investigator.
In the event that local laboratories are used (for example if patient is required to visit 
local specialists or the local oncologist), the results will be obtained and uploaded on the 
eCRF by the CRC for documentation and the investigator’s review.
4.6.7
Electrocardiograms
Single ECG recordings will be obtained at screening, baseline, and at the treatment 
discontinuation visit. ECGs will also have to be obtained if bradycardia with a resting 
heart rate below 60 bpm is observed and during study conduct as clinically indicated.
The mHCP will perform an ECG at the patient’s home per the schedule of activities, 
including handling electrodes and leads placement, confirming lead quality tracing with 
the investigator, and capturing the ECG tracing. After the mHCP performs the ECG, the 
tracing is automatically captured by the vendor’s ECG portal.
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws). 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.
The investigator will assess the quality of the tracing in real time by accessing the ECG 
portal. The CRC will upload the final report in the eCRF for final sign-off by the 
investigator. The following should be recorded in the eCRF: heart rate, RR interval, 
QRS interval, PR duration, uncorrected QT interval, and QT interval corrected through 
use of Fridericia's formula (QTcF) based on the machine readings of the individual ECG 
tracings, together with any morphologic waveform changes or other ECG abnormalities. 
The investigator may consult with a cardiologist as required. Copies of ECG tracings will 
be kept in the Science 37 Platform as part of the patient's permanent study files. If 
considered appropriate by the Sponsor, ECGs may be analyzed retrospectively at a 
central laboratory.
If the mean QTcF is500 ms and/or 60 ms longer than the baseline value, another 
ECG must be recorded, ideally within the next 5 minutes and ECG monitoring should 
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may be instituted per the discretion of the investigator. The investigator should evaluate 
the patient for potential concurrent risk factors (e.g., electrolyte abnormalities, 
co-medications known to prolong the QT interval, severe bradycardia).
If any ECG abnormality is associated with an adverse event, it must be recorded and 
managed as described in Section 5.1.2.
4.6.8
Clinical Outcome Assessments
PRO questionnaires will be completed to assess the treatment benefit of alectinib.  In 
addition, PRO questionnaires will allow to capture each patient's direct experience with 
alectinib.
PRO data will be collected through use of the following instruments:  EORTC QLQ-C30 
and EQ-5D-5L.
4.6.8.1
Data Collection Methods for Clinical Outcome Assessments
PRO questionnaires will be collected on paper by the mHCP at the patient’s home 
during the visit as per scheduled of activities (Appendix 1).  The completion of the 
questionnaire will be performed independently by patients at the start of the visit, before 
discussion with patients about any results, or health status, and prior to any other study 
assessments that could bias patient’s responses to ensure validity of the questionnaire 
is not compromised and that data quality meets regulatory requirements.
The PRO questionnaires will be collected at baseline and subsequently as per schedule 
of activities until the treatment discontinuation visit, withdrawn of consent, death, or 
study termination, whichever occurs first.
PRO questionnaires will be made available in different languages and will be provided 
by the Sponsor.
Patients should be given the following instructions for completing PRO questionnaires at 
home:

Patients should complete the instruments in a quiet area with minimal distractions 
and disruptions.

Patients should answer questions to the best of their ability; there are no right or 
wrong answers.

Patients should not obtain advice or help from others (e.g., mHCP, family members,
or friends) when completing the instruments.
4.6.8.2
Description of Clinical Outcome Assessment Instruments
EQ-5D-5L
The EQ-5D-5L is a validated self-reported health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses (EuroQol 
Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013) (see Appendix 7).  


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There are two components to the EQ-5D-5L:  a five-item health state profile that 
assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, as 
well as a VAS that measures health state.  The EQ-5D-5L is designed to capture the 
patient's current health status.  Published weighting systems allow for creation of a 
single composite score of the patient's health status.  The EQ-5D-5L takes 
approximately 3 minutes to complete.  It will be used in this study for informing 
pharmacoeconomic evaluations.
EORTC QLQ-C30
The EORTC QLQ-C30 is a validated, reliable self-reported questionnaire (Aaronson 
et al. 1993) (see Appendix 8).  It consists of 30 questions that assess five aspects of 
patient functioning (physical, emotional, role, cognitive, and social), eight symptom 
scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, 
constipation and diarrhea) and global health/quality of life, with a recall period of the 
previous week.  The EORTC QLQ-C30 module takes approximately 10 minutes to 
complete.
4.6.9
Optional Samples for Research Biosample Repository
4.6.9.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples 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.
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

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
4.6.9.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by the IRB/EC and, if applicable, an appropriate regulatory body.  Only if the IRB/EC has 


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granted approval for RBR sampling, this section of the protocol (Section 4.6.9) will be 
applicable.
4.6.9.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to ALK-positive solid tumors, 
diseases, or drug safety:

Leftover plasma collected for biomarkers and leftover tissue samples (with the 
exception of remaining archival tissue blocks, which will be returned) and any 
derivatives thereof (e.g., DNA, RNA, proteins, peptides)
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods.  Genomics is increasingly informing 
researcher's understanding of disease pathobiology.  WGS and WES provide a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events.
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
All RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.6.9.4
Confidentiality
All RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR samples 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.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to investigators or patients 


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unless required by law.  The aggregate results of any conducted research will be 
available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.6.9.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent 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 RBR samples.  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 and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.
4.6.9.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the study, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email
address:
global_rcr-withdrawal@roche.com


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A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.6.9.7
Monitoring and Oversight
All RBR samples 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 samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  Site will permit monitoring, audits, IRB/EC review, and 
health authority inspections by providing direct access to source data and documents 
related to the RBR samples.
4.7
TREATMENT, PATIENT, AND STUDY DISCONTINUATION
Patients will continue on study treatment until disease progression, discontinuation, 
withdrawal of consent, or death, whichever occurs first.
Treatment beyond radiological progression is possible in the event of isolated lesion 
progression if, in the investigator’s opinion, there is evidence of ongoing clinical benefit.
In the event of a patient’s voluntary withdrawal of consent, the investigator will make a 
reasonable effort to document the reported reason for consent withdrawal in the eCRF.
All efforts will be made to complete the assessments prior to study withdrawal, as 
detailed in the protocol.
For patients whose status is unclear because they fail to communicate with the study 
personnel without confirming discontinuation or withdrawal, study personnel will show 
due diligence by documenting all actions taken to contact the patient (e.g., dates of 
telephone calls, registered letters, etc.).
Patients will not be considered as lost to follow-up until due diligence has been 
completed or until the end of the study.
4.7.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy


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
Use of an anti-cancer therapy not required per protocol

Symptomatic deterioration attributed to disease progression

Any event that meets stopping criteria defined in Section 5.1.2
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.  Patients with ALK-fusion tumors who are enrolled in the study and do not 
receive any dose of study treatment will be replaced.
The mHCP will perform a treatment discontinuation visit 28 days after the final dose of 
alectinib for safety assessments as described in the schedule of activities (see 
Appendix 1).
If alectinib is prematurely discontinued for reasons other than disease progression, 
off-treatment disease assessments must continue until radiological progression of the 
disease as per schedule of activities (see Appendix 1). Following progression, patient 
status, and subsequent therapies will be captured as long-term follow-up every 3 months 
until death, patient withdrawal of consent, or termination of the study, whichever occurs 
first.
4.7.2
Patient Discontinuation from the Study
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 patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination

Adverse event

Patient loss to follow-up

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the eCRF.
Patients who wish to discontinue alectinib prematurely remain in the study. If patients 
wish to stop scheduled assessments after alectinib discontinuation, they will be asked to
be contacted regularly for long-term follow-up.


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If a patient requests to be withdrawn from the study completely, this request must be 
documented in the source documents and signed by the investigator.  Patients who 
withdraw from the study will not be replaced.
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status.
4.7.3
Study 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.
4.7.4
Site Discontinuation
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 ICH guideline for Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients receiving alectinib in this study is based on clinical 
experience and results from completed and ongoing studies in the metastatic setting as 
well as postmarketing experience with patients with NSCLC. For a complete summary 
of safety information, refer to the Alectinib Investigator’s Brochure.
During the study visits conducted in the patient’s homes, the following parameters will be 
evaluated and the investigator will use results of these procedures to assess safety 
throughout the study:

Physical examinations (directed by the investigator via videoconference with the 
assistance of a mHCP)

Vital signs and weight

Laboratory tests

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Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Patients will undergo safety monitoring during study, including assessment of 
the nature, frequency, and severity of adverse events.  In addition, guidelines for 
managing adverse events, dosage modification and treatment interruption or 
discontinuation are provided below.
5.1.1
Risks Associated with Alectinib
Events described in this section will be closely monitored and represent selected 
adverse events for this study.
5.1.1.1
Interstitial Lung Disease and Pneumonitis
Cases of interstitial lung disease and pneumonitis, some leading to acute respiratory 
distress syndrome or death, have been associated in patients receiving TKIs, including 
ALK inhibitors.  Signs and symptoms may include dyspnea, cough, fatigue, and 
pulmonary infiltrates.  Patients with dyspnea at rest due to complications of advanced 
malignancy and comorbidities may be at higher risk of pulmonary events.
Guidelines for management and follow-up of patients who develop ILD or pneumonitis 
are provided in Table 1.
5.1.1.2
Hepatotoxicity
Hepatobiliary findings were observed in both rat and monkey 4- and 13-week toxicity 
studies with alectinib at or close to clinically relevant exposures. Hepatobiliary effects 
included increased hepatic ALP, direct bilirubin, gamma-glutamyl transferase and liver 
weight, vacuolation, degeneration, and necrosis of the 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 in patients.  AST, ALT, and 
total bilirubin levels temporarily increased in the initial stages of treatment and then 
improved.  In patients with Grade 3 and 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 3ULN and total 
bilirubin 2ULN, with normal ALP, occurred with uncommon frequency in patients 
treated in alectinib clinical trials.
In patients treated with other tyrosine kinase ALK-inhibitor drugs, abnormal liver function 
tests and drug-induced hepatotoxicity, including cases with fatal outcome, have been 
reported.
Guidelines for management and follow-up of patients who develop hepatotoxicity are 
provided in Table 1.


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5.1.1.3
Anemia, Including Hemolytic Anemia
Hematologic findings were observed in both rat and cynomolgus monkey 4- and 
13-week toxicity studies with alectinib. The findings were at or close to clinically relevant 
exposures.  Changes in red blood cell morphology (e.g., poikilocytosis, red cell 
fragmentation) and in the erythroid system's other parameters (e.g., reticulocyte count, 
hemoglobin, hematocrit, mean corpuscular volume) were seen with alectinib, but these 
changes were very slight, considered reversible, and did not exacerbate with prolonged 
alectinib administration.
Cases of anemia, including hemolytic anemia, have been reported in patients treated 
with alectinib; the majority of the events were Grade 1 and 2.
Guidelines for anemia (including hemolytic anemia), adverse events' management, and 
follow-up are provided in Table 1.
5.1.1.4
Gastrointestinal Disorders
Gastrointestinal disorders such as nausea, vomiting, constipation, diarrhea, and 
stomatitis have been reported with alectinib.  Similar GI disorders have been observed 
with other TKIs, including ALK inhibitors.
Sodium lauryl sulfate (SLS) is a surfactant excipient in the clinical formulation at a 
concentration of 50% (weight per weight SLS to active pharmaceutical ingredient).  This 
excipient is a known GI irritant and may be associated with GI adverse events, including 
nausea, vomiting, diarrhea, and abdominal pain. Of note, GI tract toxicity due to SLS is 
not because of systemic toxicity but is a consequence of local irritation to the GI tract. In 
general, tolerability is improved when SLS is administered together with food.
Guidelines for management and follow-up of patients who develop GI disorders are 
provided in Table 1.
5.1.1.5
Skin Disorders
Skin rash has been reported with the majority of TKIs, including those targeting the ALK 
receptor (Hartmann et al. 2009).
Results of an in vitro phototoxicity study indicated that alectinib may have phototoxic 
potential, and cases of skin rash and photosensitivity (generally Grades 1 and 2) have 
been reported with alectinib.
Guidelines for management and follow-up of patients who develop skin disorders are 
provided in Table 1.
5.1.1.6
Vision Disorders
In the rat quantitative whole body autoradiography study, tissue radioactivity 
disappeared over time, following a time course comparable with that of plasma 
radioactivity, except for melanin-containing tissues such as uveal tract of eyes, which 


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had much higher and more sustained exposure in pigmented rats.  This is consistent 
with what is commonly observed with 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 blurred vision, visual impairment, vitreous floaters, reduced 
visual acuity, asthenopia, and diplopia, have been reported with alectinib and were 
generally Grades 1 and 2.
Guidelines for management and follow-up of patients who develop vision disorders are 
provided in Table 1.
5.1.1.7
Edema
Most TKIs, including ALK-inhibitor crizotinib, have been associated with edema.  Events 
of edema (mainly peripheral edema) have been reported with alectinib, mostly Grades 1 
and 2.
Guidelines for management and follow-up of patients who develop edema are provided 
in Table 1.
5.1.1.8
Bradycardia
In the cynomolgus monkey telemetry study, there were no effects on the ECG, any of 
the other cardiovascular parameters, or body temperature at doses of up to 15 mg/kg 
alectinib.
In a preliminary nonGood Laboratory Practice telemetry study in conscious cynomolgus 
monkeys, there were no effects of alectinib on ECG or heart rate observed.
Events of bradycardia have been reported with alectinib.  Data based on ECG and pulse 
measurements from alectinib clinical trials show a decrease in heart rate during alectinib 
treatment, which is mainly asymptomatic.  In patients treated with other ALK inhibitors 
(crizotinib and ceritinib), bradycardia adverse events, as well as decreases in heart rate 
based on ECG and pulse measurements, have also been reported (Xalkori U.S. 
Package Insert; ZykadiaU.S. Package Insert).
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.
In case of bradycardia adverse event related to alectinib, refer to adverse event
grade-dependent rules for dose modification outlined in Table 1.


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5.1.1.9
Abnormal Renal Function (Serum Creatinine Increased, Acute 
Kidney Injury)
In the 2-week, nonclinical primate study at 60 mg/kg alectinib, an increase in creatinine 
was observed, but no changes were observed in histopathology.  In all other nonclinical 
primate studies, no changes in creatinine were observed.
Serum creatinine increases have been reported with alectinib treatment with common 
frequency.  Acute kidney injury, including fatal outcome, has been observed with 
uncommon frequency in patients treated in alectinib clinical trials.
Serum creatinine increases and/or decreases in glomerular filtration rate, renal failure, 
and/or renal impairment have been reported for other ALK inhibitors.
Guidelines for management and follow-up of patients who develop abnormal renal 
function are provided in Table 1.
5.1.1.10
Severe Myalgia and CPK Elevations
Post-marketing experience with some TKIs includes reports of myopathy and 
rhabdomyolysis (Hohenegger 2012).
Blood CPK increases, generally Grades 1 and 2, and muscular adverse events have 
been reported with alectinib treatment. Grade 3 myalgia and CPK elevations were 
reversible upon dose reduction and interruption.
Guidelines for management and follow-up of patients who develop severe myalgia and 
CPK elevations are provided in Table 1.
5.1.1.11
Dysgeusia
Events of dysgeusia have been reported with ALK inhibitors. With alectinib, these are 
generally of Grades 1 and 2 severity.  All patients who experienced dysgeusia continued 
alectinib treatment without any dose modification.
In case of dysgeusia adverse event related to alectinib, refer to adverse event 
grade-dependent rules for dose modification outlined in Table 1.
5.1.1.12
Alkaline Phosphatase Increase
Cases of increased blood ALP have been observed after alectinib administration.  The 
majority of the cases were of Grades 1 and 2 severity.
In patients treated with other ALK inhibitors, increased blood ALP has been reported.
In case of ALP increase adverse event related to alectinib, refer to adverse event 
grade-dependent rules for dose modification outlined in the first section of Table 1.


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5.1.2
Management of Patients Who Experience Adverse Events
5.1.2.1
Dose Modifications
The dose of alectinib can be reduced in steps of 150 mg up to two times for the 
management of drug-related toxicities (i.e., from 600 mg BID to 450 mg BID, and then 
from 450 mg BID to 300 mg BID):
Dose Reduction Schedule
Dose Level
Dose
600 mg twice daily
First dose reduction
450 mg twice daily
Second dose reduction
300 mg twice daily
If further dose reduction is indicated after two dose reductions, the patient must 
discontinue alectinib.  Administration of a dose below 300 mg BID is not allowed in this 
study.
5.1.2.2
Treatment Interruption
Alectinib treatment may be temporarily suspended in patients who experience toxicity 
considered to be related to study drug.  If alectinib has been withheld for 21 days 
because of toxicity, the patient should be discontinued from alectinib, unless resumption 
of treatment is approved by the investigator following consultation with the Medical 
Monitor if needed.  Alectinib treatment may be suspended for reasons other than toxicity 
(e.g., surgical procedures), at the investigator’s discretion, following consultation with 
the Medical Monitor if needed.  The investigator may consult the Medical Monitor to 
determine the acceptable length of treatment interruption.


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5.1.2.3
Management Guidelines
Table 1
Guidelines for Management of Risks, Adverse Events, and 
Selected Laboratory Abnormalities with Alectinib
Event
Action to Be Taken
All AEs related a to 
alectinib (unless otherwise 
specified in this table)
hepatotoxicity AEs 
(irrespective of 
relatedness)
Grade 4:
Temporarily interrupt alectinib for a maximum of 21 days after 
which the drug must be permanently withdrawn. 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.
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.
Third episode:  Permanently discontinue alectinib.
Please note that dose should not be reduced below 300 mg BID.
Grade 3:
Temporarily interrupt alectinib for a maximum of 21 days after 
which drug must be permanently withdrawn.
First episode:  If improvement to Grade ≤1 or baseline occurs 
within 10 days alectinib may be restarted at the original dose or 
dose reduced by 150 mg (1 capsule) at the investigator’s
discretion.  If improvement to Grade ≤1 or baseline occurs after 
10 days but within 21 days then alectinib dose must be decreased 
by 150 mg (1 capsule BID).
Second episode:  If improvement to Grade ≤1 or baseline occurs 
within 21 days, decrease the current dose of alectinib by 150 mg 
(1 capsule) BID.
Third episode: Permanently discontinue alectinib.
Grade 2:
To be managed at the investigator’s discretion.  Please note that 
alectinib cannot be interrupted for more than 21 days and cannot 
be dose reduced below 300 mg BID.
Grade 1:  No action required
Interstitial lung disease/ 
pneumonitis
Patients should be monitored for pulmonary symptoms indicative of 
interstitial lung disease/pneumonitis.
Regardless of relatedness to alectinib, study drug should be 
permanently discontinued in patients diagnosed with interstitial lung 
disease/pneumonitis of any grade.
Hepatotoxicity
Liver test laboratory abnormalities are to be reported as AEs only if 
fulfilling the criteria listed in Section 5.3.5.4 and Section 5.3.5.6.
At any time during the study treatment, if symptoms compatible with 
liver injury are observed, liver enzymes should be measured as 
soon as possible.


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Table 1
Guidelines for Management of Risks, Adverse Events, and 
Selected Laboratory Abnormalities with Alectinib (cont.)
Event
Action to Be Taken
Hepatotoxicity (cont.)
Regardless of relatedness to alectinib, the grade-dependent 
rules for dose interruptions and dose modification outlined in the 
first section of this table must be followed.
In addition, 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 pretreatment 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, stomatitis)
The events are expected to be minimized by taking the study drug 
with a meal.  If GI events occur, appropriate measures should be 
taken in accordance with local clinical practice guidelines.
In case of AEs related to alectinib, follow the grade-dependent 
rules for dose interruption and modification outlined in the first 
section of this table.
Skin disorder AEs 
(e.g., phototoxicity, rash)
Patients should be advised to avoid prolonged sun exposure while 
taking alectinib and for at least 7 days after study drug 
discontinuation.  Patients should also be advised to use a 
broad-spectrum sunscreen and lip balm of at least SPF 50 to help 
protect against potential sunburn during this period.
In case of AEs related to alectinib, follow the grade-dependent 
rules for dose interruption and modification outlined in the first 
section of this table.
Vision disorders
Investigators should consider referring the patients for an 
ophthalmologic evaluation according to local clinical practice 
guidelines if vision disorders persist or worsen in severity and to 
advise patients to exercise caution when driving or operating 
machinery due to the risk of developing a vision disorder.
In case of AEs related to alectinib, follow the grade-dependent 
rules for dose interruption and modification outlined in the first 
section of this table.


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Table 1
Guidelines for Management of Risks, Adverse Events, and 
Selected Laboratory Abnormalities with Alectinib (cont.)
Event
Action to Be Taken
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.
In case of AEs related to alectinib, follow the grade-dependent 
rules for dose interruption and modification outlined in the first 
section of this table.
Abnormal renal function 
AEs
Kidney function laboratory abnormalities are to be reported as AEs 
if they fulfill the criteria listed in Section 5.3.5.4.
If at any time during the study treatment serum creatinine increases 
by ≥2over the baseline-visit value, the patient has to be carefully 
monitored.  All underlying factors that may have acutely impacted 
serum creatinine levels need to be evaluated and corrected (e.g., 
dehydration, recent exposure to contrast media, increased amount 
of cooked meat in diet, concomitant medications affecting renal 
function as appropriate, etc.).
Any serum creatinine value that is increased by ≥2over the 
baseline-visit value requires repeat testing.

For Grade 1 and Grade 2 AEs related to alectinib, follow the 
grade-dependent rules for dose interruption and modification 
outlined in the first section of this table.

For Grade 3 AEs related to alectinib, temporarily interrupt 
alectinib until serum creatinine recovers to Grade 1 or baseline, 
then resume at reduced dose.

For Grade 4 AEs related to alectinib, permanently discontinue 
study drug.
Severe myalgia and CPK 
elevations
CPK laboratory abnormalities are to be reported as AEs if they fulfill 
the criteria listed in Section 5.3.5.4.
Myopathy should be considered in any patient with diffuse myalgia, 
muscle tenderness or weakness, and/or marked elevations of CPK 
levels.  Patients should promptly report unexplained muscle pain, 
tenderness, or weakness, particularly if accompanied by malaise or 
fever.  CPK levels should be monitored in patients reporting these 
symptoms.
In case of AEs related to alectinib, follow the grade-dependent 
rules for dose interruption and modification outlined in the first 
section of this table.


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Table 1
Guidelines for Management of Risks, Adverse Events, and 
Selected Laboratory Abnormalities with Alectinib (cont.)
Bradycardia b
Grade 2 or Grade 3

Temporarily withhold for a maximum of 21 days (after which the 
drug must be permanently withdrawn) until recovery to Grade 
1 (asymptomatic) bradycardia or to a heart rate of 60 bpm.  
Evaluate concomitant medicinal products known to cause 
bradycardia, as well as anti-hypertensive medicinal products.

If a contributing concomitant medicinal product is identified and 
discontinued, or its dose is adjusted, resume at previous dose 
upon recovery to Grade 1 (asymptomatic) bradycardia, or to a 
heart rate of 60 bpm.
If no contributing concomitant medicinal product is identified, or if 
contributing concomitant medicinal products are not discontinued or 
dose modified, resume at reduced dose upon recovery to Grade 1 
(asymptomatic) bradycardia or to a heart rate of 60 bpm.
Grade 4

Permanently discontinue if no contributing concomitant 
medicinal product is identified.

If a contributing concomitant medicinal product is identified and 
discontinued, or its dose is adjusted, resume at reduced dose 
upon recovery to Grade 1 (asymptomatic) bradycardia or to a 
heart rate of 60 bpm within 21 days, with frequent monitoring 
as clinically indicated.
Permanently discontinue in case of recurrence.
Hemolytic anemia
If hemoglobin concentration is 10 g/dl (Grade 2) and hemolytic 
anemia is suspected, withhold alectinib and initiate appropriate 
laboratory testing in accordance with local clinical practice 
guidelines. If hemolytic anemia is confirmed, resume alectinib at a 
reduced dose (see the general dose modification table,
Section 5.1.2.1) upon resolution with improvement of hemoglobin 
to Grade 1 or baseline, or permanently discontinue alectinib.
In case of anemia of non-hemolytic mechanism, assessed as related 
to alectinib, follow the grade-dependent rules for dose interruption 
and modification outlined in the first section of this table.
AEadverse event; BIDtwice a day;CPKcreatine phosphokinase; GIgastrointestinal; 
ULNupper limit of normal.
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.
a Please refer to Section 5.3.4 to determine whether event should be assessed as related or 
unrelated.
b Heart rate less than 60 bpm.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 


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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) (see Section 5.3.5.8, 
Section 5.3.5.9 for more information)

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 5.3.5.10)

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


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
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 NCI CTCAE; 
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
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
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 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator and site designee (e.g., the mHCP or CRC) are 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).


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5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether communicated by the patient or noted by study personnel, will 
be recorded in the patient's medical record and on the Adverse Event eCRF by the 
investigator.
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 28 days after the 
final dose of study drug.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.1.1
Special Considerations Related to Decentralized Study Design
Supervision of patients during trial conduct includes identifying, managing, and 
assessing safety events.  Patients will agree, as a part of the consenting process, to 
report potential adverse events as soon as possible to study personnel (investigator, 
mHCP, or clinical trial coordinator), with the study issued smartphone facilitating 
communication between the patient and the investigator and study personnel.
Adverse events may be reported in a variety of ways, including but not limited to:  
spontaneous communication by the patient; observations via telemedicine by study 
personnel or the investigator; observations by the mHCP who visits the patients’ homes; 
communications to study personnel from the patients’ health care providers or 
specialists; and/or documentation of events in medical records provided by patients’ 
health care providers or specialists.
As soon as a patient communicates a possible adverse event, or study personnel are 
alerted to a possible adverse event through laboratory results or review of medical 
records, the investigator will evaluate the patient.  The investigator will call or have a 
videoconference with the patient to evaluate the adverse event and determine the 
course of action.  The investigator will use his or her medical judgment and dose 
modification rules as described in the protocol to determine the appropriate care needed 
to address the adverse event.  Examples of actions that could be taken include, but are 
not limited to, management via telemedicine, referral to the patient’s local oncologist, 
referral to specialist physician (such as neurologist or cardiologist) or urgent care, 
immediate referral to a local emergency department, and/or request to call a local 
emergency number (e.g., 911 in the United States) immediately, as appropriate.


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Additionally, during the study visits conducted in the patients’ homes, the following will 
be evaluated, and the investigator will use results of these procedures to assess safety 
throughout the study:

Physical examinations (directed by the investigator via videoconference with the 
assistance of a mHCP

Vital signs and weight

Laboratory tests, including urine pregnancy test

ECGs
As soon as study personnel become aware of a safety event, the investigator will assess 
the event according to medical practice, the protocol, the Alectinib Investigator’s 
Brochure, and IRB requirements.  The assessment can occur in a multitude of ways, 
including review of medical records, communication with study patients, communication 
with other medical providers, and communication with study personnel.  Events 
assessed as serious adverse events or adverse event of special interest (see 
Section 5.4.1), as well as pregnancy (see Section 5.4.3), will be reported to the Sponsor
within the required 24-hour window (see Section 5.2.2). The investigator is responsible 
for informing and updating study personnel regarding safety events and for reporting 
adverse events and serious adverse events to the Sponsor, as required.
Sponsor or Sponsor designee will prepare and submit reports of all safety events, 
including serious adverse events, to the IRB per the IRB reporting requirements.
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 (v5.0) will be used for 
assessing adverse event severity.  Table 2 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 2
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 (v5.0), 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 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 (see also 
Table 3):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of 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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Table 3
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
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
Diagnosis versus Signs and Symptoms
For adverse events, 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.
5.3.5.2
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.


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
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
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.
5.3.5.4
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.


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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.
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 whether 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 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.5
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 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) 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


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(adverse event of special interest or serious adverse event) the occurrence of either of 
the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.4) 
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 an adverse event of special interest (see 
Section 5.4.2).
5.3.5.7
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of the malignancy under study should be 
recorded on the Death Attributed to Progressive Disease eCRF.  All other deaths that 
occur during the adverse event reporting period, 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 IMC 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.  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.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an 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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5.3.5.9
Lack of Efficacy or Worsening of ALK-Positive Tumor
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 (or RANO criteria for primary CNS tumors).  
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.
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient 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.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

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
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.11
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose


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
Medication error:  accidental deviation in the administration of a drug
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, 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).  For alectinib, adverse events associated with special 
situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes.


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In addition, all special situations associated with alectinib, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF as described 
below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of
the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.3.5.12
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.  The mHCPs are expected to review the 
PRO data to make sure all questions have been completed before leaving the patient’s 
home.  Investigators are not expected to review the PRO data for adverse events.


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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 (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information 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
Medical Monitors and Emergency Medical Contacts
Contact Information for All Science 37 Locations
Medical Monitor/Roche Medical Responsible:
, M.D.
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week, in case the above-listed contacts cannot 
be reached.  The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls.  Contact information, including toll-free numbers for the Emergency Medical Call 
Center, will be distributed to investigators.


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5.4.2
Reporting Requirements for Serious Adverse Events and 
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. 
These events will be entered on the Adverse Event eCRF immediately (i.e., no more 
than 24 hours after learning of the event).
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the final dose of alectinib.  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. A report will be generated and 
sent to Roche Safety Risk Management by the electronic data capture (EDC) system.
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations 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 serious adverse events that occur more than 28 days after the 
final dose of study treatment 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 through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 90 days after the final dose of study drug.  A paper Clinical Trial Pregnancy 
Reporting Form 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 e-mail address 
provided to investigators.  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.  In addition, the investigator will submit a Clinical
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.


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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 
90 days after the final dose of study drug.  The investigator should report the pregnancy 
on the paper Clinical Trial Pregnancy Reporting Form and submit the form 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 e-mail address provided to investigators.  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.  When permitted, the pregnant partner would need to sign 
an Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator
should submit a Clinical Trial Pregnancy Reporting Form when updated information on 
the course and outcome of the pregnancy becomes available.  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.
5.4.3.3
Abortions
A spontaneous 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).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity 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).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
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).


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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 
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.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, e-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
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 28 days after the final
dose of study drug), all deaths, regardless of cause, should be reported through use of 
the Long-Term Survival Follow-Up eCRF.
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study drug, the event should be reported through use 
of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form using the fax number or e-mail 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 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.


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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below:
Drug
Document
Alectinib
Alectinib Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The following populations are defined:

The response-evaluable population is defined as all patients with ALK fusion 
(excluding patients with CUP and CNS primary tumors) solid tumors with 
measurable disease at baseline evaluable according to RECIST v1.1 who receive at 
least one dose of study drug.

All populations are defined according to the investigator or by blinded independent 
center review (BICR), depending on who is assessing the endpoint.

The response-evaluable population with measurable CNS disease at baseline is 
defined as all patients with measurable CNS disease at baseline evaluable 
according to RECIST v1.1 who receive at least one dose of study drug.

The primary CNS tumor response-evaluable population is defined as all patients 
with ALK fusion CNS primary tumors with measurable disease at baseline evaluable 
according to RANO criteria who receive at least one dose of study treatment.

The CUP response-evaluable population is defined as all patients with CUP with 
measurable disease at baseline evaluable according to RECIST v1.1 who receive at 
least one dose of study drug.

The ALK-mutations response-evaluable population is defined as all patients with 
ALK mutations with measurable disease at baseline evaluable according to 
RECIST v1.1 who receive at least one dose of study drug.
The primary analysis will be performed on the response-evaluable population.
Secondary analyses will be performed on the response evaluable population, the 
measurable CNS disease at baseline response-evaluable population, the primary CNS 
tumor response evaluable population, the CUP response-evaluable population, and the 
ALK mutation response-evaluable population, separately. The DOR will be assessed in 
the patients with confirmed or unconfirmed objective response, as appropriate.


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Safety analyses will be performed on all enrolled patients who receive at least one dose 
of study drug.
Details of all above analyses will be provided in the Statistical Analysis Plan.
6.1
DETERMINATION OF SAMPLE SIZE
Patients with both ALK fusion and selected ALK mutations will be enrolled in the study.  
Enrollment will end once around 50 patients with ALK fusions solid tumors evaluable 
according to RECIST v1.1 have been recruited (regardless of the number of enrolled 
patients with primary CNS tumors, CUP, or harboring selected ALK mutations).
This sample size has been chosen so that for the primary analysis the lower limit of the 
two-sided 95% CI (using an exact Clopper-Pearson CI) around the point estimate of the 
confirmed ORR according to RECIST v1.1 will represent a clinically relevant response. 
With a sample size of 50 patients, an observed response rate of 46% (23 of 
50 responses) would have a lower limit of the two-sided 95% CI of 31.8%, which is 
considered to be clinically relevant in this tissue-agnostic, biomarker-defined population 
with no available treatment options. With 50 patients, there is 70% power to detect a 
16% increase in ORR from clinically relevant 30% to 46% at the 5% two-sided 
significance level.
Different ORR scenarios with their associated 95% CI are presented in Table 4.
Table 4
ORR Scenarios with Associated 95% CI
Expected ORR
Expected Number of Patients 
with a Response
95% CI for ORR a
46%
23
(31.81% to 60.68%)
48%
24
(33.66% to 62.58%)
50%
25
(35.53% to 64.47%)
ORRobjective response rate.
a Using the Clopper-Pearson method and given a sample size of 50 patients.
With a sample size of 50 patients, an ORR of 46% will have an associated 95% CI of 
31.81% to 60.68%.
6.2
SUMMARIES OF CONDUCT OF STUDY
Study enrollment, study treatment administration, reasons for discontinuation from study 
treatment, and reasons for premature study discontinuation will be listed and 
summarized, including any related to COVID-19.  Reasons for screen failure will be 
extracted from the Science 37 Platform, listed, and summarized. Major protocol 
deviations, including major deviations of inclusion/exclusion criteria, as well as any 
related to the COVID-19, will be reported and summarized.


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6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
For all patients, demographic and baseline characteristics (including age, sex, 
race/ethnicity, baseline disease characteristics, and medical history) will be summarized 
using means, standard deviations, medians, ranges, and interquartile ranges for 
continuous variables and proportions for categorical variables, as appropriate.
Baseline measurements are the last available data obtained prior to the patient receiving 
the first dose of alectinib.
6.4
EFFICACY ANALYSES
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is ORR as assessed by investigator per RECIST v1.1, 
defined as the proportion of patients with an objective response.  An objective response 
is defined as a CR or a PR per RECIST v1.1.  Confirmation of objective response is 
required (confirmed 28 days apart in two separate tumor assessments).  Patients not 
meeting this criterion (including patients without a post-baseline tumor assessment) will 
be considered as non-responders.
An estimate of the ORR and its 95% CI using the Clopper-Pearson method will be 
calculated.
The primary efficacy analysis population consists of all patients with ALK fusionpositive 
solid tumors (excluding patients with CUP and primary CNS tumors) with measurable 
disease at baseline who have a baseline tumor assessment per the investigator 
according to RECIST v1.1 and have received at least one dose of study treatment.
An interim analysis will be performed as described in Section 6.9.
The primary analysis will take place once all patients have been followed for a minimum 
of 24 weeks (i.e., three tumor assessments) to allow confirmation of any observed CR or 
PR, unless they progressed or withdrew from sooner from the study.
6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are presented in Section 2.1.2.
6.4.2.1
Secondary Endpoint Definitions
The secondary endpoint definitions are as follows.
Confirmed Objective Response Rate
Proportion of patients with a confirmed objective response by BICR.  An objective 
response is defined as a CR or a PR per RECIST v1.1.  Confirmation of objective 
response is required (confirmed 28 days apart in two separate tumor assessments). 


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Patients not meeting this criterion (including patients without a post-baseline tumor 
assessment) will be considered non-responders.
An analysis of this endpoint will also be performed on the basis of RANO criteria 
assessed by investigator and BICR in patients with primary CNS tumors.  Confirmation 
of objective response is not required for patients with ALK mutations.
Duration of Response
Duration of response is defined as the time from the date of the first occurrence of a CR 
or a PR (whichever status is recorded first) to the date of the first documented disease 
progression or death due to any causes, whichever occurred first.  The DOR will be 
assessed in patients who had a confirmed objective response during the study, as 
determined by the investigator or BICR per RECIST v1.1.  Patients who have not 
progressed or died at the time of analysis will be censored at the last tumor assessment 
date.  If no tumor assessments are performed after the date of the first occurrence of a 
CR or a PR, DOR will be censored at the date of the first occurrence of a CR or a PR.  
The Kaplan-Meier method will be used to estimate the median DOR with 95% CIs.
An analysis of this endpoint will also be performed on the basis of RANO criteria 
assessed by the investigator and BICR in patients with primary CNS tumors.  
Confirmation of objective response is not required for patients with ALK mutations.
Progression-Free Survival
Progression-free survival is defined as the time from the first date of treatment to the 
date of first documented disease progression or death, whichever occurs first. Disease 
progression will be assessed by the investigator or the BICR using RECIST v1.1. 
Patients who have not experienced disease progression or died at the time of analysis 
will be censored at the last tumor assessment date.  Patients with no post-baseline 
tumor assessment will be censored at the first date of treatment.  The Kaplan-Meier 
method will be used to estimate the median PFS with 95% CIs.
An analysis of this endpoint will also be performed on the basis of RANO criteria 
assessed by investigator and BICR in patients with primary CNS tumors.
CNS Objective Response Rate
For patients with ALK-fusion positive tumors (excluding patients with CUP and patients 
with CNS primary tumors), who present with measurable CNS metastases at baseline
an analysis of CNS ORR defined as the percentage of patients who achieve a best 
overall response of a CR or a PR of CNS lesion (defined according to RECIST v1.1) will 
also be performed. CNS CR and PR will be assessed by BICR. The analysis method is 
the same as for the primary endpoint. Confirmation of objective response is not 
required.


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CNS Duration of Response
For patients who had a CNS objective response during the study, an analysis of CNS 
DOR, defined as the time from the date of the first occurrence of CNS CR or PR 
(whichever status is recorded first) to the date of the first documented disease CNS 
progression or death due to any causes, whichever occurred first, will be conducted. 
CNS disease progression will be assessed by BICR using RECIST v1.1. The analysis 
method is the same as for the DOR defined above. Confirmation of objective response 
is not required.
Overall Survival
OS is defined as the time from the first date of treatment to the date of death due to any 
cause.  Patients who are not reported as dead at the time of the analysis will be 
censored at the date when they were last known to be alive. If no post-baseline 
information is available, then OS will be censored at the date of the first treatment. The 
Kaplan-Meier method will be used to estimate the median OS with 95% confidence 
limits.
For some populations, depending on the number of patients, a formal analysis will not be 
produced; instead, listings or spider plots could be used.
6.4.3
Exploratory Biomarker Endpoints
The following exploratory biomarker endpoints are described in Section 2.4:

Relationship between biomarkers found in circulating DNA in blood and tumor 
tissue, with efficacy endpoints

Relationship between levels of cfDNA at baseline and changes in levels of cfDNA at 
different timepoints during treatment with efficacy endpoints
The primary analysis will be repeated for the subgroups of patients with results from FMI 
tests and with results from non-FMI tests, respectively.
6.5
SAFETY ANALYSES
Safety analyses will be performed on the safety evaluable population, defined as all 
enrolled patients who received any amount of study drug.
Drug exposure will be summarized to include treatment duration, number of doses, and 
dose intensity.
Verbatim description of adverse events will be mapped to Medical Dictionary for 
Regulatory Activities thesaurus terms and graded according to NCI CTCAE v5.0.  All 
adverse events that occur on or after the first study drug dose (treatment-emergent 
adverse events) will be summarized using descriptive statistics (i.e., frequencies and 
percentages) by mapped term, appropriate thesaurus level, and severity grade (NCI 
CTCAE grade).  In addition, serious adverse events, severe adverse events (Grade 3), 
adverse events of special interest, and adverse events leading to study drug 


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modification will be summarized accordingly.  Multiple occurrences of the same event 
will be counted once at the maximum severity.  Adverse events will be described in 
individual listings and by body system, as well as by severity.  In tables showing the 
overall incidence of adverse events, patients who experience the same event on more 
than one occasion will be counted only once in the calculation of the event frequency.
Summaries of all adverse events considered to be treatment-related (serious adverse 
events, adverse events of special interest, and all listings of adverse events) will include 
all events that occur on or after the first study drug treatment. On the other hand,
summaries of adverse events considered by the investigator to be unrelated to treatment 
will include treatment-emergent adverse events with onset up to 28 days after the final 
dose of alectinib or until patients receive another anti-cancer therapy, whichever comes 
first.
Laboratory data with values outside the normal ranges will be identified.  In addition, 
selected laboratory data will be summarized in shift tables.  Changes in vital signs and 
ECGs will be summarized.  Deaths reported during the study treatment period and those 
reported during the follow-up period after treatment completion or discontinuation will be 
summarized.
Subgroup analyses will be performed to evaluate the safety profile within subgroups of 
patients, including by sex, age (65 years vs. 65 years), and race.
6.6
PHARMACOKINETIC ANALYSES
The PK-evaluable population will consist of all patients who have at least one 
post-baseline quantifiable PK sample available.
Nonlinear mixed-effects modeling (with software NONMEM) (Beal et al. 1999) will be 
used to analyze the sparse plasma concentrationtime data for alectinib and its 
metabolites, as applicable.  The PK data from this study may be pooled with data from 
other studies.  Population and individual PK parameters will be estimated, and the 
influence of various covariates (such as age, sex, and body weight) on these parameters 
will be investigated.  Exploratory analyses will be conducted to investigate the 
relationship between alectinib PK exposure and efficacy/safety parameters.
Details of the mixed-effects modeling and exploratory analyses will be reported in a 
document separate from the Clinical Study Report.
6.7
BIOMARKER ANALYSES
ALK tumor tissue and plasma assays (e.g., next-generation targeted sequencing, PCR) 
will be used as exploratory assays for all enrolled ALK-positive patients.  Results from 
these analyses along with clinical data collected in this study will be used to explore 
genomic variants (e.g., ALK rearrangement variants, fusion partners, mutations in ALK 
and other cancer related genes) that may be predictive of response to study drug or may 


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be associated with progression to a more severe disease state.  As these biomarkers 
may also have prognostic value, their potential association with disease progression will 
also be explored.  Somatic mutations in ALK and other cancer related genes may be 
associated with acquired resistance to alectinib or can increase the knowledge and 
understanding of the disease biology.  Tumor mutation allele frequencies and circulating 
tumor nucleic acid amounts may also be correlated with clinical efficacy.  Efficacy 
analysis of different ALK tumor and ALK plasma subpopulations may be performed.
Information regarding the detection of ALK rearrangements from targeted DNA 
sequencing from tissue and plasma samples, and baseline demographic and 
disease-related characteristic for all enrolled patients in this study may be used for 
companion diagnostic development.  These data may be used to support potential 
registration of a companion diagnostic assay for alectinib in the tumor-agnostic setting 
and shared with health authorities.
Data will be analyzed in the context of this study but may also be explored in aggregate 
with data from other studies.  The availability of a larger dataset will assist in 
identification and characterization of important biomarkers and pathways to support 
future drug development.
Results from the exploratory biomarker analyses from baseline and recurrence tumor 
samples and from plasma samples at baseline, on treatment, and post-recurrence will 
be communicated outside the main Clinical Study Report.
6.8
HEALTH STATUS UTILITY ANALYSES
The QLQ-C30 and EQ-5D-5L questionnaires will be used to assess the impact of 
alectinib on patients' quality of life and daily function.  Completion and compliance rates 
will be summarized by number and proportion of patients among those expected to 
complete each questionnaire at each timepoint.
The QLQ-C30 and EQ-5D-5L questionnaires will be scored per authors' guidelines.
Completion and compliance rates will be summarized by number and proportion of 
patients among those expected to complete each questionnaire at each timepoint.  
Reasons for non-completion will be summarized at each timepoint.
Summary statistics (mean, standard deviation, median, and range) of linear transformed 
scores will be reported for all the items and subscales of the EORTC QLQ-C30 
questionnaire.  Only patients with a baseline assessment and at least one 
post-treatment assessment will be included in the analyses.
A single summary index from the EQ-5D-5L health states will be used in this study for 
economic modeling.
These results may not be reported in the Clinical Study Report.


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6.9
INTERIM ANALYSIS
A non-binding interim analysis will be performed after 15 RECIST 
v1.1 investigator-assessed response-evaluable patients with ALK fusions tumors 
(excluding patients with primary CNS tumors and patients with solid tumors of CUP) 
have at least a response-evaluation available at 8 weeks (unless they progressed or 
discontinued earlier from the study).  During the period waiting for a response evaluation 
of these first 15 patients, the study will continue to enroll.  If the analysis result shows 
that the response rate does not achieve at least 25% (4 responders), the study may be 
terminated due to futility.
Further details regarding the rules and guidelines of data review will be provided in the 
IMC 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.
The home-based decentralized study can be conducted by investigators with the 
investigator’s institution as the study site or with investigators without institution 
involvement; if there is no institution involvement, a central virtual study site such 
Science 37 will be used.
For countries using a virtual study site (i.e., Science 37):
The Science 37 Platform will be used in this trial for countries without investigator’s 
institution (physical study sites) or for countries with no other required or mandated 
alternatives for the collection and management of source data. The Science 37 Platform 
complies with Code of Federal Regulations Title 21 Part 11 regulation and is validated 
and maintained in a validated state throughout the lifecycle of the system.  In this trial, 
the Science 37 Platform will serve as an electronic source documentation tool.
At a minimum, source documents consistent with the type and level of detail that are 
commonly recorded at study sites will be developed in the Science 37 Platform.
Common for both approaches (i.e., virtual and physical sites):
Data entered manually will be collected via EDC through use of eCRFs.  Sites will be 
responsible for data entry into the EDC system (RAVE).  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 (RAVE).
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and other 


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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.
Electronic Case Report Forms 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.
Patient-reported outcome data will be collected on paper questionnaires.  The data from 
the questionnaires will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS
Common for both approaches (i.e., virtual and physical sites):
All eCRFs are to be completed through the EDC system (RAVE), which is Medidata’s
designated EDC system. Study personnel will receive training and have access to a 
manual for appropriate eCRF completion.  All 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 staff. The Sponsor eCRF 
database (RAVE) should be reviewed and electronically signed and dated by the 
investigator or a designee.
At the end of the study, investigator/Science 37 (depending on the approach) will 
receive a copy of the RAVE eCRF patient data in a readable format that must be kept 
with the study records.  Acknowledgement of receipt of the data is required.
7.3
SOURCE DATA DOCUMENTATION
7.3.1
Virtual Study Sites
In countries with virtual study sites, the Science 37 Platform will be used for source 
documentation. Patients’ medical records, including laboratory reports from central and 
local laboratories, ECG reports, pathology reports, tumor genetic profiling reports, 
including local NGS ALK testing report, etc., obtained during the study will be uploaded 
in the Science 37 Platform. Other records media, such as CDs containing images, will 
be maintained in a secure location as part of the patient research file.
A study monitor will perform source data verification to confirm that protocol data are 
accurate, complete, and verifiable from source documents. Before study initiation, the 
types of source documents that are to be generated will be clearly defined in the Trial 
Monitoring Plan.
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 


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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.
Source documents that are required to verify the validity and completeness of data 
entered into the Science 37 Platform must not be obliterated or destroyed and must be 
retained per the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, Science 37 and designated vendors 
(i.e., for IMP management) must provide the Sponsor direct access to applicable source 
documents and reports for trial-related monitoring, Sponsor audits, and IRB/EC review. 
Science 37 and designated vendors must also allow inspections by health authorities.
7.3.2
Physical Study Sites
In countries with physical study sites, study monitors will perform ongoing source data 
verification and review to confirm that critical protocol data (i.e., source data) entered 
into the eCRFs by authorized site personnel are accurate, complete, and verifiable from 
source documents.
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for trial-
related monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.


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7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, paper PRO data, Informed Consent Forms, laboratory test 
results, and medication inventory records, must be retained by the Principal Investigator
for 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.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
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 applicable 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 or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms) 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 


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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.
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.
In this study, informed consent may be obtained electronically using a validated system
approved by local regulations. See Section 4.6.1 for details on the process.
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.
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  For the separate 
Authorization Form for patient authorization for use and disclosure of personal health 
information under the HIPAA regulations, the review, approval, and other processes 


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outlined above apply except that IRB review and approval may not be required per study 
site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.7).
In addition to the requirements for reporting all adverse events to the Sponsor, the 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to investigators or patients
unless required by law.  The aggregate results of any conducted research will be 
available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6).


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Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC, as appropriate.
Study data, which may include data on genomic variants, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study. These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and other summary reports will be provided upon request (see Section 9.6).
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 (see definition of end of 
study in Section 3.2).
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 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 


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to study initiation, the Sponsor will identify potential risks associated with critical trial 
processes and data and will implement plans for evaluating and controlling these risks.  
Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan.
9.4
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.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 50 patients will be enrolled in this study.
Patients can be identified by means of one of the two following enrollment pathways:

The Precision Enrollment approach offered by FMI.  When nonlung cancer 
samples are determined by FMI central testing to be positive for ALK, an FMI 
medical oncologist will contact the ordering physician (local oncologist) and provide 
information about the trial.  If this is of interest to both the physician and the patient, 
enrollment procedures will begin

Patients with ALK-positive NGS test results obtained outside FMI’s Precision 
Enrollment may be identified and the local ALK NGS test report will be made 
available (see Section 4.6.6) and will be assessed by the investigator for eligibility.  
The study team and Medical Monitor are to be consulted.  If ALK positivity is not 
accepted per the criteria, prospective FMI testing is required and the patient may be 
enrolled if assessed to be ALK-positive by FMI.
For sample requirements, see Section 4.6.6 and Appendix 2, Table 3.
For eligible and enrolled patients, the tumor tissue sample must be submitted (see 
Section 4.6.6 and Appendix 2, Table 3) for retrospective analysis by FMI using the
F1CDx assay.
A decentralized, home-based approach will be adopted that minimizes the need of 
on-site visits for patients, thus making clinical trials more accessible to patients 
regardless of location.  Central facilities will be used for certain study assessments 
throughout the study (e.g., specified laboratory tests, biomarker and PK analyses), as 


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specified in Section 4.6.  Accredited local laboratories may be used for patient safety 
follow-up; local laboratory ranges will be collected.
BICR of tumor assessments will be conducted to determine the secondary endpoints of 
confirmed ORR, DOR, PFS, CNS ORR, and CNS DOR, all according to RECIST v1.1.  
In addition, BICR of tumor assessments of primary CNS tumors will be conducted 
according to the RANO criteria.
The independent review of MRI and CT scans will not be used to determine either 
eligibility or patient treatment.  All treatment decisions will be made by the investigator
using local assessments.
An IMC will monitor patient safety throughout the study, focusing on death cases and 
interim futility analysis.
9.6
DISSEMINATION 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 health care professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.


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Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Trigg RM, Turner SD. ALK in neuroblastoma: biological and therapeutic implications. 
Cancers 2018;10:113.
Trotti A, Pajak TF, Gwede CK, et al. TAME: development of a new method for 
summarising adverse events of cancer treatment by the Radiation Therapy 
Oncology Group. Lancet Oncol 2007;8:61324.
Webb TR, Slavish J, George RE, et al. Anaplastic lymphoma kinase: role in cancer 
pathogenesis and small-molecule inhibitor development for therapy. Expert Rev 
Anticancer Ther 2009;9:33156.


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Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive 
disease prolongs disease control by tyrosine kinase inhibitors in 
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Wood AC, Laudenslager M, Haglund EA, et al. Inhibition of ALK mutated 
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Yakirevich E, Resnick MB, Mangray S, et al. Oncogenic ALK fusion in rare and 
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non-small cell lung cancer. J Thorac Oncol 2017;12:155260.


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Appendix 1
Schedule of Activities
Assessment
Screening
Treatment Period
Treatment 
Discontinuation 
Visit (28 days after
Final Dose of 
Study Drug 
[5 days])
Off-Tx 
Visits b
Long-
Term 
Follow-
Up c
Days −28 
to −1
Baseline
(Week 1)
Q2W
(3 days) for 
the First 
12 Weeks h
Q4W thereafter until 
PD, Death, or 
Withdrawal from 
Study a
(3 days)
Informed consent
x
Demographic data
x
Medical history, baseline 
conditions
x
ECOG Performance Status
x
x
x
x
Vital signs
x
x
x
x
Weight
x
x
x
x
Height
x
Physical examination d
x
x
x
x
ECG
x
x
As clinically indicated
x
Coagulation e
x
x
As clinically indicated
x
Hematology f
x
x
x
x
Chemistry g
x
x
x
x
Urinalysis, dipstick
x
x
x
x


Appendix 1: Schedule of Activities
Alectinib—F. Hoffmann-La Roche Ltd
116/Protocol BO41929, Version 4
Assessment
Screening
Treatment Period
Treatment 
Discontinuation 
Visit (28 days after
Final Dose of 
Study Drug 
[5 days])
Off-Tx 
Visits b
Long-
Term 
Follow-
Up c
Days −28 
to −1
Baseline
(Week 1)
Q2W
(3 days) for 
the First 
12 Weeks h
Q4W thereafter until 
PD, Death, or 
Withdrawal from 
Study a
(3 days)
Additional mandatory 
laboratory assessments h
x
Plasma PK sample (2 mL) i
x
x
Plasma sample for 
biomarkers (10 mL) j
x
Only at Week 8, Week 
36, and at progression
Tumor tissue sample k
x l
x
Pregnancy test
x m
x n
Urine pregnancy test 
Q4W and as clinically 
indicated
x
Alectinib dispensing
x
x
Disease assessment 
(CT scans)
x
Q8W
(5 days)
Q8W 
(5 days)
MRI or CT scan of the brain o
x
x p
x p
Radionuclide bone scan q
x
Concomitant medications
x
x
x
x
Adverse events
x
x
x
x
Patient-reported outcomes r
x
x
x
Subsequent therapy and SFU
x


Appendix 1: Schedule of Activities
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CPKcreatine phosphokinase; CT computed tomography (scan); eCRFelectronic Case Report Form; ECOGEastern Cooperative Oncology 
Group; FFPEformalin fixed, paraffin embedded; FMI Foundation Medicine, Inc.; GGT gamma-glutamyl transferase; MRImagnetic resonance 
imaging; NAnot applicable; NGSnext-generation sequencing; PDprogressive disease; PKpharmacokinetic; PROpatient-reported 
outcome; Q2W every 2 weeks; Q4W every 4 weeks; Q8W every 8 weeks; RBRResearch Biosample Repository; SFUsurvival follow-up; 
Txtreatment; WESwhole exome sequencing; WGSwhole genome sequencing.
Notes:  Results of laboratory tests and ECG performed within 3 days before first dose of study drug can be used as baseline assessments.
a Treatment beyond radiological progression is possible in the event of isolated lesion progression if in the investigator’s opinion there is evidence 
of ongoing clinical benefit.  For patient receiving study drug beyond radiological progression, scheduled visits (including disease assessments) 
will continued to be performed until treatment discontinuation.
b For patients who discontinue study treatment prematurely for reasons other than disease progression, tumor assessments should continue until 
progression.
c Required follow-up information (e.g., survival status and information on further cancer therapies and procedures [radiotherapy, surgery]) will be 
collected via telephone calls every 3 months (14 days) until death, loss to follow-up, or study termination by the Sponsor.  More frequent calls 
may be required when clinical data cut-offs are performed.
d Complete physical examination (head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems). Baseline and post-baseline visits: limited physical examination, symptom-directed,
and as clinically indicated. For patients with primary CNS tumors, a neurological examination must be performed at each tumor assessment 
visit and compared with the neurological examination performed at the time of the last disease assessment.
e Coagulation includes PT (or INR) and aPTT (or PTT).
f
Includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes).
g Includes sodium, potassium, chloride, glucose, creatinine, creatinine clearance (calculated according to the method of Cockcroft and Gault), 
GGT, total protein, albumin, phosphorus, magnesium, calcium, total and direct bilirubin, ALP, CPK, ALT, AST, uric acid, BUN, or urea.
h Additional mandatory laboratory assessments include CPK at 2 weeks after baseline and liver enzymes (ALT, AST, ALP, and total and direct 
bilirubin) 2, 6, 10, and 12 weeks after baseline.  These are in addition to the regular assessments performed Q4W.
i
Plasma sample for PK to be taken during screening or before first dose of study drug at baseline.  At subsequent visits, time of sample draw 
and last dose of alectinib must be captured.  See Appendix 2 for details.
j
See Appendix 2 for details.
k Available (most recent) FFPE tissue block or 11 unstained slides 45 m thick.  Tissue sample is not required if ALK positivity was determined 
by FMI using tissue. A tissue block or 11 unstained slides are also required for all patients who have local ALK-positive test by NGS.
l
Tumor tissue sample for prospective testing at FMI if local ALK test result is not acceptable for enrollment as specified by the protocol.


Appendix 1: Schedule of Activities
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m During screening, a negative serum pregnancy test must be obtained.
n At baseline a negative urine pregnancy test must be obtained before first dose of study drug is administered (unless a negative serum test was 
obtained within 10 days of first dose of study drug).
o For primary CNS tumors, at all tumor assessment visits, corticosteroid use for CNS disease must be compared with the corticosteroid intake at 
the time of the last disease assessment.  Changes in corticosteroid dose for reasons other than for CNS tumor control do not need to be taken 
into consideration when making this comparison.
p As clinically indicated (mandatory Q8W [5 days] for primary CNS tumors or for patients with CNS metastases at baseline).
q A radionuclide bone scan is required at screening for patients with known or suspected bone metastasis.
r
The PRO questionnaires QLQ-C30 and EQ-5D-5L will be completed by patients at home during the scheduled visits performed by the 
mobile health care professional. Questionnaires are to be completed before any other visit-related assessment is performed.


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Appendix 2
Schedule of Pharmacokinetic and Biomarker Samples
Table 1
Pharmacokinetic Schedule of Activities
Visit
Timepoint
Sample Type
Baseline (Week1)
Predose 
Plasma
Week 4 and every 4 weeks 
thereafter during the 
treatment period
Record time: drawn 
plasma and last dose of 
alectinib
Plasma
Table 2
Biomarker Schedule of Activities
Visit
Sample Type
Screening
Available (most recent) tumor tissue a
Baseline (Week 1) b
Plasma for biomarkers
Week 8
Plasma for biomarkers
Week 36
Plasma for biomarkers
Disease progression c
Plasma for biomarkers
ALKanaplastic lymphoma kinase; FMIFoundation Medicine, Inc.
a Not necessary if ALK positivity was already determined by FMI on tissue. It includes patients 
identified outside FMI Precision Enrollment. Plasma may be acceptable after consultation 
with the Medical Monitor.
b Sample to be collected predose.
c Plasma for disease progression biomarker will be collected within 30 days of disease 
progression per investigator’s assessment according to Response Evaluation Criteria in Solid 
Tumors, Version 1.1 or, for patients with primary CNS tumors, Response Assessment in 
Neuro-Oncology criteria.
ANAPLASTIC LYMPHOMA KINASE (ALK)POSITIVE TESTS AND 
REQUIREMENTS FOR TISSUE
Data generated may support possible registration of tissue and plasma next-generation 
sequencing assays as a companion diagnostic for alectinib across tumor types.
The tests for determination of ALK positivity and tissue requirements are presented in 
Table 3.


Appendix 2:  Schedule of Pharmacokinetic and Biomarker Samples
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Table 3
ALK-Positive Tests and Tissue Requirements
ALK-Positive Result on
Tumor Tissue Sample
Retrospective Testing
F1CDx
Not applicable

F1LiquidCDx
Required
F1CDx
F1HEME
Required
F1CDx
Local NGS testing 
except FMI F1CDx a, b
Required
F1CDx
ALKanaplastic lymphoma kinase; CDx companion diagnostic; F1Foundation One; 
FMIFoundation Medicine, Inc.; NGSnext-generation sequencing.
a If tissue is not available, blood may be acceptable after consultation with the Medical 
Monitor.
b If local NGS test is from FMI but is not listed in the table, tissue is also required.


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Appendix 3
ECOG Performance Status Scale
Grade
ECOG Performance Status
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 house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair
5
Dead


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Appendix 4
List of P-gp Substrates
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 benefitrisk assessment 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.
P-gp Substrates
aliskiren, ambrisentan, colchicine, dabigatran, digoxin, everolimus, fexofenadine, imatinib, 
lapatinib, maraviroc, nilotinib, posaconazole, pravastatin, ranolazine, saxagliptin, sirolimus, 
sitagliptin, talinolol, tolvaptan, topotecan
P-gpP-glycoprotein.
For additional information, please refer to:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm080499.htm


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Appendix 5
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) (Eisenhauer et al. 2009; Schwartz et al. 2016), are presented below, with 
slight modifications from the original publication and the addition of explanatory text as 
needed for clarity.1
TUMOR MEASURABILITY
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression.
DEFINITION OF MEASURABLE 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 computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval 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 
recommended to be 5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters").
                                           
1 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.


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DEFINITION OF NON-MEASURABLE LESIONS
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 mm but 15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions:

Technetium-99m bone scans, sodium fluoride PET scans, and 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 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 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.


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METHODS FOR ASSESSING 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.
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, since 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 AND MRI SCANS
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is 5 mm.  When CT scans 
have slice thickness of 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 prior studies, if possible.  Each case should be 
discussed with the radiologist to determine if 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 and interpretation of 


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non-target disease or new lesions on a different modality, since the same lesion may 
appear to have a different size using a new modality.
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
utilized for objective tumor evaluation.
ASSESSMENT OF TUMOR BURDEN
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.
IDENTIFICATION 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 considered non-target lesions.
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 should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node 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 


Appendix 5: Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
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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.
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  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").
CALCULATION OF SUM OF DIAMETERS
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden.
Measuring 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 node regresses to 10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, since a normal lymph node is defined as having a 
short axis of 10 mm.
Measuring Lesions That Become Too Small to Measure
During the study, all target lesions (lymph node and nonlymph node) 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 CT scan that 
the radiologist may not feel comfortable assigning an exact measurement 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 too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" 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 too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked).


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To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is 5 mm, and in that case "too small to measure" should 
not be ticked.
Measuring Lesions That Split or Coalesce on Treatment
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  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
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to 10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis 10 mm), this should be captured on the CRF as part of the assessment of 
non-target lesions.
RESPONSE CRITERIA
CRITERIA FOR TARGET LESIONS
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below:

Complete response (CR):  Disappearance of all target lesions
Any pathological lymph nodes must have reduction in short axis to 10 mm.

Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR

Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints 
(including baseline)
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of 5 mm.

Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD


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CRITERIA FOR NON-TARGET LESIONS
Definitions of the criteria used to determine the tumor response for the group of non-
target lesions are provided below.  While 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 schedule of activities.

CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits

PD:  Unequivocal progression of existing non-target lesions
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS
Patients with Measurable and Non-Measurable Disease
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, 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 lesions in 
the face of SD or PR in target lesions will therefore be extremely rare.
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 
(for example, 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.  For example, 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, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 


Appendix 5: Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
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there is definitely a new lesion, progression should be declared using the date of the 
initial scan.
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline.
Table 1
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Timepoint Response
CR
CR
No
CR
CR
Non-CR/non-PD or NE
No
PR
PR
CR, non-CR/non-PD
or NE
No
PR
SD
CR, non-CR/non-PD or NE
No
SD
NE
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CR
NED b
No
CR
PR
NED b
No
PR
SD
NED b
No
SD
NED a
Non-CR/non-PD
No
Non-CR/non-PD
NED a
CR
No
CR
NED a
NE
No
NE
NED a
NED b
No
NED
Any non-PD
Any non-PD
NE
NE
CRcomplete response; NEnot evaluable; NEDnon-evaluable disease; PDprogressive 
disease; PRpartial response; SDstable disease,
a
No target lesions identified at baseline
b
No non-target lesions identified at baseline.


Appendix 5: Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
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Table 2
Criteria for Overall Response in Patients with 
Non-Target Disease Only
Non-Target Lesions
New Lesions
Timepoint Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD
NE
No
NE
Unequivocal progression
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
Note:  Non-CR and non-PD are used instead of stable disease 
because no lesion can be measured.
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 measurements are made on only a subset of target 
lesions at a timepoint, 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 lesions would not change the assigned timepoint response.  This 
would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and during the study only 
two lesions were assessed, but those gave a sum of 80 mm, the patient will have 
achieved PD status, regardless of the contribution of the missing lesion.
SPECIAL NOTES ON RESPONSE ASSESSMENT
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
having "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 lesions as shown in Table 1 and Table 2.
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.
Fluorodeoxyglucose positron emission tomography (FDG PET) is not validated for the 
use in clinical trials to determine response but can be used to identify new lesions and 


Appendix 5: Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
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may benefit clinical decision-making.  Use of FDG-PET imaging to identify new lesions is 
presented in Table 3.
Table 3
Use of FDG-PET Imaging to Identify New Lesions
Baseline FDG-PET
Post-Baseline FDG-PET 
Determination
Negative FDG-PET
Positive FDG-PET
New lesion (PD)
None 
Positive FDG-PET 
corresponds to a new 
site of disease 
confirmed by CT or MRI
New lesion (PD)
None
Positive FDG-PET not 
confirmed as a new site 
of disease on CT or MRI
Additional follow-up CT or MRI scans are 
needed to determine if there is truly 
progression occurring at that site.
If so:  new lesion (PD) with date of PD 
being the date of the initial abnormal FDG-
PET scan date
If not:  not a new lesion
None
Positive FDG-PET that 
corresponds to a 
preexisting site of 
disease on CT or MRI 
that is not progressing 
on the basis of the 
anatomic images
Not a new lesion
CTcomputed tomography; FDG-fluorodeoxyglucose; MRImagnetic resonance imaging; 
PET positron emission tomography; PDprogression disease.
REFERENCES
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.
Schwartz LH, Litiére S, de Vries E, et al. RECIST 1.1update and clarification: from 
RECIST Committee. Euro J Cancer 2016;62:1327.


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Appendix 6
Response Assessment in Neuro-Oncology (RANO) Criteria
The Response Assessment in Neuro-Oncology (RANO) terminology used for the RANO 
criteria for characterizes lesions as measurable versus non-measurable and target 
versus non-target lesions in the brain.  Measurable lesions are ones that can be 
assessed quantitatively.  From among the measurable lesions, up to five target lesions 
will be selected at baseline (to be followed through a patient's treatment course).  Once 
a lesion is selected as a target lesion, it remains a target lesion, even if it falls below the 
size limits for what is considered as measurable at baseline.  The remaining lesions 
(additional measurable and/or non-measurable lesions) will be categorized as non-target 
lesions and do not require measurement, only qualititative assessment.  For patients 
with primary CNS disease, any metastases outside the brain are extremely rare.  In the 
event this does occur, the patient will be assessed by the investigator according to the 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1; see 
Appendix 5) (as a non-target lesion at baseline or new lesion post-baseline).
The parameters for image acquisition are to follow the consensus guidelines and 
standardized Brain Tumor Imaging Protocol (BTIP) (Ellingson et al. 2015).
RESPONSE ASSESSMENT IN NEURO-ONCOLOGY CRITERIA FOR 
HIGH-GRADE GLIOMA
Anti-tumor activity will be assessed based on clinical and radiographic evidence as 
specified by the RANO criteria.
All measurable and non-measurable lesions should be assessed using the same 
techniques as at baseline.  Ideally, patients should undergo imaging using the same 
magnetic resonance imaging (MRI) scanner or MR scanner of at least the same magnet 
strength for the duration of the study to reduce difficulties in interpreting changes.
Measurable disease is defined as contrast enhancing lesions with clearly defined 
margins by MRI scan, with two perpendicular diameters of at least 10 mm, visible on two 
or more axial slices that are preferably, at most, 5 mm apart with 0-mm skip.  If there are 
multiple contrast-enhancing lesions, up to five of the largest lesions that are suitable for 
reproducible measurements should be selected as target lesions and the sum of the 
products of the perpendicular diameters of such lesions should be determined.  If the 
MRI is performed with thicker slices (5 mm), the minimum size of a measurable lesion 
at baseline should be two times the slice thickness.  If there are interslice gaps, the 
perpendicular diameters must be at least two times the sum of the slice thickness and 
interslice gap for lesions to be considered measurable at baseline.  Measurement of 
tumor around a cyst or surgical cavity represents a particularly difficult challenge.  In 
general, such lesions should be considered non-measurable unless there is a nodular 
component measuring 10 mm in diameter.  The cystic or surgical cavity should not be 
measured in determining response.


Appendix 6: Response Assessment in Neuro-Oncology (RANO) Criteria
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Lesions with a necrotic component can be selected as target lesions if they are the only 
lesion(s) present, otherwise they should be selected as non-target lesions.
Non-measurable disease is defined as either other enhancing measurable lesions, 
masses with margins not clearly defined (non-enhancing FLAIR or T2 lesions) or 
enhancing lesions with maximal perpendicular diameters less than the minimum size for 
measurability (e.g., 10 mm).
Radiographic response should be determined in comparison to the tumor measurements 
obtained at pretreatment baseline (see Table 1).  The smallest tumor measurements at
either pretreatment baseline or after initiation of therapy should be used for 
determination of progression.  Target lesion response categories are defined by changes 
in enhancing tumor measurements; non-target lesions are assessed qualitatively (see 
Table 2).  Target lesion, non-target lesion (both enhancing and non-enhancing), and new
lesion status are combined as the radiologic (MRI) timepoint response (see Table 3).  
The MRI timepoint response is combined with clinical status and corticosteroid use to
derive the overall response per the RANO criteria.
Table 1
Target Lesion Response Categories
Response
Definition
CR
Disappearance of all target lesions
PR
50% decrease in SPD of longest diameters, taking as reference the baseline 
SPD with no evidence of progressive disease
SD
Neither sufficient shrinkage to qualify for a PR, nor sufficient increase to qualify 
for PD
PD
25% increase in the SPD of the longest diameters and the greatest 
perpendicular diameter of target lesions compared with the smallest recorded 
sum (nadir) during the study
NE
One or more target lesions cannot be assessed or accurately determined or were 
excised or irradiated and have not re-appeared or increased.  If in the event of 
one or more NE target lesions, the remainder of the evaluable target lesions 
compute to a response of PD (a 25% increase in the SPD of the longest 
diameters), then the target response will be PD
(not NE).
If there is a change in modalities and the reader is not confident that the images 
are truly comparable or reflect underlying biology, NE should be selected unless 
there is visually clear progression of these lesions.
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease; SPDsum of products of perpendicular diameters.


Appendix 6: Response Assessment in Neuro-Oncology (RANO) Criteria
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Table 2
Radiologic (MRI) Timepoint Response Categories in RANO
Criteria for HGG
Target
Lesions
Non-Target Lesions
New 
Lesions
MRI 
Timepoint 
Response
Contrast Enhancing
(T1)
Non-Contrast Enhancing
(FLAIR T2)
Combined
CR
Complete 
disappearance
Stable or improved
CR
No
CR
CR
Stable or NE
Stable or improved
SD
No
PR
PR
No unequivocal 
progression
Stable or improved
SD
No
PR
SD
No unequivocal 
progression
Stable or improved
SD
No
SD
NE
No unequivocal 
progression
Stable or improved
SD
No
NE
PD
Any
Any

Any
PD
Any
Unequivocal 
progression
Any
PD
Any
PD
Any
Any
Unequivocal 
progression
PD
Any
PD
Any
Any
Any

Yes
PD
NA a
Complete 
disappearance or 
stable
Stable or improved
CR or SD
No
SD
NA a
NA b
Not worse
SD
No
NED 
CRcomplete response; FLAIRfluid-attenuated inversion recovery; HGGhigh-grade glioma; 
MRImagnetic resonance imaging; NAnot applicable; NEnot evaluable; NEDno evidence of 
disease; PDprogressive disease; PRpartial response; RANO Response Assessment in 
Neuro-Oncology; SDstable disease.
a
No target lesions identified at baseline.
b
No non-target lesions identified at baseline.  


Appendix 6: Response Assessment in Neuro-Oncology (RANO) Criteria
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Table 3
RANO Criteria:  Incorporating MRI and Clinical Factors
Response 
Criteria for High-Grade Glioma
CR
Requires all of the following:
Confirmed CR on MRI (response sustained for at least 4 weeks with no signs 
of progression) sustained for at least 4 weeks
Patients must be off corticosteroids (or on physiological replacement doses 
only)
Clinical status is stable or improved
Note:  Patients with non-measurable disease at baseline only cannot have a CR; 
the best response possible is SD. 
PR
Requires all of the following:
Confirmed PR on MRI (response sustained for at least 4 weeks with no signs 
of progression)
Same or lower dose of corticosteroids compared to baseline
Clinical status is stable or improved
Note:  Patients with non-measurable disease only cannot have a PR; the best 
response possible is SD.
SD
Requires both of the following:
SD on MRI
Clinical status is stable or improved
Note:  In the event that the corticosteroid dose was increased for new symptoms 
and signs without confirmation of disease progression on neuroimaging, and 
subsequent follow-up imaging shows that this increase in corticosteroids was 
required because of disease progression, the last scan considered to show 
stable disease will be the scan obtained when the corticosteroid dose was 
equivalent to the baseline dose.
Progression
Defined by any of the following:
PD on MRI
Clear clinical deterioration not attributable to other causes apart from the 
tumor (e.g., seizures, medication adverse effects, complications of therapy, 
cerebrovascular events, infection, and so on) or changes in corticosteroid 
dose
Failure to return for evaluation due to death or deteriorating condition
CRcomplete response; MRImagnetic resonance imaging; PDprogressive disease; 
PRpartial response; RANO Response Assessment in Neuro-Oncology.
MEASURING LESIONS THAT SPLIT OR COALESCE ON TREATMENT
In case of 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.


Appendix 6: Response Assessment in Neuro-Oncology (RANO) Criteria
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MEASURING LESIONS THAT BECOME TOO SMALL TO MEASURE
During the study, all target lesions recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g., 
2 mm).  However, sometimes lesions that are recorded as target lesions at baseline 
become so faint that the radiologist may not feel comfortable assigning an exact 
measurement and may report them as being too small to measure.  When this occurs, it 
is important that a value be recorded 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 too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
selected and added to the sum of the SPD
Increase in corticosteroid dose alone, in the absence of clinical deterioration related to 
tumor, will not be used as a determinant of progression.  Patients with stable imaging 
studies whose corticosteroid dose was increased for reasons other than clinical 
deterioration related to tumor do not qualify for stable disease or progression.  They 
should be observed closely. If their corticosteroid dose can be reduced back to 
baseline, they will be considered as having stable disease; if further clinical deterioration 
related to tumor becomes apparent, they will be considered to have progression.  The 
date of progression should be the first time point at which corticosteroid increase was 
necessary.
The definition of clinical deterioration is left to the discretion of the treating physician, but 
it is recommended that a decline in the Karnofsky or Lansky Performance Status from 
100 or 90 to 70 or less, a decline in Performance Status of at least 20 from 80 or less, or 
a decline in Performance Status from any baseline to 50 or less, for at least 7 days, be 
considered neurologic deterioration unless attributable to comorbid events or changes in 
corticosteroid dose.
Patients with non-measurable enhancing disease whose lesions have significantly 
increased in size and become measurable (minimal bidirectional diameter of 10 mm 
and visible on at least two axial slices that are preferably, at most, 5 mm apart with 
0-mm skip) will also be considered to have experienced progression.  The transition from 
a non-measurable lesion to a measurable lesion resulting in progression can 
theoretically occur with relatively small increases in tumor size (e.g., a 99 mm lesion 
[non-measurable] increasing to a 10 11 mm lesion [measurable]).  Ideally, the change 
should be significant (5 mm increase in maximal diameter or 25% increase in the 
sum of the products of perpendicular diameters of enhancing lesions).


Appendix 6: Response Assessment in Neuro-Oncology (RANO) Criteria
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In general, if there is doubt about whether the lesion has progressed, continued 
treatment and close follow-up evaluation will help clarify whether there is true 
progression.  If there is uncertainty regarding whether there is progression, the patient 
may continue treatment and remain under close observation (e.g., evaluated at 4-week 
intervals).  If subsequent evaluations suggest that the patient is in fact experiencing 
progression, then the date of progression should be the timepoint at which this issue 
was first raised.
REFERENCES
Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for 
high-grade gliomas: Response Assessment in Neuro-Oncology Working Group. J 
Clin Oncol 2010;8:196372.
Wen PY, Chang SM, Van den Bent M, et al. Response Assessment in Neuro-Oncology 
Clinical Trials; J Clin Oncol 2017;35:243949.
RANO CRITERIA FOR LOW-GRADE GLIOMA
To be assessed using same methodology as described above for HGG assessed 
according to the RANO criteria with the exception that RANO LGG assessments will 
focus on FLAIR T2-weighted MRI sequences for analysis (see Table 4).  However,
progression will also include evidence of enhancement (T1-weighted MRI sequences).


Appendix 6: Response Assessment in Neuro-Oncology (RANO) Criteria 
  
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Table 4 
Radiology Lesion Timepoint Response Categories in RANO 
Criteria for LGG 
Target Lesions 
(FLAIR T2) 
Non-Target Lesions 
(FLAIR T2) 
New Lesions 
(FLAIR T2, T1) 
Timepoint 
Response 
CR 
CR 
No 
CR 
CR 
SD or NE 
No 
PR 
PR 
Any non-PD or NE 
No 
PR 
MR 
Any non-PD or NE 
No 
MR 
SD 
Any non-PD or NE 
No 
SD 
NE 
Any non-PD 
No 
NE 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Yes 
PD 
NA a 
CR or SD 
No 
SD 
NA a 
NA b 
No 
NED 
CR  complete response; FLAIR  fluid-attenuated inversion recovery; LGG  low-grade 
glioma; MR  minor response; NA  not applicable; NE  not evaluable; NED  no evidence 
of disease; PD  progressive disease; PR  partial response; RANO  Response 
Assessment in Neuro-Oncology; SD  stable disease. 
a 
No target lesions identified at baseline. 
b 
No non-target lesions identified at baseline. 
 
 
 


Appendix 6: Response Assessment in Neuro-Oncology (RANO) Criteria
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Table 5
Criteria for Response Assessment Incorporating MRI and 
Clinical Factors
Response 
Criteria for Low-Grade Glioma
Complete
response
Requires all of the following criteria compared with the baseline scan:
Complete disappearance of the lesion on T2 or FLAIR imaging (if 
enhancement had been present, it must have resolved completely)
No new lesions, no new T2 or FLAIR abnormalities apart from those 
consistent with radiation effects, and no new or increased enhancement
Patients must be off corticosteroids or only receiving physiological 
replacement doses.
Patients should be stable or improved clinically.
Partial 
response
Requires all of the following criteria compared with the baseline scan:
A 50% decrease in the product of perpendicular diameters of the lesion on 
T2 or FLAIR imaging sustained for at least 4 weeks compared with baseline
No new lesions, no new T2 or FLAIR abnormalities apart from those 
consistent with radiation effects, and no new or increased enhancement
Patients should be on a corticosteroid dose that should not be greater than 
the dose at time of baseline scan and should be stable or improved clinically
Minor 
response
Requires the following criteria compared with baseline:
A decrease of the area of non-enhancing lesion on T2 or FLAIR magnetic 
resonance imaging between 25% and 50% compared with baseline
No new lesions, no new T2 or FLAIR abnormalities apart from those 
consistent with radiation effect, and no new or increased enhancement
Patients should be on a corticosteroid dose that should not be greater than 
the dose at time of baseline scan and should be stable or improved clinically
Stable disease Is present if the changes do not qualify for complete, partial, or minor response, 
or progression and requires:
Stable area of non-enhancing abnormalities on T2 or FLAIR imaging
No new lesions, no new T2 or FLAIR abnormalities apart from those 
consistent with radiation effect, and no new or increased enhancement
Patients should be on a corticosteroid dose that should not be greater than 
the dose at time of baseline scan and should be stable or improved clinically
Progression
Defined by any of the following:
Development of new lesions or increase of enhancement (radiological 
evidence of malignant transformation)
A 25% increase of the T2 or FLAIR non-enhancing lesion on stable or 
increasing doses of corticosteroids compared with baseline scan or best 
response after initiation of therapy, not attributable to radiation effect or to 
comorbid events
Definite clinical deterioration not attributable to other causes apart from the 
tumor or decrease in corticosteroid dose
Failure to return for evaluation because of death or deteriorating condition, 
unless caused by documented non-related disorders
FLAIRfluid-attenuated inversion recovery; MRImagnetic response imaging; 
RANOResponse Assessment in Neuro-Oncology.
Note:  Adapted from Wen et al. 2012.


Appendix 6: Response Assessment in Neuro-Oncology (RANO) Criteria
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REFERENCES
Ellingson BM, Bendszus M, Boxerman J, et al. Consensus recommendations for a 
standardized Brain Tumor Imaging Protocol in clinical trials. Neuro Oncol 
2015;17:118898. doi:10.1093/neuonc/nov095.
Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for 
high-grade gliomas: Response Assessment in Neuro-Oncology Working Group. 
J Clin Oncol 2012;28:1963−72.


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Appendix 7
EQ-5D-5L
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 7: EQ-5D-5L
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Appendix 7: EQ-5D-5L
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144/Protocol BO41929, Version 4


Alectinib—F. Hoffmann-La Roche Ltd
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Appendix 8
European Organisation for the Research and Treatment of 
Cancer QLQ-C30
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 8: European Organization for Research and Treatment of Cancer QLQ-C30
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Alectinib—F. Hoffmann-La Roche Ltd
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Appendix 9 Investigator Oversight of Study Personnel
All sites
All investigators for this study are qualified and licensed oncologists who are responsible 
for patient care and execution of the study. The investigator may use the infrastructure 
and delegate study-related activities to personnel at their site or external vendors as 
necessary. The investigators will need to fulfill their responsibilities as per Good Clinical 
Practice, including oversight of all health care providers and vendors who perform 
study-related activities delegated to them by the investigator.
The description of the operational processes for the specific format of the study conduct 
applicable to the site (physical site or virtual site) is described in detail in the 
county-specific operational manual.
In order to allow flexibility to participate in the study there are two operational
approaches that can be used for study conduct as outlined below.
Virtual sites in the United States (Science 37 Metasites)
In the United States, these investigators will be geographically dispersed throughout the 
country. Investigators will sign a U.S. Food and Drug Administration (FDA) Form 1572.
The Science 37 study team is composed of investigators, mobile health care 
professionals (mHCPs), clinical research coordinators (CRCs), and the clinical study 
lead (CSL) who provides project management for the study.  In addition to the study 
team members described above, Science 37 will use service providers for the conduct of 
the study (e.g., investigational medicinal product [IMP] management by a preferred IMP 
depot service provider).
All study-team members will receive protocol-specific training from Science 37 and the 
Sponsor.  At the beginning of the study, a study protocol start-up/kickoff meeting will be 
held via teleconference to prepare the study team for conducting the study and to ensure 
the team is familiar with the study documentation, administrative procedures, 
responsibilities, and other relevant study information.  The study team will complete 
additional protocol-specific training, if the protocol changes during the study.
The Science 37 study team will hold regular internal meetings via teleconference to 
discuss Science 37 operations and study execution. Topics for these meetings may 
include study status, regulatory updates, adverse events, changes to the protocol or 
other procedures, and any study-related information that may affect the patient or 
workflows.  The frequency of meetings will be adjusted as necessary.  The CSL will be 
responsible for planning, scheduling, and leading these meetings and will be supervised 
by the investigators.  Meeting minutes will be distributed to ensure all staff are aware of 
what was discussed and the decisions made during the meeting.


Appendix 9: Investigator Oversight of Study Personnel
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Investigator responsibilities for providing supervision in this remote decentralized study 
are the same as they are in a conventional study and are consistent with those outlined 
in 21 CFR 312 and ICH E6 (R2) guidance.
Investigators will ensure that the study is conducted according to the investigational plan 
and that all applicable regulations for protecting the rights, safety, and welfare of patients 
are followed.  The Science 37 Platform enables ongoing communication between all 
members of the study team.  Investigators will communicate directly with the CSL, 
mHCP, and CRCs via teleconference, email, phone, text, or any appropriate and 
convenient mode of communication throughout the study as necessary.  In addition, 
investigators will have real-time access to study source data within the Science 
37 Platform.
Investigators in this study will delegate certain study-related tasks to other members of 
the study team.  When an investigator delegates study-related tasks, he or she is 
responsible for providing adequate supervision of those to whom tasks are delegated.  
The investigator will ensure that all study staff adhere to the study protocol (i.e., inclusion 
and exclusion criteria, safety assessments, safety monitoring, assessment of adverse 
events and reporting of serious adverse events, reporting of unanticipated problems, 
etc.).  Investigators will oversee mHCP activities by monitoring study-visit data within the 
Science 37 Platform, as well as during live study telemedicine interactions.
Study data will be collected during protocol-defined visits and entered manually into the 
eCRF.  Investigators will complete protocol assessments and document directly into the 
platform. The responsibility for transcribing selected data into the eCRF may also be 
delegated to the study’s CRC.  In instances where the data are not directly entered into 
the eCRF by an investigator, the information will be made available for review during 
routine core study team meetings and via routine study activities/status update reports to 
be provided as part of the ongoing oversight process:

Quality assurance reporting will be provided for investigator review addressing data 
types focused on the study-specific primary objectives and the data required to 
answer those objectives.

Data entry and documentation that require regulatory submissions will be reviewed 
and signed off by the investigator (protocol deviations, Investigator’s Brochure
submissions, protocol amendments, etc.).
Any issues related to study operations and study personnel will be discussed during 
regularly scheduled meetings or escalated ad hoc as necessary.  Relevant meeting 
discussions and decisions will be documented in meeting minutes, circulated for 
reference, and filed in the Investigator Site File.


Appendix 9: Investigator Oversight of Study Personnel
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Issues related to the IMP that take place during delivery between Roche and the IMP 
depot or during storage at the depot will be reported to Roche by the IMP depot and/or 
Science 37 upon identification, in line with Roche’s reporting requirements directed in 
the IMP management manual.  The IMP depot will keep records of the communication 
and will inform Science 37 in a timely manner.  IMP issues taking place after study drugs 
are shipped to the patients’ homes will be documented in the Science 37 Platform and 
reported to Roche as instructed in the study protocol and IMP management manual.
The study team will ensure that all communication and records associated with this 
study, including those that demonstrate appropriate and required oversight, will be saved 
and archived.  All research records will be available for inspection by authorized 
representatives of federal regulatory agencies, the Sponsor, and/or the Institutional 
Review Board.  Each investigator will ensure that the following records in the 
Investigator Site File are maintained by Science 37, and the investigator will have 
access to review these documents in real time:

A list of qualified persons to whom the investigator has delegated significant 
research-related duties

All records submitted to the Institutional Review Board with evidence of approval

All records of the disposition of the IMP

Current curriculum vitae of the investigator and study personnel

Appropriate documentation regarding study-specific Science 37 Platform access 
distinguishing all persons and roles authorized to make entries or corrections on 
data collection forms

Reports to document findings of study monitoring
Physical Sites (Investigator-Associated Institutions) in all countries, including the 
United States
Science 37 may not be involved.  The investigator will use the hospital infrastructure to 
conduct the study.
When physical study sites are used:

There will be no Science 37 coordinator; rather, the site coordinator will conduct 
activities delegated by the investigator.
The site coordinator will liaise with the mHCP vendor to coordinate visits to the 
patient’s home and set up the telemedicine sessions with the investigator and 
the patient.

The investigational medicinal product can be managed by the hospital’s pharmacy 
or by another licensed pharmacy if necessary.

Safety samples can be analyzed by a central or a local lab (investigator’s site).


Appendix 9: Investigator Oversight of Study Personnel
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
The investigator will make arrangements for imaging assessments to be completed 
as per-protocol at a facility, ideally one that is close to the patient’s home or to the 
investigator’s site.

The patient will be visited by a licensed mHCP who has been delegated to perform 
the assessments as per protocol.

The investigator will use the hospital medical records as the source documents,
including completed patient-reported outcomes and informed consent forms. The 
mHCPs will share their notes with the investigator as detailed in the country-specific
operations manual.  Data will be reported in RAVE by the investigator or 
investigator delegate as in the traditional clinical trial model, and on-site monitoring 
will take place at the investigator’s site.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN APPROVAL
SPONSOR:
LEGAL REGISTERED 
ADDRESS:
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124
4070 Basel, Switzerland
DATE FINAL:
See electronic date stamp above
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Alectinib—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan BO41929
STATISTICAL ANALYSIS PLAN
STUDY TITLE:
A PHASE II, OPEN-LABEL, SINGLE-ARM
DECENTRALIZED HOME-BASED APPROACH STUDY TO
EVALUATE THE EFFICACY AND SAFETY OF ALECTINIB
IN LOCALLY ADVANCED OR METASTATIC ALK-
POSITIVE SOLID TUMORS
STUDY NUMBER:
BO41929
STUDY NAME:
ALPHA-T
VERSION NUMBER:
1
ROCHE COMPOUND(S):
Alectinib (RO5424802)
EUDRACT NUMBER:
2021-002352-36
IND NUMBER:
111,723
NCT NUMBER:
04644315
PLAN PREPARED BY:
, Ph.D.
Date and Time(UTC)        Reason for Signing
Name
Company Signatory
17-Mar-2022 10:55:24


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Statistical Analysis Plan BO41929
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STATISTICAL ANALYSIS PLAN VERSION HISTORY
This Statistical Analysis Plan (SAP) was developed based on Roche SAP model 
document Version 2, 26 October 2020.
SAP Version
Approval Date
Based on Protocol
(Version, Approval Date)
1
see electronic date stamp 
on title page
Version 4, 24 November 2021


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TABLE OF CONTENTS
1.
INTRODUCTION .......................................................................................... 8
1.1
Objectives and Endpoints........................................................ 8
1.1.1
Expression of Objectives and Endpoints using 
the Estimand Framework....................................................... 10
1.2
Study Design ......................................................................... 11
1.2.1
Treatment Assignment........................................................... 13
1.2.2
Blinded Independent Center Review ..................................... 13
1.2.3
Data Monitoring ..................................................................... 13
2.
STATISTICAL HYPOTHESES.................................................................... 13
3.
SAMPLE SIZE DETERMINATION.............................................................. 14
4.
ANALYSIS SETS ........................................................................................ 14
5.
STATISTICAL ANALYSES ......................................................................... 16
5.1
General Consideration........................................................... 16
5.2
Participant Disposition ........................................................... 16
5.3
Primary Endpoint Analysis..................................................... 16
5.3.1
Definition of Primary Endpoint ............................................... 16
5.3.2
Main Analytical Approach for Primary Endpoint..................... 16
5.3.3
Sensitivity Analyses for Primary Endpoint ............................. 16
5.3.4
Supplementary Analyses for Primary Endpoint ..................... 17
5.3.4.1
Subgroup Analyses for Primary Endpoint.............................. 17
5.4
Secondary Endpoints Analyses............................................. 17
5.4.1
Key Secondary Endpoint ....................................................... 17
5.4.2
Supportive Secondary Endpoints .......................................... 17
5.4.2.1
Duration of Response............................................................ 17
5.4.2.2
Progression-Free Survival ..................................................... 17
5.4.2.3
Overall Survival ..................................................................... 17
5.4.2.4
CNS Objective Response Rate ............................................. 17
5.4.2.5
CNS Duration of Response ................................................... 18
5.4.2.6
Efficacy in Patients with Primary CNS Tumors...................... 18


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5.4.2.7
Efficacy in Patients with Solid Tumors without 
ALK Fusions, Harboring Defined ALK Mutations 
(R1275Q, F1245C, F1174X, with X being any 
other amino acid)................................................................... 18
5.4.2.8
Efficacy in Patients with CUP ................................................ 19
5.5
Exploratory Endpoints Analyses............................................ 19
5.5.1.1
Efficacy in Patients with ALK-Positive CUP and 
Non-CUP Solid Tumors ......................................................... 19
5.5.1.2
Patient Reported Outcomes: EORTC Data ........................... 19
5.6
Safety Analyses..................................................................... 20
5.6.1
Extent of Exposure ................................................................ 20
5.6.2
Adverse Events ..................................................................... 20
5.6.3
Laboratory Data..................................................................... 21
5.6.4
Vital Signs.............................................................................. 21
5.6.5
ECGs..................................................................................... 21
5.7
Other Analyses...................................................................... 21
5.7.1
Summaries of Conduct of Study............................................ 21
5.7.2
Summaries of Demographics and Baseline 
Characteristics....................................................................... 21
5.7.3
Pharmacokinetic Analyses..................................................... 22
5.7.4
Biomarker Analyses............................................................... 22
5.7.5
Health Status Utility Analyses................................................ 23
5.8
Interim Analyses .................................................................... 23
6.
SUPPORTING DOCUMENTATION............................................................ 23
7.
REFERENCES ........................................................................................... 24
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints..................................... 8
Table 2
Objectives and Estimands........................................................... 11
Table 3
ORR Scenarios with Associated 95% CI .................................... 14
Table 4
Analysis Populations................................................................... 15


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LIST OF FIGURES
Figure 1
Study Schema............................................................................. 12


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation or Term
Description
AE
adverse event
ALK
anaplastic lymphoma kinase
BICR
blinded independent center review
BID
twice a day
CI
confidence interval
CNS
central nervous system
CR
complete response
COVID-19
corona virus disease 2019
CUP
cancer of unknown primary (site)
DNA
deoxyribonucleic acid
DOR
duration of response
ECOG
Eastern Cooperative Oncology Group
EORTC
European Organisation for the Research and Treatment of Cancer
EQ-5D-5L
EuroQol 5-Dimension, 5-Level
FMI
Foundation Medicine Inc.
F1HEME
FoundationOneHeme test on blood
F1CDx
FoundationOne CDx test on tissue
F1LCDx
FoundationOne Liquid CDx test on blood
ICH
International Council on Harmonization
IMC
Internal Monitoring Committee
MedDRA
Medical Dictionary for Regulatory Activities
NCI CTCAE v5.0
National Cancer Institute Common Terminology Criteria for 
Adverse Events Version 5.0
NGS
next-generation sequencing
ORR
objective response rate
OS
overall survival
PR
partial response
PFS
progression-free survival
PRO
patient-reported outcomes
PK
pharmacokinetic
QoL
quality of life
GHS/QoL
Global health status
QLQ-C30
Quality of Life Questionnaire
QTcF
QT interval corrected through use of Fridericia's formula
RANO
Response Assessment in Neuro-Oncology


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RECIST v1.1
Response Evaluation Criteria in Solid Tumors, Version 1.1
SAE
serious adverse events
SAP
Statistical Analysis Plan
SMQs
standardized MedDRA queries


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1.
INTRODUCTION
This study will evaluate the efficacy and safety of alectinib in patients with anaplastic 
lymphoma kinase (ALK)-positive locally advanced or metastatic solid tumors other than 
lung cancer.  Specific objectives and corresponding endpoints for the study are outlined 
in Table 1.
1.1
OBJECTIVES AND ENDPOINTS
Table 1
Objectives and Corresponding Endpoints
Efficacy Objectives and Endpoints patients with anaplastic lymphoma kinase 
(ALK) fusion Solid Tumors (excluding Enrolled Patients with CUP and CNS 
Primary Tumors)
Primary Objective
Corresponding Endpoint

To demonstrate a clinically 
relevant response to alectinib 
treatment

Confirmed objective response rate (ORR), 
defined as the proportion of patients with a 
complete response (CR) or a partial 
response (PR) confirmed ≥28 days after 
initial response, as determined by the 
investigator according to Response 
Evaluation Criteria in Solid Tumors, Version 
1.1 (RECIST v1.1)
Secondary Objectives
Corresponding Endpoints

The same as the primary 
endpoint

According to the blinded independent center 
review (BICR)

To evaluate the duration of 
response (DOR)

DOR, defined as the time from the first 
occurrence of a documented objective 
response to disease progression or death 
from any cause (whichever occurs first), as 
determined by both the investigator and by 
BICR according to RECIST v1.1

To evaluate progression-free 
survival (PFS)

PFS, defined as the time from first dose of 
alectinib treatment to disease progression or 
death from any cause, as determined by 
both the investigator and BICR according to 
RECIST v1.1

To evaluate overall survival 
(OS)

OS, defined as the time from first dose of 
study drug to death from any cause
Efficacy Objectives and Endpoints patients with other Disease Characteristics

To evaluate central nervous 
system (CNS) response in 
patients with measurable CNS 
metastases at baseline 

CNS ORR, defined as objective tumor 
response rate (a CR or a PR) of CNS 
lesions by BICR according to RECIST v1.1


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Table 1
Objectives and Corresponding Endpoints (cont.)

To evaluate the CNS duration 
of response

CNS DOR, defined as the time from the first 
observation of CNS response until the first 
observation of CNS progression or death 
from any cause by BICR according to 
RECIST v1.1

To evaluate the efficacy of 
alectinib in ALK fusion−positive 
patients with primary CNS 
tumors according to Response 
Assessment in Neuro-Oncology 
(RANO) criteria 

ORR, DOR, and PFS as determined by both 
the investigator and BICR

OS

To evaluate the efficacy of 
alectinib in patients with solid 
tumors without ALK fusions, 
harboring defined ALK 
mutations (R1275Q, F1245C, 
F1174X, with X being any other 
amino acid) 

ORR, DOR, and PFS as determined by both 
the investigator and BICR according to 
RECIST v1.1

CNS ORR and DOR in patients with CNS 
metastases at baseline by BICR according 
to RECIST v1.1

OS

To evaluate the efficacy of 
alectinib in patients with cancer 
of unknown primary (site) 
(CUP)

ORR, DOR, and PFS as determined by both 
the investigator and BICR according to 
RECIST v1.1

CNS ORR and DOR in patients with CNS 
metastases at baseline, as determined by 
BICR according to RECIST v1.1

OS
Exploratory Efficacy Objectives
Corresponding Endpoints

To evaluate the efficacy of 
alectinib in patients with ALK-
positive CUP and non-CUP 
solid tumors

ORR, DOR, and PFS as determined by both 
the investigator and BICR according to 
RECIST v1.1

CNS ORR and DOR in patients with CNS 
metastases at baseline, as determined by 
BICR according to RECIST v1.1

OS

To evaluate the function, 
disease/treatment-related 
symptoms, and health-related 
quality of life

Change from baseline in QLQ-C30 scores 
during study treatment


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Table 1
Objectives and Corresponding Endpoints (cont.)
Safety Objective
Corresponding Endpoints

To evaluate the safety of 
alectinib in all dosed patients

Incidence and severity of adverse events, 
including serious adverse events, with 
severity determined according to National 
Cancer Institute Common Terminology 
Criteria for Adverse Events Version 5.0 
(NCI CTCAE v5.0)

Change from baseline in targeted vital signs

Change from baseline in targeted clinical 
laboratory test results
Pharmacokinetic (PK) Objective
Corresponding Endpoints

To characterize the alectinib PK 
profile

Plasma concentrations of alectinib and its 
metabolite(s) as applicable at specified time 
points
Exploratory Biomarker Objectives
Corresponding Endpoints

To identify and/or evaluate 
biomarkers that are associated 
with primary or acquired 
resistance to alectinib in the 
biomarker-evaluable population

To evaluate the impact of levels 
of circulating free DNA (cfDNA)

Relationship between biomarkers found in 
circulating deoxyribonucleic acid (DNA) in 
blood and tumor tissue, with efficacy 
endpoints

Relationship between levels of cfDNA at 
baseline and changes in levels of cfDNA at 
different timepoints during treatment with 
efficacy endpoints
Health Status Utility Objective
Corresponding Endpoint

To evaluate health status utility 
scores

Change from baseline in EuroQol 5-
Dimension Questionnaire (5-level version; 
EQ-5D-5L) index-based and Visual Analog 
Scale (VAS) scores during study treatment
1.1.1
Expression of Objectives and Endpoints using the Estimand 
Framework
The primary study objective and corresponding endpoint, as well as the main secondary 
efficacy objective and the corresponding secondary efficacy endpoints, are expressed 
using the estimand framework in Table 2, in accordance with the International 
Conference on Harmonization E9 (R1) statistical principles for clinical trials (ICH 2020).


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Table 2
Objectives and Estimands
Primary Efficacy 
Objective
Estimand Definition

To demonstrate a 
clinically relevant 
response to 
alectinib treatment

Population: Patients with ALK fusion solid tumors 
(excluding enrolled patients with CUP and CNS primary 
tumors) with measurable disease at baseline who have a 
baseline tumor assessment per the investigator according 
to RECIST v1.1 and receive at least one dose of alectinib 
(response-evaluable population)

Variable: Confirmed ORR, defined as the proportion of 
patients with a CR or a PR 28 days after initial response 
in patients with solid tumors, as determined by the 
investigator according to RECIST v1.1

Treatment: Experimental: alectinib at the dose of 600 mg 
BID until disease progression, death, or withdrawal for any 
other reasons

Intercurrent events:

Start of additional or alternative therapy

Early discontinuation from study treatment 
for any reason or withdrawal from study

Handling of intercurrent events: A treatment policy with 
regards to the intercurrent events listed above will be 
applied for the primary analysis.

Summary measure: Confirmed ORR
Main Secondary 
Efficacy Objective
Estimand Definition

To demonstrate a 
clinically relevant 
response to 
alectinib treatment

According to the blinded independent center review (BICR)
ALKanaplastic lymphoma kinase; BIDtwice a day; CRcomplete response; CNScentral 
nervous system; CUPcancer of unknown primary (site); ORRobjective response rate; 
PRpartial response; RECISTResponse Evaluation Criteria in Solid Tumors.
1.2
STUDY DESIGN
This Phase II, open-label, single-arm study is designed to investigate the efficacy and 
safety of alectinib in patients with locally advanced or metastatic solid tumors (excluding 
lung cancer) that are determined to be ALK-positive per the Foundation Medicine Inc. 
(FMI) next-generation sequencing (NGS) test on tissue or blood (FoundationOne CDx 
[F1CDx] or FoundationOne Liquid CDx [F1LCDx] or FoundationOneHeme [F1HEME]).  


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ALK positivity determined per local accredited laboratory NGS-validated testing on tissue 
or blood may be accepted.
Patients can be identified by means of one of the two following enrollment pathways:
1.
The Precision Enrollment approach offered by FMI.  Briefly, when non−lung cancer 
samples are determined by FMI central testing to be positive for ALK, an FMI 
medical oncologist will contact the ordering physician (local oncologist) and provide 
information about the trial.  If this is of interest to both the physician and the patient, 
enrollment procedures will begin.
2.
Patients with ALK-positive NGS test results obtained outside FMI’S Precision 
Enrollment approach may be identified and the local ALK NGS test report will be 
made available (see Section 4.6.6) and will be assessed by the investigator for 
eligibility.  The study team and Medical Monitor are to be consulted.  If ALK positivity 
is not accepted per the criteria, prospective FMI testing is required and the patient 
may be enrolled if assessed to be ALK-positive by FMI.
Patients with both ALK-fusion and selected ALK mutations will be enrolled in the study.  
Enrollment will end once approximately 50 patients with ALK fusion solid tumors 
evaluable by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
have been recruited, regardless of the number of enrolled patients with primary central 
nervous system (CNS) tumors (evaluable according to Response Assessment in Neuro-
Oncology [RANO] criteria), with cancer of unknown primary (site) (CUP) or ALK 
mutations.
The study schema is shown in Figure 1.
Figure 1
Study Schema 
ALKanaplastic lymphoma kinase; BIDtwice a day; ECOG Eastern Cooperative Oncology 
Group; F/Ufollow-up; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 
1.1.
An interim, non-binding analysis will be performed once the first 15 RECIST v1.1 
investigator-assessed response-evaluable patients with ALK fusions (excluding patients 
with primary CNS tumors and patients with CUP) have a response evaluation at 8 weeks 
available (unless they progressed or discontinued earlier from the study).  If the analysis 
result shows that the response rate does not achieve at least 25% (4 responders), the 
study may be terminated due to futility.


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The primary analysis will take place once all patients have been followed for a minimum 
of 24 weeks (i.e., three tumor assessments) to allow confirmation of any observed 
complete response (CR) or partial response (PR), unless they progressed or withdrew 
from sooner from the study.
The end of this study is defined as the date when the last patient, last visit, occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is 
received from the last patient, whichever occurs later.  The end of the study is expected 
to occur approximately in 2026.
In addition, the Sponsor may decide to terminate the study at any time.
The length of the study is expected to be approximately 5 years.
1.2.1
Treatment Assignment
This is a Phase II, open-label, single-arm study.  Patients with both ALK fusion and 
selected ALK mutations will be enrolled in the study.
1.2.2
Blinded Independent Center Review
Scans will be sent for blinded independent center review (BICR) for assessment of 
responses according to RECIST v1.1 and, for patients with primary CNS tumors, 
according to RANO criteria.
Assessments performed by BICR will not be shared with the investigator and will have 
no impact on the management of the patient. Further details are included in the BICR 
Charter.
1.2.3
Data Monitoring
An internal monitoring committee (IMC) will monitor patient safety throughout the study, 
focusing on death cases and interim futility analysis.  The IMC will include Sponsor’s 
representatives from Clinical Science, Clinical Safety, and Biostatistics.  The IMC will 
review all necessary cumulative data at regular intervals during the study.  At the time of 
each review, the IMC will make appropriate recommendations (e.g., the study should 
continue as planned, the protocol should be amended, enrollment should be held 
pending further safety evaluations).  Decisions will be made in consideration of the 
totality of the available data.  Ad-hoc meetings may be called in addition to scheduled 
meetings, as necessary, to provide recommendations on management of any new safety 
issues.  Specific operational details such as the Committee's composition, frequency and 
timing of meetings, and members' roles and responsibilities are provided in the IMC 
Charter.
2.
STATISTICAL HYPOTHESES
It will be tested that the confirmed ORR is greater than 30% which is assumed to be the 
minimal clinically relevant response rate.


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3.
SAMPLE SIZE DETERMINATION
Patients with both ALK fusion and selected ALK mutations will be enrolled in the study.  
Enrollment will end once around 50 patients with ALK fusions solid tumors evaluable 
according to RECIST v1.1 have been recruited (regardless of the number of enrolled 
patients with primary CNS tumors, CUP, or harboring selected ALK mutations).
This sample size has been chosen so that for the primary analysis the lower limit of the 
two-sided 95% confidence interval (CI) (using an exact Clopper-Pearson CI) around the 
point estimate of the confirmed ORR according to RECIST v1.1 will represent a clinically 
relevant response.  With a sample size of 50 patients, an observed response rate of 
46% (23 of 50 responses) would have a lower limit of the two-sided 95% CI of 31.8%, 
which is considered to be clinically relevant in this tissue-agnostic, biomarker-defined 
population with no available treatment options.  With 50 patients, there is 70% power to 
detect a 16% increase in ORR from clinically relevant 30% to 46% at the 5% two-sided 
significance level.
Different ORR scenarios with their associated 95% CI are presented in Table 3.
Table 3
ORR Scenarios with Associated 95% CI
Expected ORR
Expected Number of Patients 
with a Response
95% CI for ORR a
46%
23
(31.81%, 60.68%)
48%
24
(33.66%, 62.58%)
50%
25
(35.53%, 64.47%)
CIconfidence interval; ORRobjective response rate.
a Using the Clopper-Pearson method and given a sample size of 50 patients.
With a sample size of 50 patients, an ORR of 46% will have an associated 95% CI of 
31.81% to 60.68%.
4.
ANALYSIS SETS
The following populations are defined:


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Table 4
Analysis Populations
Population
Definition
Response-evaluable 
population
All patients with ALK fusion−positive solid tumors (excluding 
patients with CUP and primary CNS tumors) with measurable 
disease at baseline (who have a baseline tumor assessment) 
per the investigator according to RECIST v1.1 and have 
received at least one dose of study treatment.
Response-evaluable 
population with measurable 
CNS disease at baseline
All patients with measurable CNS disease at baseline 
evaluable per the investigator according to RECIST v1.1 who 
have received at least one dose of study treatment.
Primary CNS tumor 
response-evaluable 
population
All patients with ALK fusion CNS primary tumors with 
measurable disease at baseline evaluable according to RANO 
criteria who receive at least one dose of study treatment.
CUP response-evaluable 
population
All patients with CUP with measurable disease at baseline 
evaluable according to RECIST v1.1 who receive at least one 
dose of study treatment.
ALK-mutations response-
evaluable population
All patients with ALK mutations with measurable disease at 
baseline evaluable according to RECIST v1.1 who receive at 
least one dose of study treatment.
Exploratory ALK-positive 
CUP and non-CUP 
response-evaluable 
population
All patients with ALK-positive CUP and non-CUP solid tumors 
who receive at least one dose of study treatment.
Responders
All patients with a response according to the specified 
endpoints for the analysis of the duration of response
PK-evaluable population
All patients who received any dose of study medication and 
who have at least one post-baseline PK sample available.
Safety-evaluable
All participants who received at least one dose of study 
treatment.  
ALKanaplastic lymphoma kinase; CUPcancer of unknown primary (site); CNScentral 
nervous system; PKpharmacokinetic; RANOResponse Assessment in Neuro-Oncology; 
RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1.
All populations that are defined accordingly by the investigator assessment are defined 
in the same way by BICR, depending on who is assessing the endpoint.
Replacement of patients with ALK fusion solid tumors assessed according to 
RECIST v1.1 who discontinue their participation in the study will be allowed if enrolled 
patients have not received any dose of alectinib.
All patients must have measurable disease at baseline as assessed by investigator 
according to the inclusion criteria. Therefore, progression free survival (PFS) and overall 
survival (OS) will be assessed in the response-evaluable populations of the patients with 


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the respective disease characteristics. For PFS analyses by BICR the population 
defined by the investigator is taken into account.
5.
STATISTICAL ANALYSES
5.1
GENERAL CONSIDERATION
The analyses outlined in this statistical analysis plan (SAP) supersede those specified in 
the protocol for the purpose of a regulatory filing.
ORR, duration of response (DOR), and PFS are determined by the investigator and by 
BICR according to RECIST v1.1 and RANO respectively. Secondary endpoint analyses 
for the endpoint by BICR are as well sensitivity analyses for that endpoint by 
investigator.
CNS ORR and DOR are determined in patients with CNS metastases at baseline only 
by BICR according to RECIST v1.1.
The analyses will be performed in the populations specified in Section 4.
5.2
PARTICIPANT DISPOSITION
The patient status (on treatment, off treatment, in long-term follow-up, lost-to-follow-up 
and dead) and the time of efficacy follow-up will be summarized.
5.3
PRIMARY ENDPOINT ANALYSIS
5.3.1
Definition of Primary Endpoint
The primary efficacy endpoint is confirmed ORR as determined by the investigator in 
patients with ALK fusion solid tumors (excluding enrolled patients with CUP and CNS 
primary tumors). An objective response is defined as a CR or a PR according to 
RECIST v1.1. Confirmation of objective response is required (confirmed ≥28 days apart 
in two separate tumor assessments). Patients not meeting this criterion (including 
patients without a post-baseline tumor assessment) will be considered as non-
responders. ORR is defined as the proportion of patients with measurable disease at 
baseline who have an objective response in the response-evaluable population.
5.3.2
Main Analytical Approach for Primary Endpoint
An estimate of the confirmed ORR and its two-sided 95% CI using the Clopper-Pearson 
method will be calculated. The confirmed ORR will be tested against the minimal 
clinically relevant ORR of 30% in this tissue-agnostic, biomarker-defined population with 
no available treatment options at the 5% two-sided significance level, i.e., the lower limit 
of the Clopper-Pearson CI must be bigger than 30%.
5.3.3
Sensitivity Analyses for Primary Endpoint
see Section 5.1.


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5.3.4
Supplementary Analyses for Primary Endpoint
5.3.4.1
Subgroup Analyses for Primary Endpoint
The generalizability of the confirmed ORR results will be investigated by estimating the 
effect in subgroups including by sex, age, and race.
5.4
SECONDARY ENDPOINTS ANALYSES
5.4.1
Key Secondary Endpoint
The key secondary efficacy endpoint is confirmed ORR as determined by the BICR in 
patients with ALK fusion solid tumors (excluding enrolled patients with CUP and CNS 
primary tumors). The same analyses as for the primary endpoint will be applied.
5.4.2
Supportive Secondary Endpoints
5.4.2.1
Duration of Response
DOR is defined as the time from the date of the first occurrence of a CR or a PR 
(whichever status is recorded first) to the date of the first documented disease 
progression or death due to any causes, whichever occurred first.  The DOR will be 
assessed in patients who had a confirmed objective response during the study, as 
determined by the investigator or BICR per RECIST v1.1.  Patients who have not 
progressed or died at the time of analysis will be censored at the last tumor assessment 
date.  If no tumor assessments are performed after the date of the first occurrence of a 
CR or a PR, DOR will be censored at the date of the first occurrence of a CR or a PR.  
The Kaplan-Meier methodology will be used to estimate the median DOR and to 
construct survival curves.  The Brookmeyer-Crowley methodology will be used to 
construct the 95% CI for the median DOR (Brookmeyer and Crowley 1982).
5.4.2.2
Progression-Free Survival 
Progression free survival is defined as the time from the first date of treatment to the 
date of first documented disease progression or death, whichever occurs first.  Disease 
progression will be assessed by the investigator or the BICR using RECIST v1.1.  
Patients who have not experienced disease progression or died at the time of analysis 
will be censored at the last tumor assessment date.  Patients with no post-baseline 
tumor assessment will be censored at the first date of treatment. The analysis methods 
are the same as for the DOR defined above.
5.4.2.3
Overall Survival
Overall survival is defined as the time from the first date of treatment to the date of death 
due to any cause.  Patients who are not reported as dead at the time of the analysis will 
be censored at the date when they were last known to be alive. If no post-baseline 
information is available, then OS will be censored at the date of the first treatment.  The 
analysis methods are the same as for the DOR defined above.
5.4.2.4
CNS Objective Response Rate
For patients with ALK-fusion positive tumors (excluding patients with CUP and patients 
with CNS primary tumors), who present with measurable CNS metastases at baseline 


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an analysis of CNS ORR defined as the percentage of patients who achieve a best 
overall response of a CR or a PR of CNS lesion (defined according to RECIST v1.1) will 
also be performed in the response-evaluable population with measurable CNS disease 
at baseline.  CNS CR and PR will be assessed by BICR.  The analysis methods are the 
same as for the primary endpoint. Confirmation of objective response is not required.
5.4.2.5
CNS Duration of Response
For patients who had a CNS objective response during the study, an analysis of CNS 
DOR, defined as the time from the date of the first occurrence of CNS CR or PR 
(whichever status is recorded first) to the date of the first documented disease CNS 
progression or death due to any causes, whichever occurred first, will be conducted.  
CNS disease progression will be assessed by BICR using RECIST v1.1.  The analysis 
methods are the same as for the DOR defined above. Confirmation of objective 
response is not required.
5.4.2.6
Efficacy in Patients with Primary CNS Tumors
For patients with primary CNS tumors with measurable disease at baseline who have a 
baseline tumor assessment per the investigator according to RANO criteria and receive 
at least one dose of alectinib:

ORR, DOR, and PFS in all ALK fusion−positive patients who have measurable 
disease at baseline as determined by both the investigator and BICR

OS
The analysis methods are the same as for the respective endpoints defined above.
5.4.2.7
Efficacy in Patients with Solid Tumors without ALK Fusions, 
Harboring Defined ALK Mutations (R1275Q, F1245C, F1174X, 
with X being any other amino acid)
For patients with solid tumors without ALK fusions, harboring defined ALK mutations 
(R1275Q, F1245C, F1174X, with X being any other amino acid) and receive at least 
one dose of alectinib:

ORR, DOR, and PFS as determined by the investigator and by BICR according to 
RECIST v1.1

CNS ORR and DOR in patients with CNS metastases at baseline by BICR
according to RECIST v1.1

OS
Confirmation of objective response is not required.
The analysis methods are the same as for the respective endpoints defined above.


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5.4.2.8
Efficacy in Patients with CUP
For patients with CUP who receive at least one dose of alectinib:

ORR, DOR, and PFS as determined by both the investigator and BICR according to 
RECIST v1.1

CNS ORR and DOR in patients with CNS metastases at baseline, as determined by 
BICR according to RECIST v1.1

OS
The analysis method is the same as for the respective endpoints defined above.
For some populations, depending on the number of patients, a formal analysis will not be 
produced; instead, listings or spider plots could be used.
5.5
EXPLORATORY ENDPOINTS ANALYSES
5.5.1.1
Efficacy in Patients with ALK-Positive CUP and Non-CUP Solid 
Tumors
For patients with ALK-positive CUP and non-CUP solid tumors who receive at least one 
dose of alectinib:

ORR, DOR, and PFS as determined by both the investigator and BICR according to 
RECIST v1.1

CNS ORR and DOR in patients with CNS metastases at baseline, as determined by 
BICR according to RECIST v1.1

OS
The analysis methods are the same as for the respective endpoints defined above.
5.5.1.2
Patient Reported Outcomes: EORTC Data
The quality of life questionnaire core 30 (QLQ-C30) questionnaires will be used to 
assess the impact of alectinib on patients' quality of life and daily function.  All patients 
who receive at least one dose of alectinib will be analyzed. Completion rates will be 
summarized by number and proportion of patients among those expected to complete 
each questionnaire at each timepoint. Reasons for non-completion will be summarized 
at each timepoint if available.
The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 
(Version 3) data will be scored according to the EORTC scoring manual 
(Fayers et al. 2001).  In the event of incomplete data, if the scale has more than 50% of 
the constituent items completed, a pro-rated score will be computed consistent with the 
scoring manual and validation papers of the measure.  For subscales with less than 50% 
of the items completed, the subscale will be considered missing.
Summary statistics (mean, standard deviation, median, and range) of linearly 
transformed absolute scores and mean changes from baseline will be calculated for the 
function, disease/treatment-related symptom-, and Global Health Status (GHS)/Quality 


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of life (QoL) scales of the EORTC QLQ-C30 at each assessment timepoint.  The mean 
(and 95% CI) and median of the absolute scores and the changes from baseline will be 
reported on patients with a baseline and at least one post-baseline assessment.  
Previously published minimally important differences will be used to identify meaningful 
change from baseline within the treatment group on the functional and GHS/QoL scales 
(Osoba et al. 1998; Cocks et al. 2011).
5.6
SAFETY ANALYSES
Safety analyses will be performed on the safety evaluable population, defined as all 
enrolled patients who received any amount of study drug
5.6.1
Extent of Exposure
Study drug exposure, including treatment duration, number of doses, dose intensity and 
total cumulative dose will be summarized with descriptive statistics.  
5.6.2
Adverse Events
Verbatim description of adverse events (AEs) will be mapped to Medical Dictionary for 
Regulatory Activities thesaurus terms and graded according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
After informed consent has been obtained but prior to initiation of study drug, only 
serious AEs caused by a protocol-mandated intervention (e.g., invasive procedures such 
as biopsies, discontinuation of medications) are collected.
After initiation of study drug, all adverse events will be collected until 28 days after the 
final dose of study drug.
After the end of the adverse event reporting period, all deaths, regardless of cause, and 
serious adverse events that are believed to be related to prior exposure to study drug 
are collected.
All AEs that occur on or after the first study drug dose (treatment-emergent AEs) will be 
reported. They will be summarized using descriptive statistics (i.e., frequencies and 
percentages) by Medical Dictionary for Regulatory Activities (MedDRA) term, 
appropriate MedDRA levels, and NCI CTCAE v5.0 grade, regardless of relationship to 
study drug as assessed by the investigator.  For each patient, if multiple incidences of 
the same adverse events occur, the maximum severity reported will be used in the 
summaries.
The following treatment-emergent adverse events will be summarized separately:

AEs

AEs leading to withdrawal of study drug

AEs leading to dose reduction or interruption


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
Grade 3/4 AEs, Grade 5 AEs, serious adverse events 

AEs of special interest
All deaths and causes of death will be summarized.
Subgroup analyses will be performed to evaluate the safety profile within subgroups of 
patients, including by sex, age (< 65 years vs. ≥65 years), region, and race.
5.6.3
Laboratory Data
Clinically relevant shifts from baseline in NCI CTCAE v5.0 grade (defined as shifts from 
Grade 0, 1, or 2 at baseline to Grade 3 or 4 post baseline) will be also provided.  Of 
note, abnormal laboratory data that are clinically significant will be reported as AEs and 
summarized in the AE tables.
A Hy’s Law analysis will be provided:  the finding of an elevated ALT or AST 
(>3 ⋅baseline value) in combination with either an elevated total bilirubin (>2 ⋅upper limit 
of normal) 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).
5.6.4
Vital Signs
Change from baseline in selected vital signs will be summarized (diastolic/systolic blood 
pressure, pulse rate, temperature, respiratory rate).
5.6.5
ECGs
Changes from baseline in the following ECGs parameters will be summarized: heart 
rate, RR interval, QRS interval, PR duration, uncorrected QT interval, and QT interval 
corrected through use of Fridericia's formula (QTcF) based on the machine readings of 
the individual ECG tracings.
5.7
OTHER ANALYSES
5.7.1
Summaries of Conduct of Study
Study enrollment, reasons for discontinuation from study drug, and reasons for 
premature study discontinuation will be listed and summarized for all patients, including 
any related to Corona virus disease 2019 (COVID-19).
Major protocol deviations, including major deviations of inclusion/exclusion criteria, as 
well as any related to the COVID-19, will be reported and summarized.
5.7.2
Summaries of Demographics and Baseline Characteristics
For all patients, demographic and baseline characteristics (including age, sex, 
race/ethnicity, baseline disease characteristics, and medical history) will be summarized 
using means, standard deviations, medians, ranges, and interquartile ranges for 


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continuous variables, and frequencies and percentages for categorical variables, as 
appropriate.
Baseline measurements are the last available data obtained prior to the patient receiving 
the first dose of alectinib.
Previous and concomitant cancer therapy will be summarized, including radiotherapy 
and surgery, as well as subsequent anti-cancer therapy.  Previous and concurrent 
diseases and medications will also be summarized.
5.7.3
Pharmacokinetic Analyses
The pharmacokinetic (PK)-evaluable population will consist of all patients who have at 
least one post-baseline quantifiable PK sample available.
Nonlinear mixed-effects modeling (with software NONMEM) will be used to analyze the 
sparse plasma concentration−time data for alectinib and its metabolites, as applicable.  
The PK data from this study may be pooled with data from other studies.  Population and 
individual PK parameters will be estimated, and the influence of various covariates (such 
as age, sex, and body weight) on these parameters will be investigated.  Exploratory 
analyses will be conducted to investigate the relationship between alectinib PK exposure 
and efficacy/safety parameters.
Details of the mixed-effects modeling and exploratory analyses will be reported in a 
document separate from the Clinical Study Report.
5.7.4
Biomarker Analyses
ALK tumor tissue and plasma assays (e.g., next-generation targeted sequencing, 
polymerase chain reaction) will be used as exploratory assays for all enrolled ALK-
positive patients.  Results from these analyses along with clinical data collected in this 
study will be used to explore genomic variants (e.g., ALK rearrangement variants, fusion 
partners, mutations in ALK and other cancer related genes) that may be predictive of 
response to study drug or may be associated with progression to a more severe disease 
state.  As these biomarkers may also have prognostic value, their potential association 
with disease progression will also be explored.  Somatic mutations in ALK and other 
cancer related genes may be associated with acquired resistance to alectinib or can 
increase the knowledge and understanding of the disease biology.  Tumor mutation 
allele frequencies and circulating tumor nucleic acid amounts may also be correlated 
with clinical efficacy.  Efficacy analysis of different ALK tumor and ALK plasma 
subpopulations may be performed.
Information regarding the detection of ALK rearrangements from targeted DNA 
sequencing from tissue and plasma samples, and baseline demographic and disease-
related characteristics for all enrolled patients in this study may be used for companion 
diagnostic development.  These data may be used to support potential registration of a 


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companion diagnostic assay for alectinib in the tumor-agnostic setting and shared with 
health authorities.
Data will be analyzed in the context of this study but may also be explored in aggregate 
with data from other studies.  The availability of a larger dataset will assist in 
identification and characterization of important biomarkers and pathways to support 
future drug development.
Results from the exploratory biomarker analyses from baseline and recurrence tumor 
samples and from plasma samples at baseline, on treatment, and post-recurrence will 
be communicated outside the main Clinical Study Report.
5.7.5
Health Status Utility Analyses
The EuroQol 5-Dimension Questionnaire 5-level version (EQ-5D-5L) questionnaires will 
be scored per authors' guidelines. A single summary index from the EQ-5D-5L health 
states will be used in this study for economic modeling.
These results may not be reported in the Clinical Study Report.
5.8
INTERIM ANALYSES
A non-binding interim analysis will be performed after 15 RECISTv1.1 investigator-
assessed response-evaluable patients with ALK fusions tumors (excluding patients with 
primary CNS tumors and patients with solid tumors of CUP) have at least a response-
evaluation available at 8 weeks (unless they progressed or discontinued earlier from the 
study).  During the period waiting for a response evaluation of these first 15 patients, the 
study will continue to enroll.  If the analysis result shows that the response rate does not 
achieve at least 25% (4 responders), the study may be terminated due to futility.
Further details regarding the rules and guidelines of data review will be provided in the 
IMC Charter.
6.
SUPPORTING DOCUMENTATION
This section is not applicable, since there is no additional supporting document.


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7.
REFERENCES
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:2941.
Cocks K, King MT, Velikova G, et al. Evidence-based guidelines for determination of 
sample size and interpretation of the European Organisation for the Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30. J Clin Oncol 
2011;29:8996.
Fayers PM, Aaronson NK, Bjordal K, et al. The EORTC QLQ-C30 scoring manual, 
3rd ed. Brussels: European Organisation for Research and Treatment of Cancer, 
2001.
International Council for Harmonisation (ICH). E9 (R1) addendum on estimands and 
sensitivity analysis in clinical trials to the guideline on statistical principles for 
clinical trials. 2020.
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in 
health-related quality of life score. J Clin Oncol 1998;16:13944.