Clinical trial NCT04422210
Conditions: Small Cell Lung Cancer
Sponsor: Hoffmann-La Roche
Start date: 2020-09-22; Completion date: 2020-11-06
Enrollment: 2 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
A study consisting of a dose-escalation phase and a dose-expansion phase to evaluate the safety, tolerability, pharmacokinetics, and efficacy of venetoclax in combination with atezolizumab, carboplatin, and etoposide.

Detailed description:

Arms: arm 1: Cohort A1: Participants with ES-SCLC who completed 4-6 cycles of carboplatin and etoposide first-line induction chemotherapy, with or without atezolizumab, were administered continuous maintenance therapy with Venetoclax (400mg) once daily (QD) from Day 1 to 21 and Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1. arm 2: Cohort A2: Participants with ES-SCLC who completed 4-6 cycles of carboplatin and etoposide first-line induction chemotherapy, with or without atezolizumab, were to be administered continuous maintenance therapy with Venetoclax (800mg) once daily (QD) from Day 1 to 21 and Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1. arm 3: Cohort A3: Participants with ES-SCLC who completed 4-6 cycles of carboplatin and etoposide first-line induction chemotherapy, with or without atezolizumab, were to be administered continuous maintenance therapy with Venetoclax (200mg) once daily (QD) from Day 1 to 21 and Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1. This cohort maybe explored if Dose-Limiting Toxicities (DLTs) are experienced and adverse events are thought to be potentially mitigated with a lower dose of venetoclax. arm 4: Cohort B1: Participants with ES-SCLC were to be administered non-continuous induction therapy with Venetoclax (200mg) once daily (QD) from Day 1 to 7, Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1, Carboplatin (5mg/mL/min) on Day 1 and Etoposide (100mg/m\^2) on Days 1-3. Participants who tolerated study treatment without excessive toxicity, and had not undergone disease progression were to be then proceeded to maintenance treatment with venetoclax plus atezolizumab. The venetoclax dose for the maintenance setting in Arm B will be the dose that has been cleared in the maintenance only arm (Arm A) of the study (maintenance RP2D, RP2D-M). arm 5: Cohort B2: Participants with ES-SCLC were to be administered non-continuous induction therapy with Venetoclax (400mg) once daily (QD) from Day 1 to 7, Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1, Carboplatin (5mg/mL/min) on Day 1 and Etoposide (100mg/m\^2) on Days 1-3. Participants who tolerated study treatment without excessive toxicity, and had not undergone disease progression were to be then proceeded to maintenance treatment with venetoclax plus atezolizumab. The venetoclax dose for the maintenance setting in Arm B will be the dose that has been cleared in the maintenance only arm (Arm A) of the study (maintenance RP2D, RP2D-M). arm 6: Cohort B3: Participants with ES-SCLC were to be administered non-continuous induction therapy with Venetoclax (800mg) once daily (QD) from Day 1 to 7, Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1, Carboplatin (5mg/mL/min) on Day 1 and Etoposide (100mg/m\^2) on Days 1-3. Participants who tolerated study treatment without excessive toxicity, and had not undergone disease progression were to be then proceeded to maintenance treatment with venetoclax plus atezolizumab. The venetoclax dose for the maintenance setting in Arm B will be the dose that has been cleared in the maintenance only arm (Arm A) of the study (maintenance RP2D, RP2D-M). arm 7: Cohort B4: Participants with ES-SCLC were to be administered non-continuous induction therapy with Venetoclax (800mg) once daily (QD) from Day 1 to 14, Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1, Carboplatin (5mg/mL/min) on Day 1 and Etoposide (100mg/m\^2) on Days 1-3. Participants who tolerated study treatment without excessive toxicity, and had not undergone disease progression were to be then proceeded to maintenance treatment with venetoclax plus atezolizumab. The venetoclax dose for the maintenance setting in Arm B will be the dose that has been cleared in the maintenance only arm (Arm A) of the study (maintenance RP2D, RP2D-M). arm 8: If the Recommended Phase II Dose (RP2D) for Venetoclax during induction is established, then the dose-expansion cohort would continue to test venetoclax in both induction and maintenance. Participants would be administered non-continuous induction therapy with Venetoclax (RP2D-I/induction RP2D), Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1, Carboplatin (5mg/mL/min) on Day 1 and Etoposide (100mg/m\^2) on Days 1-3 followed by continuous maintenance therapy with Venetoclax (RP2D-M) and Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1. If significant toxicity and DLTs in induction precluded identification of an RP2D for venetoclax in induction treatment, then the safety and efficacy of venetoclax would only be investigated in dose-expansion in the maintenance setting. Participants would be administered continuous maintenance therapy with Venetoclax (RP2D-M) and Atezolizumab (1200mg) every 3 weeks (Q3W) on Day 1.
Interventions: intervention 1: Venetoclax intervention 2: Atezolizumab intervention 3: Carboplatin intervention 4: Etoposide
Intervention descriptions: intervention 1: Venetoclax will be administered orally at escalating doses from 200mg to 800mg as 100mg tablets as per the dosing schedules described above. intervention 2: Atezolizumab will be administered via intravenous (IV) infusion at a fixed dose of 1200mg as per the dosing schedules described above. intervention 3: Carboplatin will be administered via IV infusion at a dose of 5mg/mL/min as per the dosing schedules described above. intervention 4: Etoposide will be administered via IV infusion at a dose of 100mg/m\^2 as per the dosing schedules described above.

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: A Phase Ib Dose-Escalation and Dose-Expansion Study Evaluating 
the Safety, Tolerability, Pharmacokinetics, and Efficacy of Venetoclax 
in Combination With Atezolizumab, Carboplatin, and Etoposide in 
Patients With Untreated Extensive-Stage Small Cell Lung Cancer 
NCT Number: NCT04422210 
Document Date: Protocol Version 2: 11-March-2020 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Venetoclax—F. Hoffmann-La Roche Ltd
Protocol GO41864, Version 2
PROTOCOL
TITLE:
A PHASE Ib DOSE-ESCALATION AND DOSE-
EXPANSION STUDY EVALUATING THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS, AND 
EFFICACY OF VENETOCLAX IN COMBINATION 
WITH ATEZOLIZUMAB, CARBOPLATIN, AND 
ETOPOSIDE IN PATIENTS WITH UNTREATED 
EXTENSIVE-STAGE SMALL CELL LUNG CANCER
PROTOCOL NUMBER:
GO41864
VERSION NUMBER:
2
EUDRACT NUMBER:
2019-004487-22
IND NUMBER:
146772
NCT NUMBER:
To be determined
TEST PRODUCT:
Venetoclax (RO5537382)
Atezolizumab (RO5541267)
MEDICAL MONITOR:
 M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
16 January 2020
DATE AMENDED:
See electronic date stamp below.
 
11-Mar-2020 19:10:30
Title
Approver's Name
Company Signatory
Date and Time (UTC)


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PROTOCOL HISTORY 
Protocol
Version
Date Final
1
16 January 2020


 
Venetoclax—F. Hoffmann-La Roche Ltd 
Page 3 of 214 Protocol GO41864, Version 2 
PROTOCOL AMENDMENT, VERSION 2: 
RATIONALE 
Protocol GO41864 has been amended to incorporate feedback from the U.S. Food and 
Drug Administration.  Changes to the protocol, along with a rationale for each change, 
are summarized below: 
 
The overview of the study design has been modified to only allow the use of 
atezolizumab instead of a variety of single-agent checkpoint inhibitors (anti-PD-
1/PD-L1) (Section 3.1.1).  
 
Additional modifications in study design include a reduction in the number of cycles 
of induction therapy from a total number of 6 to 4 in Arm B (Section 3.1.1 and 
Section 3.1.2.2).  
 
The protocol inclusion criteria (Section 4.1.1) has been amended to allow patients 
who have completed 3 cycles of atezolizumab in combination with 4 cycles of 
carboplatin and etoposide induction chemotherapy compared with 2 cycles of 
atezolizumab in combination with 4 cycles of carboplatin and etoposide induction 
chemotherapy to be eligible for the maintenance arm of the study (Section 3.1.5).  
 
Clarification regarding the assessment period for dose-limiting toxicities (DLT) has 
been provided, and new definitions of DLTs have been included in Section 3.1.3. 
 
Exact parameters that would trigger the requirement for primary growth-colony 
stimulating factor prophylaxis in Arm B have been clarified in Section 3.1.2.2.  
 
Term “NC” (non-continuous) dose levels have been replaced with “lower” dose level 
in Section 3.1.4. 
 
The clarification for patients who continue treatment beyond radiographic disease 
progression has been added to Section 4.5.5: 
 
Venetoclax dose reduction levels have been clarified in Section 5.1.5.1. 
 
The language describing reporting requirements and the duration of reproductive 
risk as female patients or as partners of male patients has been updated in Sections 
5.4.3.1 and 5.4.3.2. 
 
Protocol language has been updated with additional details regarding the potential 
dose expansion cohort to evaluate maintenance therapy with venetoclax and 
atezolizumab only (Arm A), including ORR values, in Section 6.1. 
 
Appendix 1 (Schedule of Activities for Dose-Escalation Arm A and Dose-Expansion 
Maintenance Only (Arm A) and Dose-Expansion Maintenance Only) has been 
updated to reflect tumor assessment schedule after radiographic disease 
progression as outlined in Section 4.5.5.  
 
Appendix 2 (Schedule of Activities for Dose-Escalation Induction  Maintenance 
[Arm B] and Dose-Expansion Induction  Maintenance) has been updated to reflect 
tumor assessment schedule after radiographic disease progression as outlined in 
Section 4.5.5.  
 
Appendix 3 (Schedule of Pharmacokinetic and Immunogenicity Sampling) has been 
updated with further clarification of sample collection at Treatment Discontinuation.  


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Page 4 of 214 Protocol GO41864, Version 2
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.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14
PROTOCOL SYNOPSIS .................................................................................... 15
1.
BACKGROUND .......................................................................................... 35
1.1
Background on Lung Cancer................................................. 35
1.2
First-Line Treatment for Extensive-Stage Small 
Cell Lung Cancer................................................................... 36
1.3
BCL-2 Signaling Pathway and Small Cell Lung 
Cancer................................................................................... 38
1.4
Background on Atezolizumab................................................ 40
1.5
Background on Venetoclax.................................................... 41
1.6
Study Rationale and Benefit–Risk Assessment..................... 42
1.6.1
Study Rationale ..................................................................... 43
1.6.2
BenefitRisk Assessment...................................................... 44
2.
OBJECTIVES AND ENDPOINTS ............................................................... 45
2.1
Objectives and Endpoints for Dose-Escalation 
Phase .................................................................................... 45
2.1.1
Safety Objective (Primary Objective)..................................... 45
2.1.2
Pharmacokinetic Objectives .................................................. 46
2.1.3
Immunogenicity Objective...................................................... 46
2.1.4
Biomarker Objectives............................................................. 46
2.2
Objectives and Endpoints for Dose-Expansion 
Phase .................................................................................... 46
2.2.1
Efficacy Objectives ................................................................ 46
2.2.1.1
Primary Efficacy Objective..................................................... 46
2.2.1.2
Secondary Efficacy Objective................................................ 47
2.2.2
Safety Objective .................................................................... 47
2.2.3
Pharmacokinetic Objectives .................................................. 48
2.2.4
Immunogenicity Objective...................................................... 48
2.2.5
Biomarker Objectives............................................................. 48
3.
STUDY DESIGN......................................................................................... 48
3.1
Description of the Study......................................................... 48


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3.1.1
Overview of Study Design ..................................................... 48
3.1.2
Dose-Escalation Phase ......................................................... 49
3.1.2.1
Maintenance Only (Arm A) .................................................... 52
3.1.2.2
Induction Plus Maintenance (Arm B). .................................... 54
3.1.3
Definition of Dose-Limiting Toxicity........................................ 56
3.1.4
Dose-Escalation Rules, Determination of 
Dose-Limiting Toxicities, and Recommended 
Phase II Dose........................................................................ 58
3.1.5
Dose-Expansion Cohort......................................................... 60
3.1.6
Treatment After Disease Progression .................................... 62
3.2
End of Study and Length of Study......................................... 62
3.3
Rationale for Study Design.................................................... 62
3.3.1
Rationale for Patient Population ............................................ 62
3.3.2
Rationale for Venetoclax and/or 
AtezolizumabTreatment Beyond Initial 
Radiographic Progression ..................................................... 63
3.3.1
Rationale for Atezolizumab Dose and Schedule.................... 63
3.3.2
Rationale for Venetoclax Dosing Schedule............................ 64
3.3.2.1
Rationale for Venetoclax Dose Selection for 
Maintenance in Phase I Dose-Escalation Portion 
of the Study ........................................................................... 64
3.3.2.2
Rationale for Venetoclax Dose Selection for 
Induction in the Phase I Dose-Escalation Portion 
of the Study ........................................................................... 65
3.3.2.3
Rationale for Preferential Venetoclax Dose 
Modifications in the Setting of Overlapping 
Toxicities................................................................................ 66
3.3.3
Rationale for Dose Finding Rules.......................................... 66
3.3.4
Rationale for Biomarker Assessments................................... 67
4.
MATERIALS AND METHODS .................................................................... 68
4.1
Patients.................................................................................. 68
4.1.1
Inclusion Criteria.................................................................... 68
4.1.2
Exclusion Criteria................................................................... 72
4.2
Method of Treatment Assignment and Blinding..................... 76
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 76


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4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 77
4.3.1.1
Atezolizumab......................................................................... 77
4.3.1.2
Venetoclax............................................................................. 77
4.3.1.3
Carboplatin and Etoposide .................................................... 77
4.3.2
Study Treatment Dosage, Administration,
Sequence, and Compliance................................................... 77
4.3.2.1
Atezolizumab......................................................................... 79
4.3.2.2
Venetoclax............................................................................. 79
4.3.2.3
Atezolizumab/Venetoclax ...................................................... 82
4.3.2.4
Carboplatin and Etoposide .................................................... 82
4.3.3
Investigational Medicinal Product Accountability ................... 84
4.3.4
Continued Access to Atezolizumab and 
Venetoclax............................................................................. 84
4.4
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 85
4.4.1
Permitted Therapy................................................................. 85
4.4.2
Prohibited and Cautionary Therapy....................................... 86
4.4.2.1
Herbal Therapies................................................................... 90
4.4.3
Prohibited Food ..................................................................... 91
4.5
Study Assessments ............................................................... 91
4.5.1
Informed Consent Forms and Screening Log........................ 92
4.5.2
Medical History, Baseline Conditions,
Concomitant Medication, and Demographic Data ................. 92
4.5.3
Physical Examinations........................................................... 92
4.5.4
Vital Signs.............................................................................. 92
4.5.5
Tumor and Response Evaluations......................................... 93
4.5.6
Other Disease-Specific Assessments.................................... 95
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 95
4.5.8
Electrocardiograms................................................................ 99
4.5.9
Blood Samples for Whole Genome Sequencing 
or Whole Exome Sequencing (Patients at 
Participating Sites)................................................................. 99
4.5.10
Optional Tumor Biopsies ..................................................... 100


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4.5.11
Optional Samples for Research Biosample 
Repository ........................................................................... 100
4.5.11.1
Overview of the Research Biosample Repository................ 100
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee ................................................................ 101
4.5.11.3
Sample Collection................................................................ 101
4.5.11.4
Confidentiality...................................................................... 102
4.5.11.5
Consent to Participate in the Research 
Biosample Repository.......................................................... 102
4.5.11.6
Withdrawal from the Research Biosample 
Repository ........................................................................... 103
4.5.11.7
Monitoring and Oversight..................................................... 103
4.6
Treatment, Patient, Study, and Site 
Discontinuation.................................................................... 103
4.6.1
Study Treatment Discontinuation......................................... 103
4.6.2
Patient Discontinuation from the Study................................ 105
4.6.3
Study Discontinuation.......................................................... 105
4.6.4
Site Discontinuation............................................................. 105
5.
ASSESSMENT OF SAFETY..................................................................... 106
5.1
Safety Plan .......................................................................... 106
5.1.1
Risks Associated with Atezolizumab ................................... 106
5.1.2
Risks Associated with Etoposide......................................... 106
5.1.3
Risks Associated with Carboplatin....................................... 106
5.1.4
Risks Associated with Venetoclax ....................................... 107
5.1.4.1
Tumor Lysis Syndrome........................................................ 107
5.1.4.2
Neutropenia......................................................................... 107
5.1.4.3
Serious Infections................................................................ 108
5.1.4.4
Other Hematological Effects................................................ 108
5.1.4.5
Reproductive System Effects and Pregnancy...................... 108
5.1.4.6
Treatment-Emergent Malignancies (Second 
Primary Malignancies) ......................................................... 109
5.1.5
Dose Modification................................................................ 109
5.1.5.1
Venetoclax Dose Modifications............................................ 110


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5.1.5.2
Atezolizumab Dose Modification, Treatment 
Delays, or Treatment Discontinuation and 
Management of Specific Adverse Events ............................ 110
5.1.5.3
Chemotherapy Dose Modifications, Treatment 
Delays, or Treatment Discontinuation and 
Management of Specific Adverse Events ............................ 111
5.1.6
Management Guidelines...................................................... 113
5.1.6.1
Management of Venetoclax-Specific Adverse 
Events.................................................................................. 113
5.1.6.2
Management of Atezolizumab-Specific Adverse 
Events.................................................................................. 113
5.1.6.3
Management of Potential Overlapping Toxicities................. 114
5.2
Safety Parameters and Definitions ...................................... 118
5.2.1
Adverse Events ................................................................... 118
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 119
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 120
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 121
5.3.1
Adverse Event Reporting Period ......................................... 121
5.3.2
Eliciting Adverse Event Information..................................... 121
5.3.3
Assessment of Severity of Adverse Events ......................... 121
5.3.4
Assessment of Causality of Adverse Events ....................... 122
5.3.5
Procedures for Recording Adverse Events.......................... 123
5.3.5.1
Infusion-Related Reactions.................................................. 123
5.3.5.2
Diagnosis Versus Signs and Symptoms............................... 123
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................. 124
5.3.5.4
Persistent or Recurrent Adverse Events.............................. 124
5.3.5.5
Abnormal Laboratory Values ............................................... 125
5.3.5.6
Abnormal Vital Sign Values ................................................. 125
5.3.5.7
Abnormal Liver Function Tests............................................ 126
5.3.5.8
Deaths ................................................................................. 126
5.3.5.9
Preexisting Medical Conditions............................................ 127
5.3.5.10
Lack of Efficacy or Worsening of SCLC............................... 127


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5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 127
5.3.5.12
Cases of Overdose, Medication Error, Drug 
Abuse, or Drug Misuse ........................................................ 128
5.3.5.13
Safety Biomarker Data......................................................... 130
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 130
5.4.1
Emergency Medical Contacts.............................................. 131
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 131
5.4.2.1
Events That Occur Prior to Study Treatment 
Initiation ............................................................................... 131
5.4.2.2
Events That Occur After Study Treatment 
Initiation ............................................................................... 131
5.4.3
Reporting Requirements for Pregnancies............................ 132
5.4.3.1
Pregnancies in Female Patients.......................................... 132
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 132
5.4.3.3
Abortions ............................................................................. 133
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 133
5.5
Follow-Up of Patients After Adverse Events........................ 133
5.5.1
Investigator Follow-Up......................................................... 133
5.5.2
Sponsor Follow-Up .............................................................. 133
5.6
Adverse Events That Occur After the Adverse 
Event Reporting Period........................................................ 134
5.7
Expedited Reporting to Health Authorities,
Investigators, Institutional Review Boards,
and Ethics Committees........................................................ 134
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 135
6.1
Determination of Sample Size ............................................. 135
6.2
Summaries of Conduct of Study.......................................... 136
6.3
Summaries of Demographic and Baseline 
Characteristics..................................................................... 136
6.4
Safety Analyses................................................................... 136
6.4.1
Analyses of Exposure, Adverse Event,
Laboratory, Vital Sign, and ECG Data ................................. 136
6.5
Efficacy Analyses ................................................................ 137
6.5.1
Primary Efficacy Endpoint.................................................... 137


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6.5.2
Secondary Efficacy Endpoints............................................. 138
6.5.2.1
Duration of Response.......................................................... 138
6.5.2.2
Progression-Free Survival ................................................... 138
6.5.2.3
Overall Survival ................................................................... 138
6.5.2.4
Progression-Free Survival Rate at 6 Months....................... 139
6.5.2.5
Overall Survival Rate at 1 Year ........................................... 139
6.6
Pharmacokinetic Analyses................................................... 139
6.7
Immunogenicity Analyses.................................................... 139
6.8
Biomarker Analyses............................................................. 140
6.9
Interim Analysis ................................................................... 140
7.
DATA COLLECTION AND MANAGEMENT ............................................. 140
7.1
Data Quality Assurance....................................................... 140
7.2
Electronic Case Report Forms............................................. 140
7.3
Source Data Documentation................................................ 141
7.4
Use of Computerized Systems ............................................ 141
7.5
Retention of Records........................................................... 142
8.
ETHICAL CONSIDERATIONS.................................................................. 142
8.1
Compliance with Laws and Regulations .............................. 142
8.2
Informed Consent................................................................ 142
8.3
Institutional Review Board or Ethics Committee.................. 143
8.4
Confidentiality...................................................................... 144
8.5
Financial Disclosure ............................................................ 145
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 145
9.1
Study Documentation .......................................................... 145
9.2
Protocol Deviations.............................................................. 145
9.3
Management of Study Quality ............................................. 145
9.4
Site Inspections ................................................................... 146
9.5
Administrative Structure....................................................... 146
9.6
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 146
9.7
Protocol Amendments ......................................................... 147


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10. REFERENCES ......................................................................................... 148
LIST OF TABLES
Table 1
Results from Randomized Studies Using Platinum-Based 
Chemotherapy for ES-SCLC ...................................................... 38
Table 2
Administration of First and Subsequent Atezolizumab 
Infusions .................................................................................. 81
Table 3
Therapies Prohibited for Specific Study Phases, or Allowed 
with Caution, Restrictions, and/or Dose Adjustments ............... 88
Table 4
Venetoclax Dose Reductions for Strong and Moderate 
CYP3A Inhibitors ..................................................................... 90
Table 5
Timing for Vital Sign Measurements for First and 
Subsequent Infusions ................................................................ 93
Table 6
Venetoclax Dose Reduction ..................................................... 110
Table 7
Chemotherapy Dose Modification for Hematologic Toxicities... 112
Table 8
Dose Modifications or Treatment Discontinuation for 
Non-Hematologic Toxicities .................................................... 113
Table 9
Etoposide Dose Modification for Renal Impairment ................. 113
Table 10
Management Guidelines for Specific Adverse Events with 
Venetoclax, Atezolizumab, and Carboplatin Etoposide ............ 115
Table 11
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE .......................................... 122
Table 12
Causal Attribution Guidance .................................................. 123
Table 13
Operating Characteristics for Proposed Study Design for 
Several Possible True Underlying Overall Response Rate........ 135
Table 14
90% Confidence Interval Estimates for Potential Adverse 
Event Rates ............................................................................ 136
LIST OF FIGURES
Figure 1
Overall Study Schema............................................................... 49
Figure 2
Dose-Escalation Study Schema ................................................. 51
Figure 3
Study Schema: Dose-Escalation, Maintenance Only (Arm A)..... 53
Figure 4
Study Schema: Dose-Escalation, Induction (Arm B)................... 55
Figure 5
Study Schema: Dose-Expansion Cohort...................................... 61


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LIST OF APPENDICES
Appendix 1
Schedule of Activities: Dose-Escalation Maintenance Only
(Arm A) and Dose-Expansion Maintenance Only...................... 156
Appendix 2
Schedule of Activities: Dose-Escalation Induction 
Maintenance (Arm B) and Dose-Expansion Induction 
Maintenance ............................................................................. 161
Appendix 3
Schedule of Pharmacokinetic and Immunogenicity Sampling... 168
Appendix 4
Schedule of Biomarker Assessments ....................................... 172
Appendix 5
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 174
Appendix 6
Examples of Prohibited and Cautionary Medications................ 183
Appendix 7
Preexisting Autoimmune Diseases and Immune Deficiencies .. 185
Appendix 8
Anaphylaxis Precautions........................................................... 186
Appendix 9
Guidelines for Defining Tumor Lysis Syndrome........................ 187
Appendix 10
Recommendations for Secondary Prophylaxis with Growth 
Factors...................................................................................... 189
Appendix 11
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome............. 190
Appendix 12
Guidelines for Management of Patients Who Experience 
Adverse Events Associated with Venetoclax ............................ 191
Appendix 13
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 192


Venetoclax—F. Hoffmann-La Roche Ltd
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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE Ib DOSE-ESCALATION AND DOSE-
EXPANSION STUDY EVALUATING THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS, AND 
EFFICACY OF VENETOCLAX IN COMBINATION 
WITH ATEZOLIZUMAB, CARBOPLATIN, AND 
ETOPOSIDE IN PATIENTS WITH UNTREATED 
EXTENSIVE-STAGE SMALL CELL LUNG CANCER
PROTOCOL NUMBER:
GO41864
VERSION NUMBER:
2
EUDRACT NUMBER:
2019-004487-22
IND NUMBER:
146772
NCT NUMBER:
To be determined
TEST PRODUCT:
Venetoclax (RO5537382)
Atezolizumab (RO5541267)
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 as instructed by your local study monitor.


Venetoclax—F. Hoffmann-La Roche Ltd
Page 15 of 214 Protocol GO41864, Version 2
PROTOCOL SYNOPSIS
TITLE:
A PHASE Ib DOSE-ESCALATION AND DOSE-EXPANSION 
STUDY EVALUATING THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND EFFICACY OF VENETOCLAX IN 
COMBINATION WITH ATEZOLIZUMAB, CARBOPLATIN, AND 
ETOPOSIDE IN PATIENTS WITH UNTREATED EXTENSIVE-
STAGE SMALL CELL LUNG CANCER
PROTOCOL NUMBER:
GO41864
VERSION NUMBER:
2
EUDRACT NUMBER:
2019-004487-22
IND NUMBER:
146772
NCT NUMBER:
To be determined
TEST PRODUCT:
Venetoclax (RO5537382)
Atezolizumab (RO5541267)
PHASE:
Ib
INDICATION:
Small cell lung cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This is a Phase Ib, open-label, multicenter, two-stage study, consisting of a dose-escalation 
phase and a dose-expansion phase, to evaluate the safety, tolerability, pharmacokinetics, and 
efficacy of venetoclax in combination with atezolizumab, carboplatin, and etoposide as induction 
therapy and venetoclax in combination with atezolizumab as maintenance therapy following 
induction, for patients with extensive-stage small cell lung cancer (ES-SCLC) who are 
chemotherapy-naïve for their extensive-stage disease.  
The objectives for the dose-escalation phase of this study are to assess safety and tolerability 
as well as to determine the maximum tolerated dose (MTD) and the recommended Phase II 
dose (RP2D) for venetoclax in both induction (Arm B) and maintenance (Arm A) therapies. 
The objectives of the dose-expansion phase are to evaluate the safety, tolerability, 
pharmacokinetics, and efficacy of venetoclax at the RP2D in induction followed by maintenance 
therapies or in maintenance therapy only, as determined in the dose-escalation phase of the 
study. 
Specific objectives and corresponding endpoints for the study are outlined in the protocol.
In this protocol, "study treatment" refers to the combination of treatments assigned to patients 
as part of this study (i.e., venetoclax plus atezolizumab, carboplatin, and etoposide in the 
induction setting or venetoclax plus atezolizumab in the maintenance setting).
Objectives and Endpoints for Dose-Escalation Phase
Safety Objective (Primary Objective)
The safety objective for the dose-escalation phase is to evaluate the safety and tolerability of 
venetoclax plus atezolizumab as maintenance therapy (Arm A) and venetoclax in combination 
with atezolizumab, carboplatin, and etoposide as induction therapy followed by venetoclax plus 
atezolizumab as maintenance therapy (Arm B) including estimation of the MTD, determination 


Venetoclax—F. Hoffmann-La Roche Ltd
Page 16 of 214 Protocol GO41864, Version 2
of the RP2D, and characterization of DLTs (refer to full protocol)on the basis of the following 
endpoints:

The incidence and severity of adverse events, with severity determined according to the 
National Cancer Institute Common Technology Criteria for Adverse Events version 5.0 (NCI 
CTCAE v5.0)

Change from baseline in targeted vital signs

Change from baseline in targeted laboratory test results
Pharmacokinetic Objectives 
The pharmacokinetic (PK) objectives for the dose-escalation phase are the following:

To characterize the pharmacokinetics of venetoclax and atezolizumab when given in 
combination as part of the maintenance therapy on the basis of the following endpoints:
–
Plasma concentrations of venetoclax at specified timepoints  
–
Serum concentrations of atezolizumab at specified timepoints

To characterize the pharmacokinetics of venetoclax and atezolizumab when given in 
combination with carboplatin and etoposide as part of the induction therapy on the basis of 
the following endpoints:
–
Plasma concentrations of venetoclax at specified timepoints 
–
Serum concentrations of atezolizumab at specified timepoints 
Immunogenicity Objectives 
The exploratory immunogenicity objective for the dose-escalation phase is to evaluate the 
immune response to atezolizumab on the basis of the following endpoints:

Incidence of anti-drug antibodies (ADAs) to atezolizumab in the presence of venetoclax

Incidence of ADAs to atezolizumab in the presence of venetoclax, carboplatin, and 
etoposide 
Biomarker Objectives 
The exploratory biomarker objectives for the dose-escalation phase are to identify and evaluate 
biomarkers that are predictive of response to venetoclax (i.e., predictive biomarkers), are early 
surrogates of efficacy, are associated with progression to a more severe disease state 
(i.e., prognostic biomarkers), are associated with acquired resistance to venetoclax, are 
associated with susceptibility to developing adverse events or can lead to improved adverse 
event monitoring or investigation (i.e., safety biomarkers), can provide evidence of venetoclax 
activity (i.e., pharmacodynamic biomarkers), or can increase the knowledge and understanding 
of disease biology and drug safety, on the basis of the following endpoint:

Relationship between biomarkers in tumor tissue and blood (listed in the protocol) and 
efficacy, safety, PK, immunogenicity, or other biomarker endpoints
Objectives and Endpoints for Dose-Expansion Phase
Efficacy Objectives 
Primary Efficacy Objective
The primary efficacy objective for the dose-expansion phase is to evaluate the preliminary 
efficacy of venetoclax in combination with atezolizumab as maintenance therapy or venetoclax 
in combination with atezolizumab, carboplatin, and etoposide as induction therapy followed by 
venetoclax plus atezolizumab as maintenance therapy on the basis of the following endpoint:

Overall response rate (ORR), defined as the proportion of patients with a complete 
response (CR) or partial response (PR) on two consecutive occasions 28 days apart, as 
determined by the investigator according to Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)


Venetoclax—F. Hoffmann-La Roche Ltd
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Secondary Efficacy Objective
The secondary efficacy objective for the dose-expansion phase is to evaluate the preliminary 
efficacy of venetoclax in combination with atezolizumab as maintenance therapy or venetoclax 
in combination with atezolizumab, carboplatin, and etoposide as induction therapy followed by 
venetoclax plus atezolizumab as maintenance therapy on the basis of the following endpoints:

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 the investigator according to RECIST v1.1 

Progression-free survival (PFS) after enrollment, defined as the time from enrollment to the 
first occurrence of disease progression or relapse or death from any cause (whichever 
occurs first), as determined by the investigator according to RECIST v1.1 

Overall survival (OS) after enrollment, defined as the time from enrollment to death from 
any cause

PFS rate at 6 months, defined as the proportion of patients who have not experienced 
disease progression, relapse, or death from any cause at 6 months, as determined by the 
investigator according to RECIST v1.1 

OS rate at 1 year, defined as the proportion of patients who have not experienced death 
from any cause at 1 year
Safety Objectives 
The safety objective for the dose-expansion phase are to evaluate the safety and tolerability of 
venetoclax in combination with atezolizumab, carboplatin, and etoposide as induction therapy or 
venetoclax in combination with atezolizumab, carboplatin, and etoposide as induction therapy 
followed by venetoclax plus atezolizumab as maintenance therapy on the basis of the following 
endpoints:

To determine the incidence and severity of adverse events, with severity determined 
according to NCI CTCAE v5.0 

Change from baseline in targeted vital signs

Change from baseline in targeted laboratory test results
Pharmacokinetic Objectives 
The PK objectives for the dose-expansion phase are the following:

To characterize the pharmacokinetics of venetoclax and atezolizumab when given in 
combination as part of the maintenance therapy on the basis of the following endpoints:
–
Plasma concentrations of venetoclax at specified timepoints  
–
Serum concentrations of atezolizumab at specified timepoints

To characterize the pharmacokinetics of venetoclax, atezolizumab, carboplatin, and 
etoposide when given in combination as part of the induction therapy on the basis of the 
following endpoints:
–
Plasma concentrations of venetoclax at specified timepoints 
–
Serum concentrations of atezolizumab at specified timepoints 
–
Plasma concentrations of carboplatin at specified timepoints 
–
Plasma concentrations of etoposide at specified timepoints 
Immunogenicity Objective 
The exploratory immunogenicity objective for the dose-expansion phase are the same as those 
described for the dose-escalation phase and are described in the protocol.
Biomarker Objectives 
The exploratory biomarker objectives for the dose-expansion phase are the same as those 
described for the dose-escalation phase and are described in protocol.


Venetoclax—F. Hoffmann-La Roche Ltd
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Study Design
Description of the Study
This is a Phase Ib, multicenter, open-label, two-stage study consisting of a dose-escalation 
phase and a dose-expansion phase to evaluate the safety, tolerability, pharmacokinetics, and 
efficacy of venetoclax in combination with atezolizumab, carboplatin, and etoposide.
Overview of the Study Design
In the dose-escalation stage, venetoclax will be tested first in the maintenance setting (Arm A) 
followed by testing in both the induction and maintenance settings (Arm B). 

Arm A:  Venetoclax and atezolizumab as maintenance therapy for patients with ES-SCLC 
who have completed 4-6 cycles of carboplatin and etoposide first-line induction 
chemotherapy, with or without atezolizumab

Arm B:  Venetoclax, atezolizumab, carboplatin, and etoposide as induction therapy (4 
cycles) followed by venetoclax plus atezolizumab as maintenance therapy for patients with 
previously untreated ES-SCLC
The dose-escalation stage will then be followed by the dose-expansion portion of the study to 
evaluate the safety and efficacy of adding venetoclax to induction and/or maintenance therapy 
at the RP2D and schedule as determined during dose-escalation.
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 two screenings per participant) at the 
investigator's discretion.  Patients are not required to re-sign the consent form if they are re-
screened within 30 days after previously signing the consent form.  The investigator will record 
reasons for screen failure within the interactive voice or web-based response system (IxRS) and 
electronic Case Report Form (eCRF).
Dose-Escalation Phase
The purpose of the dose-escalation phase of the study is to determine the RP2D and maximum 
tolerated dose (MTD) for venetoclax when given in combination with atezolizumab in the 
maintenance setting and in combination with atezolizumab, carboplatin, and etoposide in the 
induction setting (followed by venetoclax in combination with atezolizumab as maintenance 
therapy) in patients with ES-SCLC.
The dose-escalation cohort will use a standard 3 + 3 design (refer to the protocol) to assess the 
safety, tolerability, and pharmacokinetics of study treatment.  Venetoclax will be tested 
sequentially in the maintenance setting first (Arm A).  Once the MTD and the RP2D are 
identified for maintenance treatment, the RP2D identified in Arm A will be applied to the 
maintenance portion of the induction plus maintenance setting (Arm B).  The MTD and RP2D of 
venetoclax will be determined separately for maintenance and induction settings. 
Within each arm, dose-escalation cohorts will be run sequentially (e.g., 200 mg followed by 
400 mg, etc.; see the protocol).  
Maintenance Only (Arm A)
In the maintenance-only arm, venetoclax will be explored on a continuous dosing schedule at 
doses ranging from 400 mg QD to 800 mg/QD in the following dose-escalation treatment 
cohorts using a standard 3 3 design:

Maintenance Cohort A1 (Dose Level 1):
Venetoclax:  400 mg QD continuous on Days 121
Atezolizumab:  1200 mg every 3 weeks (Q3W) on Day 1

Maintenance Cohort A2 (Dose Level 2):
Venetoclax:  800 mg QD continuous on Days 121
Atezolizumab:  1200 mg Q3W on Day 1
Dose-escalation to 200 mg QD continuous on Days 121 may be explored if dose-limiting 
toxicities (DLTs) are experienced and adverse events are thought to be potentially mitigated 
with a lower dose of venetoclax (refer to the protocol).


Venetoclax—F. Hoffmann-La Roche Ltd
Page 19 of 214 Protocol GO41864, Version 2
Once tolerability and dose are established in the maintenance-only arm (Arm A), the induction 
followed by maintenance arm (Arm B) will be opened, based on thorough review led by the 
Medical Monitor in consultation with the Principal Investigators and a committee composed of, 
at a minimum, the following Sponsor representatives: statistician, safety scientist, PK scientist, 
and clinical scientist.  Patients on maintenance therapy who do not experience unacceptable 
toxicity and have evidence of clinical benefit (as defined in the protocol) may continue to receive 
maintenance study treatment every 21 days until documented disease progression determined 
by investigator or unacceptable toxicity, whichever occurs first.
Induction Plus Maintenance (Arm B)
In the induction plus maintenance arm (Arm B; see protocol), venetoclax will be explored on a 
non-continuous (NC) dosing schedule in the following dose-escalation treatment cohorts using a 
standard 3  3 design:
•
Induction Cohort B1 (Dose Level 1):
Venetoclax:  200 mg/QD NC on Days 17
Atezolizumab:  1200 mg Q3W on Day 1
Carboplatin:  AUC 5 mg/mL min (Calvert formula) on Day 1
Etoposide:  100 mg/m2 on Days 13
•
Induction Cohort B2 (Dose Level 2):
Venetoclax:  400 mg/QD NC on Days 17
Atezolizumab: 1200 mg Q3W on Day 1
Carboplatin:  AUC 5 mg/mL min (Calvert formula) on Day 1
Etoposide:  100 mg/m2 on Days 13
•
Induction Cohort B3 (Dose Level 3):
Venetoclax:  800 mg/QD NC on Days 17
Atezolizumab:  1200 mg Q3W on Day 1
Carboplatin:  AUC 5 mg/mL min (Calvert formula) on Day 1
Etoposide:  100 mg/m2 on Days 13
•
Induction Cohort B4 (Dose Level 4):
Venetoclax:  800 mg/QD NC on Days 114
Atezolizumab:  1200 mg Q3W on Day 1
Carboplatin:  AUC 5 mg/mL min (Calvert formula) on Day 1
Etoposide:  100 mg/m2 on Days 1-3
Patients may be treated in up to five NC dosing cohorts (i.e., venetoclax 200 mg Days 17 NC, 
400 mg Days 17 NC, 800 mg Days 17 NC, 800 mg Days 114 NC, and any of the dose 
levels integrating primary prophylactic growth factor support).  Specifically, at the initiation of the 
induction phase of dose-escalation Arm B, cohorts will be treated without primary prophylactic 
growth-colony stimulating factor (G-CSF).  If, after review of available data, the MTD is 
exceeded in a specific cohort due to DLTs associated with a high frequency of febrile 
neutropenia, severe neutropenia or prolonged neutropenia, then that cohort level will be tested 
again at the same dose with primary prophylactic growth factor support (see protocol for 
additional details).  Of note, primary G-CSF prophylaxis is only mandated during induction and 
not during maintenance therapy.  Such cohorts will be designated with “-P” to denote the 
primary G-CSF prophylactic requirement (e.g., Cohort B1-P).  Subsequent dose-escalation 
cohorts will then be required to incorporate primary G-CSF prophylaxis. 
Patients will be treated for a total of 4 cycles of study treatment for induction.  Each cycle will 
consist of 21 days.  Dose-escalation will continue until DLTs are observed.  If there is excessive 


Venetoclax—F. Hoffmann-La Roche Ltd
Page 20 of 214 Protocol GO41864, Version 2
toxicity and DLTs at the lowest tested venetoclax dose in induction, then venetoclax will be 
subsequently expanded in the maintenance setting only. 
Patients initially treated in the induction arm who tolerate study treatment without excessive 
toxicity, and have not undergone disease progression, will then proceed to maintenance 
treatment with venetoclax plus atezolizumab.  The venetoclax dose for the maintenance setting 
in Arm B will be the dose that has been cleared in the maintenance-only arm (Arm A) of the 
study (maintenance RP2D, RP2D-M).  The venetoclax RP2D for the induction setting (induction 
RP2D, RP2D-I) will be based on the MTD of venetoclax in combination with atezolizumab, 
carboplatin and etoposide. 
During the maintenance phase in either Arm A or Arm B, prophylactic cranial irradiation (PCI) is 
permitted (though not mandated) prior to the commencement of maintenance therapy per local 
standard of care. Due to the lack of data with concurrent use of PCI with either atezolizumab or 
venetoclax, concurrent administration of PCI during maintenance therapy is not permitted. PCI 
will be reported on the Prophylactic Cranial Irradiation electronic Case Report Form (eCRF).  
Consolidative thoracic radiation with curative intent or the intent to eliminate residual disease is 
not permitted.  Palliative radiation for symptomatic management is allowed (refer to protocol for 
further details).
Definition of Dose-Limiting Toxicity
Patients will be closely monitored for adverse events during a DLT assessment period, which 
starts on Day 1 of Cycle 1 and continues through Day 1 of Cycle 2.  Adverse events meeting 
criteria for DLT within the assessment period must be reported to the Sponsor within 24 hours.  
The expected start of Cycle 2 would be on Day 22 if there are no treatment delays.  The same 
DLT criteria will be used in the maintenance and induction settings.
Determination of whether a patient is evaluable for DLT assessment will be made in accordance 
with the following rules:

Patients who receive study treatment and remain on study through the DLT assessment 
period will be considered DLT-evaluable.

Patients who discontinue from treatment with venetoclax prior to completing the DLT 
assessment period for reasons other than a DLT will be considered non-evaluable for dose-
escalation decisions and MTD determination, and will be replaced by an additional patient 
at that same dose level.

Patients who receive less than 50% of planned venetoclax doses during the DLT 
assessment period will be considered non-evaluable for dose-escalation decisions and will 
be replaced by another patient in that cohort.
A DLT is defined in this trial as any one of the following events occurring during the DLT 
assessment period and is assessed by the investigator as possibly being related to study 
treatment.
The following events will be considered DLTs only if they are associated with treatment delay 
beyond 14 days in initiating Cycle 2, Day 1: 

Grade 4 thrombocytopenia (platelet count <25,000/mm3) 

Grade 3 thrombocytopenia with severe bleeding

Grade 4 anemia 

Grade 4 neutropenia (absolute neutrophil count [ANC] 500/L) 
The following events will be considered DLTs regardless of whether they result in a treatment 
delay:

Any treatment-related death

Grade 3 febrile neutropenia lasting for more than 7 days with growth factor support and 
supportive care

Grade 4 febrile neutropenia of any duration 

Grade 3 diarrhea, nausea, or vomiting lasting for 72 hours despite adequate treatment 
and supportive care (e.g., anti-emetics, anti-diarrheals, etc.)


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Page 21 of 214 Protocol GO41864, Version 2

Laboratory tumor lysis syndrome (TLS) lasting for 7 days with best supportive care or 
clinical TLS according to the Howard criteria (Howard et al. 2011)

Treatment related Grade 3 non-hematologic, non-hepatic toxicities lasting for 72 hours

Laboratory abnormalities consistent with Hy's Law will be considered a DLT. Hy's Law 
is defined as AST and/or ALT elevation 3 ULN, in conjunction with an elevation in 
total bilirubin to 2 ULN, without findings of cholestasis (ALP within normal limits), 
in patients for whom no other cause of hepatotoxicity is evident.

All study treatment-related adverse events requiring permanent discontinuation of any of 
the study drugs
Dose-Escalation Rules, Determination of Dose-Limiting Toxicities, and Recommended 
Phase II Dose
Dose-escalation for venetoclax in the maintenance only (Arm A) as well as in the induction and 
maintenance (Arm B) settings will occur in accordance with the rules listed below.
Arm A (Refer to protocol):
A minimum of 3 DLT-evaluable patients will initially be enrolled into each cohort.
If none of the first 3 DLT-evaluable patients experiences a DLT, enrollment of the next 
cohort at the next dose level may proceed.
If 1 of the first 3 DLT-evaluable patients experiences a DLT, the cohort will be expanded to 
6 patients.  If there are no further DLTs in the first 6 DLT-evaluable patients, enrollment of 
the next cohort at the next dose level may proceed.
If 2 or more of the first 6 DLT-evaluable patients in the cohort experience a DLT, an 
additional 3 patients will be evaluated for DLTs at a lower NC dose level.  If none of the 
first 3 DLT-evaluable patients experiences a DLT, the MTD in maintenance will have been 
reached.
If 1 of the first 3 DLT-evaluable patients experiences a DLT, the NC dose level cohort will 
be expanded to 6 patients.  If there are no further DLTs in the first 6 DLT-evaluable 
patients, the MTD in maintenance will have been reached.
If 2 or more of the first 6 DLT-evaluable patients in the NC dose-escalation cohort 
experience a DLT, the MTD will have been exceeded and dose-escalation in maintenance 
will stop. 
If the MTD is exceeded at any dose level, the highest dose at which fewer than 2 of 6 DLT-
evaluable patients (i.e., ≥33%) experience a DLT will be declared the MTD.
If the MTD is not exceeded at any dose level, the highest dose of venetoclax (800 mg) 
administered in maintenance will be declared the MTD for the maintenance setting.
Arm B (Refer to protocol):
A minimum of 3 DLT-evaluable patients will initially be enrolled into each cohort.
If none of the first 3 DLT-evaluable patients experiences a DLT, enrollment of the next 
cohort at the next dose level may proceed.
If 1 of the first 3 DLT-evaluable patients experiences a DLT, the cohort will be expanded to 
6 patients. If there are no further DLTs in the first 6 DLT-evaluable patients, enrollment of 
the next cohort at the next dose level may proceed.
If 2 or more of the first 6 DLT-evaluable patients in the next cohort at the next dose level 
experience a DLT, the MTD in induction will have been exceeded and dose-escalation will 
stop. 
If the MTD is exceeded at any dose level, the highest dose at which fewer than 2 of 6 DLT-
evaluable patients (i.e., ≥33%) experience a DLT will be declared the MTD.


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If the MTD is not exceeded at any dose level, the highest dose of venetoclax (800 mg 
NC Day 17) administered in induction will be declared the MTD for the induction 
setting.
If a particular cohort in induction dose-escalation (Arm B) exceeds MTD due to DLTs associated 
with neutropenia or febrile neutropenia without primary prophylactic growth factor support, then 
that cohort level will be tested again with primary prophylactic growth factor support.  For 
example, if venetoclax 400 mg Day 17 exceeds the MTD due to DLTs associated with 
neutropenia or febrile neutropenia without primary prophylactic growth factor support, then 
primary prophylactic growth factor support will be implemented in the study and that dose level 
cohort will be tested again with another 3 3 cohort.  Of note, primary G-CSF prophylaxis is 
only mandated during induction and not during maintenance therapy.  Once prophylactic growth 
factor support is instituted, then this will be required for further escalation cohorts during all 
induction cycles. For guidance on the use of prophylactic growth factor support, please refer to 
the protocol.
Patients exhibiting acceptable safety and evidence of clinical benefit (as determined by the 
investigator) may continue to receive study treatment until confirmed objective disease 
progression or unacceptable toxicity, whichever occurs first.
The Sponsor will review cumulative safety data and make recommendations regarding dose
escalation and overall study conduct on the basis of trial safety data to ensure patient safety 
while receiving study treatment.  These include recommendations to open or suspend patient 
enrollment in a given dose-escalation cohort based on the overall benefitrisk profile of 
venetoclax in combination with atezolizumab, carboplatin, and etoposide.
Relevant demographic, adverse event, laboratory, dose administration, and PK data (if 
available) will be reviewed prior to the selection of a RP2D in the maintenance (RP2D-M) and 
RP2D in the induction setting (RP2D-I).  The RP2D-I will be based on the MTD of venetoclax 
when combined with standard doses of atezolizumab, carboplatin, plus etoposide and the 
RP2D-M will be based on the MTD of venetoclax when combined with standard dose of 
atezolizumab. Both RP2D-I and RP2D-M will integrate aggregate safety data during treatment.  
Decision making will be led by the Medical Monitor in consultation with the Principal 
Investigators and a committee composed of at a minimum the following Sponsor 
representatives: statistician, safety scientist, PK scientist, and clinical scientist.  
Dose-Expansion Cohort
Once the MTD in the induction and in the maintenance settings has been established from the 
dose-escalation cohorts, additional patients will be enrolled in the dose-expansion cohort to 
further assess the safety and efficacy of venetoclax in combination with carboplatin, etoposide 
and/or atezolizumab.  If an MTD for venetoclax during induction was established, then the dose-
expansion cohort will continue to test venetoclax in both induction and maintenance.  If 
significant toxicity and DLTs in induction preclude identification of an MTD for venetoclax in 
induction treatment, then the safety and efficacy of venetoclax will only be investigated in a 
dose-expansion cohort in the maintenance setting.  If the maintenance-only cohort is expanded, 
then prior induction treatment of carboplatin and etoposide for 4 cycles in combination with 
atezolizumab for at least 3 cycles will be required.  If there are concerns about the tolerability of 
venetoclax during the dose-expansion stage, then a lower dose or alternative dosing schedule 
may be explored based on the severity and timing of DLTs as well as the specific adverse 
events encountered.  For example, consideration may be given to enrolling an expansion cohort
at the next lower dose level (as defined in dose-escalation stage; see protocol).  Decision 
making will integrate cumulative safety and efficacy data during treatment and will be led by the 
Medical Monitor in consultation with the Principal Investigators and a committee composed of at 
a minimum the following Sponsor representatives: statistician, safety scientist, PK scientist, and 
clinical scientist.


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Treatment after Disease Progression
During the study, patients who meet criteria for disease progression per RECIST v1.1 and show 
evidence of clinical benefit may continue treatment at the investigator’s discretion, provided that 
the patients meet all of the following criteria: 
Evidence of clinical benefit, as assessed by the investigator
Absence of symptoms and signs (including worsening of laboratory values [e.g., new or 
worsening hypercalcemia]) indicating unequivocal progression of disease
No decline in Eastern Cooperative Oncology Group (ECOG) performance status that can be 
attributed to disease progression
Absence of tumor progression at critical anatomical sites (e.g., CNS, leptomeningeal disease, 
etc.) that cannot be managed by protocol-allowed medical interventions 
Investigator assessment of overall tumor response at all timepoints will be based only on 
RECIST v1.1.
Number of Patients
Approximately 1842 patients will be enrolled in the dose-escalation cohorts.  An additional 
estimated 20 patients will be enrolled in the dose-expansion cohort of this study.
Target Population
Inclusion Criteria
Dose-Escalation, Maintenance Arm A

Patients with ES-SCLC who have completed 4-6 cycles of carboplatin and etoposide 
induction chemotherapy, with or without atezolizumab, as their first-line therapy for 
extensive-stage disease and have responded (CR or PR) or have stable disease (SD) are 
eligible for the maintenance arm of the study.

All side effects attributed to prior anti-cancer therapy must have resolved to Grade 1 or
baseline.

A maximum of 8 weeks (56 days) is allowed between last chemotherapy dose (Cycle 4, 
Day 3) given in induction and the start of maintenance therapy.
Dose-Escalation, Induction Arm B

Patients with no prior systemic treatment for ES-SCLC are eligible for this study.

ANC 1,500 cells/L without granulocyte colony-stimulating factor support 
Dose-Expansion, Maintenance Only

Patients with ES-SCLC who have completed 4 cycles of carboplatin and etoposide induction 
chemotherapy and at least 3 cycles of atezolizumab as their first-line therapy for extensive-
stage disease and have responded (CR or PR) or have SD are eligible for the maintenance 
arm of the study.
Dose-Escalation (Arms A and B) and Dose-Expansion

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator's judgment

ECOG performance status of 0 or 1

Patients must be able to swallow pills

Histologically or cytologically confirmed diagnosis of ES-SCLC per the Veterans 
Administration Lung Study Group (VALG) staging system


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
Patients who received prior chemoradiotherapy for limited-stage SCLC must have been 
treated with curative intent and experienced a treatment-free interval of at least 6 months 
since last chemotherapy, radiotherapy, or chemoradiotherapy cycle prior to diagnosis of ES-
SCLC

Patients with a history of treated CNS metastases that are currently asymptomatic are 
eligible, provided they meet all of the following criteria:
–
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, 
pons, medulla or spinal cord)
–
No ongoing requirement for corticosteroids as therapy for CNS disease
–
No evidence of interim progression between the completion of CNS-directed therapy 
and enrollment
–
Patients with new asymptomatic CNS metastases detected at the screening scan must 
receive radiation therapy and/or surgery for CNS metastases.  Following treatment, 
these patients may then be eligible without the need for an additional brain scan prior to
enrollment, if all other criteria are met.

Measurable disease, as defined by RECIST v1.1.  Baseline measurements and evaluation of 
all sites of disease must be obtained 4 weeks prior to enrollment.
–
Previously irradiated lesions can only be considered as measurable disease if disease 
progression has been unequivocally documented at that site since radiation and the 
previously irradiated lesion is not the only site of disease.

Eligible to receive a carboplatin-based chemotherapy regimen

Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 14 days prior to enrollment: 
–
ANC 1500 cells/L (without granulocyte-colony stimulating factor support within 7 
days prior to Cycle 1, Day 1)
–
Lymphocyte count 500 cells/L
–
Platelet count 100,000 cells/L without transfusion
–
Hemoglobin 9.0 g/dL
Patients may be transfused to meet this criterion. 
–
INR or aPTT 1.5 ULN
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation should be on a stable dose and with 
INR 3.5 ULN.
–
AST (SGOT), ALT (SGPT), and alkaline phosphatase   2.5 ULN with the following 
exceptions:
Patients with documented liver metastases: AST and/or ALT
5 ULN
Patients with documented bone or liver metastases: alkaline phosphatase 5 
ULN
–
Serum total bilirubin 1.5 ULN
Patients with known Gilbert disease who have serum bilirubin level 3 ULN may 
be enrolled.
–
Albumin 25 g/L (2.5 g/dL)


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–
Creatinine clearance (CRCL) 50 mL/min calculated with the use of the 24-hour CRCL 
or modified Cockcroft-Gault equation (i.e., estimation of creatinine clearance rate [eCCr]) 
with the use of ideal body mass (IBM) instead of mass:
eCCr =  (140 age) (weight in kg) (0.85 if female)
72 (serum creatinine in mg/dL)
Or, if serum creatinine is in μmol/L:
eCCr = (140age) IBM (kg) (1.04 if female)
serum creatinine (μmol/L)

Patients must submit a pre-treatment tumor tissue sample.  Any available tumor tissue 
sample can be submitted (fresh, paraffin-embedded tissue block, or serial cut slides [15 
preferred]).  The tissue sample should be submitted before or within 4 weeks after 
enrollment; however, patients may be enrolled into the study before the pre-treatment tumor
tissue sample is submitted.  If tissue is not available, approval from the Medical Monitor is 
required before enrolling. 

Patients must submit a blood sample for exploratory biomarker research before treatment, 
on-study, and following progression of disease.

For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use non-hormonal contraceptive methods that result in a failure 
rate of 1% per year during the treatment period and for at least 30 days after the final 
dose of venetoclax, 5 months after the final dose of atezolizumab, or 6 months after the final 
dose of carboplatin or etoposide, whichever is longer.  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.  If required per local guidelines or regulations, 
locally recognized adequate methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form.

Women who are not postmenopausal (12 months of nontherapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test result within 14 days prior to 
initiation of study drug.   
If a serum pregnancy test has not been performed 14 days prior to dosing, a urine 
pregnancy test must be performed 7 days prior to dosing.  If the test result is positive, 
patient dosing will be postponed until the patient’s status is confirmed by a serum 
pregnancy test.


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
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom plus an additional contraceptive method that 
together result in a failure rate of 1% per year during treatment with chemotherapy 
(i.e., carboplatin and etoposide) and for at least 6 months after the final dose of 
carboplatin or etoposide to avoid exposing the embryo.  Men must refrain from donating 
sperm during this same period.
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, sympotothermal, or postovulation methods) are not 
acceptable methods of contraception.  If required per local guidelines or regulations, 
locally recognized acceptable methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
Exclusion Criteria

Use of nonprotocol-specified anti-cancer therapies or other combination partners with 
carboplatin/etoposide during induction

Symptomatic or actively progressing CNS metastases 
Note:  Asymptomatic patients with treated (i.e., local CNS-directed therapy) or 
untreated CNS lesions are eligible, provided that all of the following criteria are met:
–
Measurable disease, per RECIST v1.1, must be present outside the CNS.
–
The patient has no history of intracranial hemorrhage or spinal cord hemorrhage 
from CNS disease. 
–
Metastases are limited to the cerebellum or the supratentorial region (i.e., no 
metastases to the midbrain, pons, medulla, or spinal cord).
–
The patient has no symptoms caused by CNS disease (i.e., no headache, nausea, 
vomiting, convulsion, paralysis, etc.).
–
The patient has no ongoing requirement for anticonvulsants for CNS disease.  
–
The patient has no ongoing requirement for dexamethasone/corticosteroids for 
CNS disease (previously untreated patients must also not have any history of 
requiring or receiving dexamethasone/corticosteroids for CNS disease).
–
For patients with previously treated CNS metastases, there is no evidence of 
interim CNS progression between the completion of CNS-directed therapy and 
enrollment. 
–
For previously untreated patients, there is no evidence of brain edema related to 
CNS disease (e.g., vasogenic edema).
–
For previously untreated patients, a brain magnetic resonance imaging (MRI) scan 
with contrast is required at screening and is the preferred modality for all 
subsequent scheduled follow-up tumor assessments.
Note:  Computed tomography (CT) scan with contrast may be acceptable for 
all subsequent scheduled follow-up tumor assessments if the following criteria 
are met.
–
Both brain MRI and CT scan with contrast must be performed at 
screening to assess untreated CNS disease. 
–
The CT scan with contrast can be used to reliably evaluate lesions 
identified on the screening MRI with contrast.


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If CT scan with contrast cannot be used to reliably evaluate lesions identified 
on the screening MRI with contrast, then MRI scan with contrast must be 
used at all subsequent scheduled follow-up tumor assessments.
The same modality must be used at every tumor assessment.

Pregnant or breastfeeding, or intending to become pregnant during the study
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to initiation of study drug.

Spinal cord compression not definitively treated with surgery and/or radiation or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for 1 week prior to enrollment

Leptomeningeal disease

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once a month or more frequently)
Patients with indwelling catheters (e.g., PleurX) are allowed regardless of drainage 
frequency.

Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, total serum 
calcium 12 mg/dL, or corrected calcium ULN)

History of malignancy other than SCLC within 5 years prior to enrollment, with the exception 
of those with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) 
treated with expected curative outcome (such as adequately treated carcinoma in situ of the 
cervix, basal or squamous cell cancer of the skin, localized prostate cancer treated surgically 
with curative intent, ductal carcinoma in situ treated surgically with curative intent)

History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis 
Patients with a history of autoimmune-mediated hypothyroidism on a stable dose of 
thyroid replacement hormone are eligible for this study. 
Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen are 
eligible for this study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., no psoriatic arthritis) are permitted provided that they meet 
the following conditions: 
–
Rash must cover less than 10% of body surface area. 
–
Disease is well-controlled at baseline and only requiring low potency topical 
steroids.
–
No acute exacerbations of underlying condition within the last 12 months requiring 
treatment with either psoralen plus ultraviolet A radiation (PUVA), methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral topical 
steroids 

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive test result for HIV


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All patients must be tested for HIV; patients who test positive for HIV will be excluded.

Active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen 
[HBsAg] test result at screening) or hepatitis C virus (HCV)
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined 
as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are 
eligible.  HBV DNA should be obtained in these patients prior to enrollment and should 
be undetectable.  These patients must be willing to undergo monthly DNA testing.
Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) 
is negative for HCV RNA.

Active tuberculosis

Known infection with human T-cell leukemia virus 1

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding 
fungal infections of nail beds) at study enrollment, or any major episode of infection requiring 
treatment with IV antibiotics or hospitalization (relating to the completion of the course of 
antibiotics) within 4 weeks prior to Cycle 1, Day 1

Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction, or cerebrovascular accident within the previous 3 
months, unstable arrhythmias, or unstable angina 
Patients with known coronary disease, congestive heart failure not meeting the above 
criteria, or left ventricular ejection fraction <50% must be on a stable medical regimen 
that is optimized in the opinion of the treating physician, in consultation with a 
cardiologist if appropriate. 

Major surgical procedure within 28 days prior to enrollment or anticipation of need for major 
surgical procedure during the course of the study 

Prior allogenic bone marrow transplantation or solid organ transplant 

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or render 
the patient at high risk for treatment complications

Illnesses or conditions that interfere with their capacity to understand, follow, and/or comply 
with study procedures

Treatment with investigational therapy with therapeutic intent within 28 days prior to 
enrollment

Administration of a live, attenuated vaccine within 4 weeks before enrollment or anticipation 
that such a live attenuated vaccine will be required during the study
Patients must not receive live, attenuated influenza vaccines (e.g. FluMist) within 4 
weeks prior to enrollment, during treatment, and for 5 months following the last dose of 
atezolizumab or chemotherapy. 

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-PD-1, 
and anti-PD-L1 therapeutic antibodies

Treatment with systemic immunosuppressive medications (including, but not limited to 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 
necrosis factor [anti-TNF] agents) within 1 week prior to enrollment
Patients who have received acute systemic immunosuppressant medications (e.g., use 
of corticosteroids for nausea, vomiting, or management of or premedication for allergic 
reactions) may be enrolled in the study after discussion with and approval by the 


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Medical Monitor.  In those patients, the need and length of the washout period prior to 
enrollment will also be established in conjunction with the Medical Monitor.
The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and 
low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or 
any component of the atezolizumab formulation 

History of allergic reactions to carboplatin or etoposide or to any of its excipients (etoposide)

Known hypersensitivity to venetoclax or to any of its excipients

Administration of the following agents within 7 days prior to the first dose of study drug:
–
Steroid therapy for anti-neoplastic intent (stable steroid mediation not more than 10 
mg prednisolone per day or an equivalent dose of other corticosteroids for 
controlling CNS metastases is acceptable)
–
Strong or moderate CYP3A inhibitors (see protocol for examples)
–
Strong or moderate CYP3A inducers (see protocol for examples)
Additional restrictions for on-study use of CYP3A inhibitors/inducers are outlined in the 
protocol.

Consumption of grapefruit, grapefruit products, Seville oranges (including marmalade-
containing Seville oranges), or starfruit (carambola) within 3 days before within 3 days prior 
to the first dose of study drug

Malabsorption syndrome or other condition that would interfere with enteral absorption

Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator’s 
judgment

Inability or unwillingness to swallow a large number of tablets

History of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) or active 
bowel inflammation (e.g., diverticulitis)
End of Study
The end of this study is defined as 6 months after the last patient’s radiographic last 
assessment.  The end of the study is expected to occur 24 months after the last patient is 
enrolled. In addition, the Sponsor may decide to terminate the study at any time.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be 31 to 49 months.
Investigational Medicinal Products
The investigational medicinal products (IMP) for this study are atezolizumab and venetoclax.  
Carboplatin and etoposide are background treatments and are thus considered 
non-investigational medicinal products (NIMPs) in this study.  
Atezolizumab
The atezolizumab Drug Product will be supplied by the Sponsor as a sterile liquid in a single-
use, 20 mL glass vial.  The vial contains approximately 20 mL (1200 mg) of atezolizumab 
solution.
Venetoclax
Patients will self-administer venetoclax tablets by mouth daily.  Venetoclax is formulated as 100-
mg tablets; patients may take up to eight 100-mg tablets daily to receive an 800-mg continual 
dose.  Each dose of venetoclax will be taken with approximately 240 mL of water within 30 


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minutes after the patient’s first meal of the day (e.g., breakfast).  For continuous venetoclax 
dose (Days 121), patients should continue taking venetoclax without a break between cycles.
Carboplatin and Etoposide 
Carboplatin and etoposide will be used in the commercially available formulation. 
Dosage, Administration, Sequence, and Compliance 
Atezolizumab will be given at fixed dose of 1200 mg by IV infusion every 21 [2] days in both 
induction and maintenance.  For more information on the formulation, packaging, and handling 
of atezolizumab, please refer to the prescribing information. 
Carboplatin and etoposide induction therapy will be administered as follows:
During induction, patients will be treated with carboplatin and etoposide chemotherapy. For 
information on the formulation, packaging, and handling of these therapies, please see the 
prescribing information for each drug.
Standard doses of each agent will be administered for a total of four 21-day cycles during 
induction.

Carboplatin AUC 5 mg/mL min (Calvert formula dosing) IV infusion over 3060 minutes on 
Day 1 of each cycle after completion of atezolizumab IV infusion with standard anti-emetics 
per local practice guidelines.

Etoposide 100 mg/m2 IV on Days 13 of each cycle.  On Day 1 of each cycle, etoposide 
should be administered intravenously over 60 minutes following carboplatin administration.  
On Days 2 and 3 of each cycle, etoposide (100 mg/m2) should be administered 
intravenously over 60 minutes.  Premedication should be administered according to local 
standard of care. 
On Day 1 of each cycle, all eligible patients will receive treatment in the following order:
Induction:  atezolizumab carboplatin etoposidevenetoclax
Maintenance:  atezolizumab venetoclax
On Days 2 and 3, patients will receive etoposide infusions. 
Because the effects of corticosteroids on T-cell proliferation have the potential to attenuate 
atezolizumab-mediated anti-tumor immune activity, premedication with corticosteroids should 
be minimized to the extent that is clinically feasible.  Secondly, at the initiation of the induction 
phase of dose-escalation Arm B, cohorts will be treated without primary prophylactic G-CSF.  
The administration of secondary prophylactic G-CSF for high-frequency febrile neutropenia, 
severe neutropenia, or prolonged neutropenia must be discussed and agreed upon between the 
investigator and the Medical Monitor.  Please refer to protocol administration details, which are 
in accordance with institutional standards and American Society of Clinical Oncology (ASCO), 
National Comprehensive Cancer Network (NCCN), or ESMO guidelines.  Of note, if and once 
primary prophylactic G-CSF is deemed to be necessary as determined in the dose-escalation
phase (see the protocol), then this requirement will be implemented during induction therapy for 
all subsequent patients.
For information on the formulation and handling of atezolizumab, see the pharmacy manual and 
the Atezolizumab Investigator's Brochure.
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.  For anaphylaxis precautions, see the protocol.  Atezolizumab 
infusions will be administered per the instructions outlined in the protocol.
Cycles in which no chemotherapy is given do not count toward the total number of induction 
chemotherapy cycles.
After the induction phase, patients will begin maintenance therapy with atezolizumab plus 
venetoclax. 
The suggested infusion times for carboplatin and etoposide may be adapted in accordance with 
local standard of care.


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Any dose modification should be noted on the Study Drug Administration eCRF.  Cases of 
accidental overdose or medication error, along with any associated adverse events, should be 
reported as described in the protocol.
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.  For anaphylaxis precautions, see the protocol.  
Guidelines for dose modification and treatment interruption or discontinuation for carboplatin 
and etoposide are provided in the protocol.
Statistical Methods
Primary Analysis
The analysis population for the efficacy analyses will consist of all enrolled patients in the dose-
expansion cohort, with patients grouped according to their assigned dose levels and treatment 
schedules.  
The primary efficacy objective for the Phase Ib dose-expansion cohort is to evaluate the 
preliminary efficacy of venetoclax in combination with atezolizumab as maintenance therapy or 
venetoclax in combination with atezolizumab, carboplatin, and etoposide as induction therapy 
followed by venetoclax plus atezolizumab as maintenance therapy on the basis of the following 
endpoint:

ORR, defined as the proportion of patients with a CR or PR on two consecutive occasions 
4 weeks apart, as determined by the investigator according to RECIST v1.1 criteria. 
Patients with no disease assessments for any reason will be classified as non-responders.  An 
estimate of ORR with 90% exact confidence interval (CI) will be presented using the method of 
Pearson Clopper.
Interim Analyses 
Planned Interim Analyses
None planned.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody, also called anti-therapeutic antibody
AML
acute myeloid leukemia
Bcl-2
B-cell lymphoma 2
CBR
clinical benefit rate
CE
carboplatin and etoposide
CI
confidence interval
CLL
chronic lymphocytic leukemia
CR
complete response
CRCL
creatinine clearance
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
DDI
drug-drug interaction
DLTs
dose-limiting toxicities
DOR
duration of response
EBV
Epstein-Barr virus
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EORTC
European Organisation for Research and Treatment of 
Cancer
ER
estrogen receptor
ES-SCLC
extended stage small cell lung cancer
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
G-CSF
growth-colony stimulating factor
GFR
glomerular filtration rate
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
HR
hazard ratio
IBM
ideal body mass
ICH
International Council for Harmonisation


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Abbreviation
Definition
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IRR
infusion-related reactions
IV
intravenous
IxRS
interactive voice or web-based response system
LS-SCLC
limited stage small cell lung cancer
MM
multiple myeloma
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NC
non-continuous (dosing schedule)
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NGS
next-generation sequencing
NHL
non-Hodgkin lymphoma
NIMPs
non-investigational medicinal products
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
Q3W
every 3 weeks
QD
daily
RBR
Research Biosample Repository
RECIST
Response Evaluation Criteria in Solid Tumors
R-ICE
rituximab, ifosfamide, carboplatin, etoposide
RP2D
recommended Phase II dose
R/R
relapsed and refractory
SCLC
small cell lung cancer
SD
stable disease
SLL
small lymphocytic lymphoma
T3
triiodothyronine
TLS
tumor lysis syndrome
ULN
upper limit of normal


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Abbreviation
Definition
WES
whole exome sequencing
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON LUNG CANCER
Lung cancer is the leading cause of cancer deaths worldwide. It is the second most 
common cancer in both men and women, accounting for approximately 13% of all new 
cancers (Surveillance, Epidemiology, and End Results [SEER] 2019).  In 2018, it was 
estimated that there were 470,039 new cases of lung cancer and 387,913 lung cancer 
deaths in Europe (Bray et al. 2018). In the United States, an estimated 228,150 new 
cases of lung cancer and 142,670 lung cancer deaths are projected in 2019 (Siegel et al. 
2019; SEER 2019).
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all cases of lung 
cancer (Molina et al. 2008; Howlader et al. 2014). Small cell lung cancer (SCLC)
accounts for approximately 13% of all lung cancer cases, and is distinguished from 
NSCLC by its rapid growth time and early development of metastatic disease (Govindan 
et al. 2006). Nearly all cases of SCLC are attributable to cigarette smoking (Pesch et al. 
2012). SCLC has a simple staging system that divides patients into 2 groups: limited 
stage (LS-SCLC) and extended stage (ES-SCLC).  LS-SCLC is defined as Stage I to III
(T any, N any, M0) that can be safely treated with definitive radiation therapy, excluding 
T3-4 due to multiple lung nodules that are too extensive or have tumor/nodal volume too 
large to be encompassed in a tolerable radiation plan. ES-SCLC is defined as Stage IV 
(T any, N any, M1a/b) and represents tumors beyond the boundaries of LS-SCLC,
including distant metastases, malignant pericardial or pleural effusions, and contralateral 
supraclavicular and contralateral hilar involvement.
Poor prognostic factors for survival in patients with SCLC include extensive-stage 
disease, poor performance status, weight loss, number of organs involved, and markers 
associated with excessive bulk of disease (e.g., lactate dehydrogenase) (Yip et al. 2000; 
Foster et al. 2009). Central nervous system, bone marrow, and liver metastases; as well 
as endocrinologic paraneoplastic syndromes, are also generally associated with worse 
outcomes. Smoking cessation should be strongly encouraged in SCLC patients 
because patients who smoke have an increased toxicity during treatment and shorter 
survival (Videtic et al. 2003; National Comprehensive Cancer Network [NCCN] 2019). 
Patients with LS-SCLC can be treated with chemotherapy and radiation with the 
potential for long-term survival (Stinchcombe et al. 2008). However, the majority
(approximately 70%) of patients with SCLC are diagnosed with ES-SCLC, which has 
poor survival prospects (median overall survival [OS] approximately 10 months) 
(Socinski et al. 2009). The aggressiveness of ES-SCLC, which may result in the 
development of symptomatic disease between annual scans, limits the potential effect of 
screening on mortality. Chest pain, dyspnea, and cough are among the most frequent 
disease-related symptoms experienced by patients with SCLC. Less commonly, SCLC 
can present with an endocrinologic or neurologic paraneoplastic syndrome. Of note, 
SCLC is the most common malignancy associated with neurologic paraneoplastic 


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syndromes (e.g., cerebellar degenerative syndromes or the Lambert Eaton myasthenic 
syndrome). Chemotherapy alone can palliate symptoms and prolong survival for 
patients with ES-SCLC; however, long-term survival is rare (Johnson et al. 2004;
Demedts et al. 2010).
1.2
FIRST-LINE TREATMENT FOR EXTENSIVE-STAGE SMALL 
CELL LUNG CANCER
A PD-L1 inhibitor (atezolizumab or durvalumab) given in combination with platinum-
based chemotherapy consisting of carboplatin and etoposide (CE) or cisplatin and 
etoposide as induction therapy for 4 cycles, followed by atezolizumab or durvalumab
maintenance therapy, is the current standard first-line treatment for patients with ES-
SCLC in the United States (NCCN 2019). The regimen with atezolizumab has also 
recently gained European Commission approval (Roche Media Release, 2019) based on 
the results of the randomized Phase III Study GO30081 (IMpower133). A total of 403 
patients were randomized in IMpower133, with 201 patients randomly assigned to the
atezolizumab plus CE group and 202 patients assigned to the placebo plus CE group. 
With a median follow-up of 13.9 months, the hazard ratio (HR) for death was 0.70 (95% 
confidence interval [CI]: 0.54, 0.91; p0.007) with a median OS of 12.3 months in the 
atezolizumab plus CE group and 10.3 months in the placebo plus CE group. The HR for 
progression-free survival (PFS) was 0.77 (95% CI: 0.62, 0.96; p0.02), with a median 
PFS of 5.2 months and 4.3 months for atezolizumab plus CE and placebo plus CE, 
respectively (Horn et al. 2018).  Response rates were similar in both arms, with an 
overall response rate (ORR) of 60% in the atezolizumab arm and 64% in the placebo 
arm.
The safety profile of atezolizumab plus CE was consistent with the previously reported 
safety profile of the individual agents, with no new findings observed. Specifically, 
adverse events related to any component of the trial regimen occurred in 188 patients 
(94.9%) in the atezolizumab group and in 181 patients (92.3%) in the placebo group. 
The most common Grade 3 or 4 adverse events related to the trial regimen were 
neutropenia and anemia. The number of deaths related to the trial regimen was the 
same in both arms: 3 patients (1.5%) in the atezolizumab group (death was due to 
neutropenia in 1 patient, pneumonia in 1 patient, and an unspecified cause in 1 patient) 
and in 3 patients (1.5%) in the placebo group (death was due to pneumonia in 1 patient, 
septic shock in 1 patient, and cardiopulmonary failure in 1 patient). Immune-related 
adverse events occurred in 79 patients (39.9%) in the atezolizumab group and in 
48 patients (24.5%) in the placebo group, with rash and hypothyroidism being the most 
common (Horn et al. 2018).
Results from the CASPIAN study with another PD-L1 inhibitor, durvalumab, in the same 
patient population were published showing consistent results with the IMpower133 trial
(Paz-Ares et al. 2019). The randomized, open-label, Phase III CASPIAN study 
randomized 805 patients: 268 were assigned to durvalumab plus platinum–etoposide,


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268 to durvalumab plus tremelimumab plus platinum–etoposide, and 269 to platinum–
etoposide alone. The results of the tremelimumab containing arm will be reported at the 
time of the final OS analysis. Durvalumab plus platinum–etoposide was associated with 
a significant improvement in OS, with a HR of 0.73 (95% CI 0.59–0.91; p=0.0047]); 
median OS was 13.0 months (95% CI 11.514.8) in the durvalumab plus 
platinumetoposide group versus 10.3 months (9.3–11.2) in the platinum–etoposide 
group. Although PFS was not formally tested for statistical significance, the HR was 
0.78 (95% CI: 0.65, 0.94), with a median PFS of 5.1 months for durvalumab plus 
platinum–etoposide and 5.4 months for platinum–etoposide. Grade 3 or 4 adverse 
events of any cause occurred in 163 (62%) of 265 treated patients in the durvalumab 
plus platinum–etoposide group and 166 (62%) of 266 in the platinum–etoposide group; 
adverse events leading to death occurred in 13 (5%) and 15 (6%) patients in each 
group.
Prior to the approval of the IMpower133 regimen, the standard of care for nearly 
30 years was platinum-based chemotherapy with etoposide, a topoisomerase II inhibitor 
(Fruh et al. 2013). Clinical studies with the combination of cisplatin and etoposide as 
first-line treatment in patients with ES-SCLC showed complete response (CR) rates
exceeding 40% and median survival time of approximately 9 months (Evans et al. 1985). 
Subsequently, small randomized studies have suggested similar efficacy of cisplatin and 
carboplatin in patients with SCLC (Skarlos et al. 1994; Okamoto et al. 2007). A meta-
analysis of four randomized studies compared cisplatin-based versus carboplatin-based
regimens in patients with SCLC (Rossi et al. 2012). Of the 663 patients included in this 
meta-analysis, 68% had extensive-stage disease. In patients receiving cisplatin- versus 
carboplatin-containing regimens, there was no significant difference observed in 
response rate (67% vs. 66%), PFS (5.5 vs. 5.3 months; HR: 1.10; 95% CI: 0.94, 1.29),
or OS (9.6 vs. 9.4 months; HR: 1.08; 95% CI: 0.92, 1.27), suggesting equivalent efficacy 
in patients with SCLC. Several studies using cisplatin or carboplatin with etoposide (at 
various doses) have shown consistent outcomes (see Table 1).


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Table 1
Results from Randomized Studies using Platinum-Based 
Chemotherapy for ES-SCLC
Platinum Dosing
Etoposide Dosing
ORR
(%)
Median 
PFS
(mo)
Median 
OS
(mo)
Roth et al. 1992 
Cisplatin 20 mg/m2 Days 15
80 mg/m2 Days 15
61%
4.3
8.6
Pujol et al. 2001
Cisplatin 100 mg/m2 Day 2
100 mg/m2 Days 13
61%
6.3
9.3
Noda et al. 2002
Cisplatin 80 mg/m2 Day 1
100 mg/m2 Days 13
68%
4.8
9.4
Eckardt et al. 2006
Cisplatin 80 mg/m2 Day 1
100 mg/m2 Days 13
69%
6.3
10.1
Hanna et al. 2006
Cisplatin 60 mg/m2 Day 1
120 mg/m2 Days 13
44%
4.6
10.2
Okamoto et al. 2007
Cisplatin 25 mg/m2 Days 13
80 mg/m2 Days 13
73%
4.7
9.9
Okamoto et al. 2007
Carboplatin AUC 5 Day 1
80 mg/m2 Days 13
73%
5.2
10.6
Rudin et al. 2008
Carboplatin AUC 5 Day 1
100 mg/m2 Days 13
52%
5.4
10.6
Socinski et al. 2009
Carboplatin AUC 5 Day 1
80 mg/m2 Days 13
60%
7.6
10.6
Nagel et al. 2011
Carboplatin AUC 6 Day 1
120 mg/m2 Days 13
67%
7.0
11.0
Schmittel et al. 2011
Carboplatin AUC 5 Day 1
140 mg/m2 Days 13
52%
6.0
9.0
AUC area under the concentration-time curve; ES-SCLC extensive-stage small cell lung cancer; 
mo months; ORR objective response rate; OS overall survival; PFS progression-free survival.
Despite the impressive initial response rates observed with first-line chemotherapy
regimens, most patients with ES-SCLC develop resistance and their prognosis is poor. 
PFS is approximately 6 months and median survival is approximately 1 year. Unlike 
NSCLC, SCLC is devoid of kinase vulnerabilities such as EGFR, ROS, and ALK. 
Instead, SCLC survival and proliferation are largely reliant on the currently undruggable 
MYC family of transcription factors, and through the loss of tumor suppressors p53 and 
Rb (George et al. 2015), underlining a significant need for improved novel treatment 
options for patients with ES-SCLC. With this consideration, combining a pro-apoptotic 
molecule such as venetoclax with chemotherapeutic and immunotherapeutic agents,
such as antibodies that modulate immune cell activity, offer an alternative treatment
approach that could potentially improve the prognosis of patients with this disease.
1.3
BCL-2 SIGNALING PATHWAY AND SMALL CELL LUNG 
CANCER
Cancer cells are characterized by their capacity for relentless growth, survival, and 
evasion of cell death (Adams and Cory 2007; Strasser et al. 2011). Apoptosis is the 
dominant mode of programmed cell death with two distinct pathways: the intrinsic 
mitochondrial pathway and the extrinsic death receptor pathway (Strasser et al. 2011). 
Intrinsic apoptosis is regulated by a balance between pro-apoptotic proteins and the 
B-cell lymphoma 2 (Bcl-2) family of anti-apoptotic proteins, of which key members are 
Bcl-2, Bcl-XL, Bcl-w, A1, and MCL-1 (Cory et al. 2003). Cancer cells often overexpress 
anti-apoptotic Bcl-2 family proteins to promote survival (Korsmeyer 1992; Thomas et al. 


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2013). Many cytotoxic cancer therapies ultimately induce apoptosis and altered 
expression of pro- and anti-apoptotic proteins and can promote therapy resistance 
(Longley and Johnston 2005; Thomas et al. 2013; Delbridge and Strasser 2015). 
Therefore, Bcl-2 family members have emerged as attractive targets for therapeutic 
development.  Small-molecule inhibitors of the Bcl-2 family have been studied, including 
the dual Bcl-2/Bcl-XL inhibitor ABT-737 (Oltersdorf et al. 2005) and its orally bioavailable 
analog ABT-263 (navitoclax; Tse et al. 2008), as well as ABT-199 (venetoclax or 
GDC-0199), a platelet-sparing, selective Bcl-2 inhibitor (Souers et al. 2013).
Elevated Bcl-2 expression in SCLC tumors was first described nearly 25 years ago, with 
a reported 65% to 76% of patients having Bcl-2-positive tumor samples by 
immunohistochemistry (IHC) analysis (Ben-Ezra et al. 1994; Kaiser et al. 1996). Recent 
internal analysis of procured SCLC tumor samples confirmed this earlier data by 
demonstrating that 77% of samples were Bcl-2 positive by IHC, and further revealed that 
35% of the samples were Bcl-2-high based on a cutoff of 50% of tumor cells stained 
with an intensity of 2+ or 3+ (Genentech internal data, unpublished). 
Nonclinical studies have also demonstrated that SCLC cell lines are sensitive to the dual 
Bcl-2/Bcl-XL inhibitors ABT-737 and navitoclax (Oltersdorf et al. 2005; Tse et al. 2008;
Inoue-Yamauchi et al. 2017). Through the development of the Bcl-2 specific inhibitor 
venetoclax, the dependence of SCLC cell lines on Bcl-2 has been more thoroughly 
described. Utilizing a panel of SCLC cell lines, Lochmann et al. demonstrated positive 
correlation between BCL2 mRNA expression and venetoclax sensitivity in vitro 
(Lochmann et al. 2018). Importantly, this sensitivity was maintained in vivo and oral 
daily (QD) dosing of venetoclax at 100 mg/kg QD was sufficient to induce tumor stasis or 
tumor regressions in several xenograft models of SCLC, including chemorefractory 
patient-derived xenograft models. These studies suggest that Bcl-2 is an important 
mediator of survival in nonclinical SCLC models.  
Activity of Bcl-2 family inhibitors have also been tested in the clinic in patients with ES-
SCLC.  Despite nonclinical data showing activity of navitoclax in that setting, its activity 
in the clinic as a single agent seems to be limited.  In a phase I trial of single-agent 
navitoclax in 20 pretreated ES-SCLC evaluable patients, 1 patient had partial response 
(PR) and 5 patients had stable disease (SD) (Gandhi et al. 2011).  In a Phase II open-
label trial for recurrent SCLC (Rudin et al. 2012), of 39 enrolled patients, 1 had PR and 9 
SD, with the most common adverse event being thrombocytopenia, an on-target result of 
BCL-XL inhibition in platelets.  Moreover, 1 PR was observed out of 19 patients treated in 
a phase I study evaluating navitoclax in combination with paclitaxel in untreated ES-
SCLC (Vlahovic et al. 2014).
Another agent, obatoclax, a pan-Bcl-2 family antagonist, was tested in a randomized 
Phase II study and was shown to be relatively well tolerated when added to CE in first-
line treatment of ES-SCLC, but failed to significantly improve ORR, PFS, or OS (Langer 
et al. 2014). The ORR was 62% with obatoclax plus CE versus 53% with CE (1-sided p 


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= 0.143).  The median PFS was 5.8 months (95% CI: 5.3–6.5) with obatoclax plus CE 
and 5.2 months (95% CI: 4.1–5.7) with CE.  Median OS was 10.5 months (95% CI: 8.9–
13.8) and 9.8 months (7.2–11.2) with a nonstatistically significant HR for OS, 0.823; 1-
sided p 0.121.  Grade 3/4 adverse events were primarily hematologic and similar in 
frequency between treatment arms.  Because nonclinical data indicate that obatoclax 
has weaker potency against Bcl-2 and Bcl-XL compared to ABT-737/navitoclax (Zhai et 
al. 2006) and weaker potency against Bcl-2 compared to venetoclax, there may have 
been insufficient inhibition of Bcl-2 family members in this trial.  Furthermore, the relative 
dose intensity could have been affected by neurotoxicity, which was dose-limiting in this 
study.  Some OS improvement was observed in patients who completed 6 cycles (14.2 
months vs. 11.6 months). 
As described above, the non-selective Bcl-2 inhibitors navitoclax and obatoclax have 
shown a mixed benefit/toxicity profile in SCLC, where thrombocytopenia hindered the 
management of these patients. Therefore, selective and potent Bcl-2 inhibition with 
venetoclax is hypothesized to have improved efficacy and to be more tolerable 
compared with the non-selective inhibitors.
1.4
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding
to Fc receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells.
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy.
Safety findings of single-agent atezolizumab across multiple tumor types are consistent 
with the known mechanism of action of atezolizumab and the underlying disease. 
Overall, treatment with atezolizumab is well tolerated with a manageable adverse event 
profile. Currently, the most commonly reported adverse events (10%) include fatigue, 
decreased appetite, cough, nausea, dyspnea, constipation, diarrhea, pyrexia, vomiting, 
arthralgia, back pain, asthenia, anemia, pruritus, rash, headache, and peripheral edema. 
The adverse events observed with atezolizumab in combination with chemotherapy 
and/or targeted therapies are consistent with the known risks of the individual study 
treatment. Systemic immune activation, characterized by an excessive immune 


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response, is a potential risk associated with atezolizumab when used in combination 
with another immunomodulating compound. There are no atezolizumab-related adverse 
events that are exacerbated when used in combination with other agents.
Immune-related adverse events are consistent with the role of the PD-L1/PD-1 pathway 
in regulating peripheral tolerance. Given the mechanism of action of atezolizumab, 
events associated with inflammation and/or immune-related adverse events are 
expected. Immune-related adverse events associated with atezolizumab include 
pneumonitis, hepatitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, 
myasthenic syndrome/myasthenia gravis, meningoencephalitis, myocarditis, and 
nephritis.
Atezolizumab is approved for the treatment of urothelial carcinoma, NSCLC, SCLC, and 
triple-negative breast cancer.
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies.
1.5
BACKGROUND ON VENETOCLAX
Venetoclax (also referred to as GDC-0199, RO5537382, ABT-199, A-1195425.0, 
Venclexta, and Venclyxto) is an orally bioavailable, selective small-molecule inhibitor 
of Bcl-2 in the biaryl acylsulfonamide chemical class.  Venetoclax binds with high affinity 
(Ki 0.01 nM) to the anti-apoptotic protein Bcl-2 and with lower affinity to other anti-
apoptotic Bcl-2 family proteins such as Bcl-XL and Bcl-w (4,000-fold and 2,000- to 
20,000-fold lower affinity than to Bcl-2, respectively; Souers et al. 2013).  Survival of 
platelets depends on BCL-XL, and thrombocytopenia is therefore a major DLT caused by 
inhibition of BCL-XL in the clinic.  Venetoclax has an improved therapeutic index by 
maintaining efficacy against tumor cells while avoiding dose-limiting thrombocytopenia. 
Venetoclax has been extensively studied in oncology, particularly in hematological 
malignancies but also in some solid tumors. Efficacy data indicate that venetoclax, both 
as a monotherapy and in combination with other therapeutic agents, shows promising 
safety, tolerability, pharmacokinetics, and efficacy. This includes combinations with 
rituximab, obinutuzumab, bendamustine plus rituximab, O6-benzylguanine, rituximab
plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), 
obinutuzumab plus CHOP (G-CHOP), bortezomib plus dexamethasone, azacitidine or 
decitabine, and cytarabine in patients with hematologic malignancies including chronic 
lymphocytic leukemia (CLL]/small lymphocytic lymphoma (SLL), non-Hodgkin lymphoma 
(NHL), multiple myeloma (MM), myelodysplastic syndrome (MDS), and acute myeloid 
leukemia (AML). 
In the United States, venetoclax is currently indicated for the treatment of adult patients 
with CLL or SLL. In addition, it is also approved in combination with azacitidine or 


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decitabine or low-dose cytarabine (LDAC) for the treatment of newly diagnosed AML in 
adults aged 75 years or older, or who have comorbidities that preclude use of intensive 
induction chemotherapy. This indication is approved under accelerated approval based 
on response rates. Continued approval for this indication may be contingent upon 
verification and description of clinical benefit in confirmatory trials.
In the EU, venetoclax in combination with rituximab is indicated for the treatment of adult 
patients with CLL who have received at least 1 prior therapy. Monotherapy is indicated 
for the treatment of CLL in the presence of 17p deletion or TP53 mutation in adult 
patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor, or in 
the absence of 17p deletion or TP53 mutation in adult patients who have failed both 
chemoimmunotherapy and a B-cell receptor pathway inhibitor.
Moreover, data with venetoclax in solid tumors such as ER-positive, Bcl-2 positive 
metastatic breast cancer (Lok et al. 2019) show promising activity.  In a Phase Ib dose-
escalation study, venetoclax dosed at 200, 400, 600, or 800 mg/daily in combination with 
tamoxifen 20 mg/daily, was shown to be well tolerated with no dose-limiting toxicities 
(DLTs) being observed in any of the cohorts and the maximum tolerated dose (MTD) not 
being reached. Efficacy was promising, with an observed ORR of 54% and clinical 
benefit rate (CBR) of 75% for the 800-mg cohort, comparing favorably with historical 
studies of patients treated with tamoxifen in first-line relapse (e.g., ORR 17%33% and 
CBR 38%56%).
Refer to the Venetoclax Investigator's Brochure for details on nonclinical and clinical 
studies.
1.6
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
SCLC is a very aggressive disease characterized by poor survival, with little progress 
being made in developing novel treatments in more than two decades. However, 
advances with immunotherapies have opened new therapeutic avenues. Recently, 
regulatory approval has been granted for atezolizumab plus CE in the United States and 
European Union, based on the IMpower133 study (see Section 1.2), for the first-line 
treatment of patients with ES-SCLC. Moreover, results from the randomized, open-
label, Phase III CASPIAN study with another PD-L1 inhibitor, durvalumab, in the same 
patient population demonstrated consistent results with the IMpower133 trial (Paz-Ares 
et al. 2019).  
However, despite the survival benefit observed with this regimen, median survival 
remains at approximately 1 year, leaving considerable room for improvement in 
outcomes.  Bcl-2 is highly expressed in SCLC, and Bcl-2 inhibition with venetoclax has 
been shown to be active and well tolerated both as a monotherapy as well as in 
combination with various chemotherapy backbones in different (mostly hematological) 
malignancies. In light of these observations, this study (Study GO41864) is designed to 
evaluate whether the anti-tumor effect of the standard combination of atezolizumab plus 


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CE can be enhanced by adding venetoclax in treating patients with chemotherapy-naive 
ES-SCLC.  
1.6.1
Study Rationale
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with metastatic cancer, including SCLC.  
Recent approvals in the United States and European Union of atezolizumab plus 
chemotherapy in metastatic SCLC based on the IMpower133 study in the first-line 
setting as well as the results of the CASPIAN phase III study validate the inhibition of the 
PD-L1/PD-1 pathway for achieving clinical benefit in these patients. Furthermore, the 
safety profile of atezolizumab or durvalumab plus chemotherapy appears to be as 
tolerable as chemotherapy doublet combinations in the front-line setting. Despite this 
advancement, patient outcomes in ES-SCLC continue to be very poor and a need 
remains for effective therapeutics that can be added to the approved regimen of 
atezolizumab, carboplatin, and etoposide. 
The high levels of Bcl-2 expressed in SCLC and the single-agent activity of venetoclax in 
nonclinical SCLC models suggest that the combination of a Bcl-2 inhibitor, such as 
venetoclax, and the atezolizumab plus chemotherapy standard of care treatment may 
improve the therapeutic outcome of SCLC through enhanced tumor killing. In nonclinical
studies, cisplatin and etoposide have been shown to synergistically combine with ABT-
737 (dual Bcl-2/Bcl-XL inhibitor) in vitro (Li et al. 2009), where cisplatin and etoposide 
were both shown to downregulate the anti-apoptotic protein MCL-1, which is a known to 
be a resistance factor for venetoclax.  Additionally, upregulation of Bcl-2 protein has 
been identified as a mechanism of drug resistance in vitro in SCLC cell lines that were 
generated to be etoposide resistant and showed cross-resistance to cisplatin and 
doxorubicin (Sartorius and Krammer 2002).  Together, these data provide a mechanistic 
rationale for combining Bcl-2 inhibition with etoposide and platinum to enhance tumor 
cell killing.  
Tumor-cell killing by cytotoxic chemotherapy, augmented by pro-apoptotic activity of 
venetoclax, can reasonably be expected to expose the immune system to high levels of 
tumor antigens. Importantly, recent studies have shown that venetoclax does not inhibit 
T-cell activation in vitro and does not antagonize anti-PD-1/PD-L1 efficacy in vivo 
(Lasater et al. 2018; Matthew et al. 2018).  Therefore, invigorating tumor-specific T-cell 
immunity by inhibiting PD-L1/PD-1 signaling and combining with pro-apoptotic therapy 
such as venetoclax may result in deeper and more durable responses compared with 
standard treatment alone.  This approach has a strong scientific rationale, and the 
evaluation of its safety and efficacy is warranted and could open new doors for the future 
treatment of patients with SCLC.
Venetoclax has been evaluated in a variety of oncological indications, particularly in 
hematological malignancies. Many of those evaluations have translated into regulatory 


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approvals in many indications within CLL and AML. From a safety perspective, 
venetoclax has been generally well tolerated as a single agent as well as in combination 
with targeted therapies and chemotherapy (refer to the Venetoclax Investigator’s 
Brochure for more details). Adverse events commonly observed with venetoclax include 
nausea, vomiting, diarrhea, myelotoxicity (including neutropenia, febrile neutropenia, 
anemia, thrombocytopenia, and leukopenia), and infections. To date, the majority of 
these adverse events have been manageable without requiring treatment 
discontinuation. Important identified risks for venetoclax include tumor lysis syndrome 
(TLS), particularly in CLL and mantle cell lymphoma, and neutropenia. Serious infection 
is also an identified risk. Of note, cytopenias and TLS are commonly observed in 
hematologic malignances in some cases independently of treatment, and their 
prevalence in solid tumors remains to be elucidated.
Therefore, the current Phase Ib study is designed to identify a safe and tolerable dose of 
venetoclax in the context of atezolizumab plus chemotherapy, as well as to explore 
whether the anti-tumor effects of atezolizumab plus chemotherapy can be improved with 
the addition of the pro-apoptotic small molecule venetoclax to atezolizumab and 
chemotherapy in patients with ES-SCLC.
1.6.2
BenefitRisk Assessment
This study will enroll patients with ES-SCLC with no prior systemic treatment, and all 
patients will receive an approved regimen that will include atezolizumab plus standard 
chemotherapy (CE).  Atezolizumab plus CE was well tolerated in the pivotal IMpower133 
study, with a safety profile consistent with the known risks of individual treatment and 
comparable to treatment with chemotherapy alone. Overall, the toxicity profile is
considered to be tolerable and manageable. 
The addition of venetoclax to chemotherapy and immunotherapy is believed to enhance 
apoptosis and to improve tumor growth inhibition. Moreover, tumor-cell killing by 
cytotoxic chemotherapy and augmented by the pro-apoptotic activity of venetoclax may 
bolster the immune-mediated mechanism of action of atezolizumab. Therefore, this 
study will offer an opportunity to evaluate the safety and activity of a promising novel 
approach combining venetoclax with chemotherapy and immunotherapy for the 
treatment of SCLC in the clinical setting.
Although the combination is expected to have limited overlapping toxicities, which 
include neutropenia, febrile neutropenia and thrombocytopenia, there remains the 
potential for unexpected toxicities. To minimize this risk, stringent inclusion and 
exclusion criteria (Sections 4.1.1 and 4.1.2), close safety monitoring (Section 5.1),
together with rules for dose modifications and safety management guidelines 
(Section 5.1.5) for known risks of single-agent atezolizumab and venetoclax have been 
implemented.  The addition of venetoclax to atezolizumab and chemotherapy, based on 
the manageable safety profile and potential for augmented efficacy, can represent a 


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potential valuable treatment option and offer a favorable benefitrisk balance for patients 
in this study. 
2.
OBJECTIVES AND ENDPOINTS
This is a Phase Ib, open-label, multicenter, two-stage study, consisting of a dose-
escalation phase and dose-expansion phase, to evaluate the safety, tolerability, 
pharmacokinetics, and efficacy of venetoclax in combination with atezolizumab, 
carboplatin, and etoposide as induction therapy and venetoclax in combination with 
atezolizumab as maintenance therapy following induction, for patients with ES-SCLC
who are chemotherapy-naïve for their extensive-stage disease.  
The objectives for the dose-escalation phase of this study are to assess safety and 
tolerability as well as to determine the maximum tolerated dose (MTD) and the 
recommended Phase II dose (RP2D) for venetoclax in both induction (Arm B) and 
maintenance (Arm A) therapies. 
The objectives of the dose-expansion phase are to evaluate the safety, tolerability, 
pharmacokinetics, and efficacy of venetoclax at the RP2D in induction followed by 
maintenance therapies or in maintenance therapy only, as determined in the dose-
escalation phase of the study. 
Specific objectives and corresponding endpoints for the study are outlined below.
In this protocol, "study treatment" refers to the combination of treatments assigned to 
patients as part of this study (i.e., venetoclax plus atezolizumab, carboplatin, and 
etoposide in the induction setting or venetoclax plus atezolizumab in the maintenance 
setting.
2.1
OBJECTIVES AND ENDPOINTS FOR DOSE-ESCALATION 
PHASE
2.1.1
Safety Objective (Primary Objective)
The safety objective for the dose-escalation phase is to evaluate the safety and 
tolerability of venetoclax plus atezolizumab as maintenance therapy (Arm A) and 
venetoclax in combination with atezolizumab, carboplatin, and etoposide as induction 
therapy followed by venetoclax plus atezolizumab as maintenance therapy (Arm B) 
including estimation of the MTD, determination of the RP2D, and characterization of 
DLTs (see Section 3.1.3)on the basis of the following endpoints:

The incidence and severity of adverse events, with severity determined according to 
the National Cancer Institute Common Technology Criteria for Adverse Events 
version 5.0 (NCI CTCAE v5.0)

Change from baseline in targeted vital signs

Change from baseline in targeted laboratory test results


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2.1.2
Pharmacokinetic Objectives
The pharmacokinetic (PK) objectives for the dose-escalation phase are the following:

To characterize the pharmacokinetics of venetoclax and atezolizumab when given in 
combination as part of the maintenance therapy on the basis of the following 
endpoints:
–
Plasma concentrations of venetoclax at specified timepoints  
–
Serum concentrations of atezolizumab at specified timepoints

To characterize the pharmacokinetics of venetoclax and atezolizumab when given in 
combination with carboplatin and etoposide as part of the induction therapy on the 
basis of the following endpoints:
–
Plasma concentrations of venetoclax at specified timepoints
–
Serum concentrations of atezolizumab at specified timepoints
2.1.3
Immunogenicity Objective
The exploratory immunogenicity objective for the dose-escalation phase is to evaluate 
the immune response to atezolizumab on the basis of the following endpoints:

Incidence of anti-drug antibodies (ADAs) to atezolizumab in the presence of 
venetoclax

Incidence of ADAs to atezolizumab in the presence of venetoclax, carboplatin, and 
etoposide 
2.1.4
Biomarker Objectives
The exploratory biomarker objectives for the dose-escalation phase are to identify and 
evaluate biomarkers that are predictive of response to venetoclax (i.e., predictive 
biomarkers), are early surrogates of efficacy, are associated with progression to a more 
severe disease state (i.e., prognostic biomarkers), are associated with acquired 
resistance to venetoclax, are associated with susceptibility to developing adverse events 
or can lead to improved adverse event monitoring or investigation (i.e., safety 
biomarkers), can provide evidence of venetoclax activity (i.e., pharmacodynamic 
biomarkers), or can increase the knowledge and understanding of disease biology and 
drug safety, on the basis of the following endpoint:

Relationship between biomarkers in tumor tissue and blood (listed in Section 4.5.7) 
and efficacy, safety, PK, immunogenicity, or other biomarker endpoints
2.2
OBJECTIVES AND ENDPOINTS FOR DOSE-EXPANSION
PHASE
2.2.1
Efficacy Objectives
2.2.1.1
Primary Efficacy Objective
The primary efficacy objective for the dose-expansion phase is to evaluate the 
preliminary efficacy of venetoclax in combination with atezolizumab as maintenance 
therapy or venetoclax in combination with atezolizumab, carboplatin, and etoposide as


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induction therapy followed by venetoclax plus atezolizumab as maintenance therapy on 
the basis of the following endpoint:

ORR, defined as the proportion of patients with a CR or PR on two consecutive 
occasions 28 days apart, as determined by the investigator according to Response 
Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
2.2.1.2
Secondary Efficacy Objective
The secondary efficacy objective for the dose-expansion phase is to evaluate the 
preliminary efficacy of venetoclax in combination with atezolizumab as maintenance 
therapy or venetoclax in combination with atezolizumab, carboplatin, and etoposide as
induction therapy followed by venetoclax plus atezolizumab as maintenance therapy on 
the basis of the following endpoints:

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 the investigator according to RECIST v1.1 

PFS after enrollment, defined as the time from enrollment to the first occurrence of 
disease progression or relapse or death from any cause (whichever occurs first), as 
determined by the investigator according to RECIST v1.1 

OS after enrollment, defined as the time from enrollment to death from any cause

PFS rate at 6 months, defined as the proportion of patients who have not 
experienced disease progression, relapse, or death from any cause at 6 months, as 
determined by the investigator according to RECIST v1.1 

OS rate at 1 year, defined as the proportion of patients who have not experienced 
death from any cause at 1 year
2.2.2
Safety Objective
The safety objective for the dose-expansion phase are to evaluate the safety and 
tolerability of venetoclax in combination with atezolizumab, carboplatin, and etoposide as 
induction therapy or venetoclax in combination with atezolizumab, carboplatin, and 
etoposide as induction therapy followed by venetoclax plus atezolizumab as
maintenance therapy on the basis of the following endpoints:

To determine the incidence and severity of adverse events, with severity determined 
according to NCI CTCAE v5.0 

Change from baseline in targeted vital signs

Change from baseline in targeted laboratory test results


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2.2.3
Pharmacokinetic Objectives
The PK objectives for the dose-expansion phase are the following:

To characterize the pharmacokinetics of venetoclax and atezolizumab when given in 
combination as part of the maintenance therapy on the basis of the following 
endpoints:
–
Plasma concentrations of venetoclax at specified timepoints  
–
Serum concentrations of atezolizumab at specified timepoints

To characterize the pharmacokinetics of venetoclax, atezolizumab, carboplatin, and 
etoposide when given in combination as part of the induction therapy on the basis of 
the following endpoints:
–
Plasma concentrations of venetoclax at specified timepoints
–
Serum concentrations of atezolizumab at specified timepoints
–
Plasma concentrations of carboplatin at specified timepoints
–
Plasma concentrations of etoposide at specified timepoints
2.2.4
Immunogenicity Objective
The exploratory immunogenicity objective for the dose-expansion phase are the same 
as those described for the dose-escalation phase and are described in Section 2.1.3.
2.2.5
Biomarker Objectives
The exploratory biomarker objectives for the dose-expansion phase are the same as
those described for the dose-escalation phase and are described in Section 2.1.4. 
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase Ib, multicenter, open-label, two-stage study consisting of a dose-
escalation phase and a dose-expansion phase to evaluate the safety, tolerability, 
pharmacokinetics, and efficacy of venetoclax in combination with atezolizumab, 
carboplatin, and etoposide.
3.1.1
Overview of Study Design
In the dose-escalation stage, venetoclax will be tested first in the maintenance setting 
(Arm A) followed by testing in both the induction and maintenance settings (Arm B). 

Arm A:  Venetoclax and atezolizumab as maintenance therapy for patients with 
ES-SCLC who have completed 46 cycles of carboplatin and etoposide first-line 
induction chemotherapy, with or without atezolizumab

Arm B:  Venetoclax, atezolizumab, carboplatin, and etoposide as induction therapy 
(4 cycles) followed by venetoclax plus atezolizumab as maintenance therapy for
patients with previously untreated ES-SCLC


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The dose-escalation stage will then be followed by the dose-expansion portion of the 
study to evaluate the safety and efficacy of adding venetoclax to induction and/or 
maintenance therapy at the RP2D and schedule as determined during dose -escalation.
Figure 1 presents an overview of the overall study design.  A schedule of assessments
for maintenance cohorts (dose-escalation and expansion) is provided in Appendix 1; and 
for induction plus maintenance cohorts (dose-escalation and expansion) in Appendix 2.
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 two screenings per participant) at 
the investigator's discretion.  Patients are not required to re-sign the consent form if they 
are re-screened within 30 days after previously signing the consent form.  The 
investigator will record reasons for screen failure within the interactive voice or 
web-based response system (IxRS) and electronic Case Report Form (eCRF [see 
Section 4.5.1]).
Figure 1
Overall Study Schema
DLT dose-limiting toxicity; DORduration of response; ECOG Eastern Cooperative Oncology 
Group; ESextensive-stage; INVinvestigator; MTD maximum tolerated dose; ORRobjective 
response rate; PFSprogression-free survival; RECIST v1.1Response Evaluation Criteria in 
Solid Tumors, Version 1.1; RP2Drecommended Phase II dose; SCLCsmall cell lung cancer.
3.1.2
Dose-Escalation Phase
The purpose of the dose-escalation phase of the study is to determine the RP2D and 
MTD for venetoclax when given in combination with atezolizumab in the maintenance 
setting and in combination with atezolizumab, carboplatin, and etoposide in the induction 
setting (followed by venetoclax in combination with atezolizumab as maintenance 
therapy) in patients with ES-SCLC.


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The dose-escalation cohort will use a standard 33 design (see Section 3.1.4) to assess 
the safety, tolerability, and pharmacokinetics of study treatment. Venetoclax will be 
tested sequentially in the maintenance setting first (Arm A). Once the MTD and the 
RP2D are identified for maintenance treatment, the RP2D identified in Arm A will be 
applied to the maintenance portion of the induction plus maintenance setting (Arm B)
(Figure 2). The MTD and RP2D of venetoclax will be determined separately for 
maintenance and induction settings. 
Within each arm, dose-escalation cohorts will be run sequentially (e.g., 200 mg followed 
by 400 mg, etc.; see Figure 3 and Figure 4).    


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Figure 2
Dose-Escalation Study Schema
ECOGEastern Cooperative Oncology Group; ESextensive-stage; Iinduction; IVintravenous; Mmaintenance; MTD maximum tolerated 
dose; Q3W every3 weeks; RP2Drecommended Phase II dose.


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3.1.2.1
Maintenance Only (Arm A)
In the maintenance-only arm, venetoclax will be explored on a continuous dosing 
schedule at doses ranging from 400 mg QD to 800 mg/QD in the following dose-
escalation treatment cohorts using a standard 33 design:

Maintenance Cohort A1 (Dose Level 1):
Venetoclax: 400 mg QD continuous on Days 121
Atezolizumab: 1200 mg every 3 weeks (Q3W) on Day 1

Maintenance Cohort A2 (Dose Level 2):
Venetoclax: 800 mg QD continuous on Days 121
Atezolizumab: 1200 mg Q3W on Day 1
Dose de-escalation to 200 mg QD continuous on Days 121 may be explored if DLTs 
are experienced and adverse events are thought to be potentially mitigated with a lower 
dose of venetoclax (refer to Figure 3).
Once tolerability and dose are established in the maintenance-only arm (Arm A), the 
induction followed by maintenance arm (Arm B) will be opened, based on thorough 
review led by the Medical Monitor in consultation with the Principal Investigators and a 
committee composed of, at a minimum, the following Sponsor representatives: 
statistician, safety scientist, PK scientist, and clinical scientist. Patients on maintenance 
therapy who do not experience unacceptable toxicity and have evidence of clinical 
benefit (as defined in the protocol) may continue to receive maintenance study treatment 
every 21 days until documented disease progression determined by investigator or 
unacceptable toxicity, whichever occurs first. 


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Figure 3
Study Schema: Dose-Escalation, Maintenance Only (Arm A)
DLT dose-limiting toxicity; ECOG Eastern Cooperative Oncology Group; ESextensive-stage; Iinduction; Mmaintenance; MTD maximum 
tolerated dose; RP2D-Mrecommended Phase II dose for maintenance; SCLCsmall cell lung cancer.


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3.1.2.2
Induction Plus Maintenance (Arm B):
In the induction plus maintenance arm (Arm B; see Figure 4), venetoclax will be explored 
on a non-continuous (NC) dosing schedule in the following dose-escalation treatment 
cohorts using a standard 33 design:

Induction Cohort B1 (Dose Level 1):
Venetoclax: 200 mg/QD NC on Days 17
Atezolizumab: 1200 mg Q3W on Day 1
Carboplatin: AUC 5 mg/mL min (Calvert formula) on Day 1
Etoposide: 100 mg/m2 on Days 13

Induction Cohort B2 (Dose Level 2):
Venetoclax: 400 mg/QD NC on Days 17
Atezolizumab: 1200 mg Q3W on Day 1
Carboplatin: AUC 5 mg/mL min (Calvert formula) on Day 1
Etoposide: 100 mg/m2 on Days 13

Induction Cohort B3 (Dose Level 3):
Venetoclax: 800 mg/QD NC on Days 17
Atezolizumab: 1200 mg Q3W on Day 1
Carboplatin: AUC 5 mg/mL min (Calvert formula) on Day 1
Etoposide: 100 mg/m2 on Days 13

Induction Cohort B4 (Dose Level 4):
Venetoclax: 800 mg/QD NC on Days 114
Atezolizumab: 1200 mg Q3W on Day 1
Carboplatin: AUC 5 mg/mL min (Calvert formula) on Day 1
Etoposide: 100 mg/m2 on Days 13


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Figure 4
Study Schema: Dose-Escalation, Induction (Arm B)
Note:  Cohorts may incorporate primary prophylactic growth factor support as described below and in Section 3.1.4. 
DLT dose-limiting toxicity; MTD maximum tolerated dose; NC non-continuous; RP2D-I recommended Phase II dose for induction.


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Patients may be treated in up to five NC dosing cohorts (i.e., venetoclax 200 mg 
Days 17 NC, 400 mg Days 17 NC, 800 mg Days 17 NC, 800 mg Days 114 NC, and 
any of the dose levels integrating primary prophylactic growth factor support).  
Specifically, at the initiation of the induction phase of dose -escalation Arm B, cohorts 
will be treated without primary prophylactic growth-colony stimulating factor (G-CSF). If
2 or more patients out of the first 6 DLT-evaluable patients in a particular cohort 
without primary prophylactic growth factor support experienced neutropenia-related 
adverse events (Grade 4 neutropenia resulting in treatment delay beyond 14 days or 
Grade 3–4 febrile neutropenia), then that particular cohort level will be tested again at 
the same dose level with mandatory primary prophylactic growth factor support (see 
Section 3.1.4 for additional details). Of note, primary G-CSF prophylaxis is only 
mandated during induction and not during maintenance therapy. Such cohorts will be 
designated with “-P” to denote the primary G-CSF prophylactic requirement (e.g., Cohort 
B1-P).  Subsequent dose -escalation cohorts will then be required to incorporate primary 
G-CSF prophylaxis.
Patients will be treated for a total of 4 cycles of study treatment for induction. Each cycle 
will consist of 21 days. Dose-escalation will continue until DLTs are observed. If there 
is excessive toxicity and DLTs at the lowest tested venetoclax dose in induction, then 
venetoclax will be subsequently expanded in the maintenance setting only. 
Patients initially treated in the induction arm who tolerate study treatment without 
excessive toxicity, and have not undergone disease progression, will then proceed to 
maintenance treatment with venetoclax plus atezolizumab. The venetoclax dose for the
maintenance setting in Arm B will be the dose that has been cleared in the maintenance-
only arm (Arm A) of the study (maintenance RP2D, RP2D-M).  The venetoclax RP2D for 
the induction setting (induction RP2D, RP2D-I) will be based on the MTD of venetoclax
in combination with atezolizumab, carboplatin and etoposide.
During the maintenance phase in either Arm A or Arm B, prophylactic cranial irradiation 
(PCI) is permitted (though not mandated) prior to the commencement of maintenance 
therapy per local standard of care. Due to the lack of data with concurrent use of PCI 
with either atezolizumab or venetoclax, concurrent administration of PCI during 
maintenance therapy is not permitted. PCI will be reported on the Prophylactic Cranial 
Irradiation electronic Case Report Form (eCRF).  Consolidative thoracic radiation with 
curative intent or the intent to eliminate residual disease is not permitted.  Palliative 
radiation for symptomatic management is allowed (refer to Section 4.4.1 for further 
details).
3.1.3
Definition of Dose-Limiting Toxicity
Patients will be closely monitored for adverse events during a DLT assessment period, 
which starts on Day 1 of Cycle 1 and continues through Day 1 of Cycle 2. The DLT 
assessment period is the same for maintenance phase (Arm A) and induction phase 
(Arm B).  Adverse events meeting criteria for DLT within the assessment period must be 


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reported to the Sponsor within 24 hours. The expected start of Cycle 2 would be on Day 
22 if there are no treatment delays.  The same DLT criteria will be used in the 
maintenance and induction settings.
Determination of whether a patient is evaluable for DLT assessment will be made in 
accordance with the following rules:

Patients who receive study treatment and remain on study through the DLT 
assessment period will be considered DLT-evaluable.

Patients who discontinue from treatment with venetoclax prior to completing the DLT 
assessment period for reasons other than a DLT will be considered non-evaluable 
for dose-escalation decisions and MTD determination, and will be replaced by an 
additional patient at that same dose level.

Patients who receive less than 50% of planned venetoclax doses during the DLT 
assessment period will be considered non-evaluable for dose-escalation decisions 
and will be replaced by another patient in that cohort.
A DLT is defined in this trial as any one of the following events occurring during the DLT 
assessment period and is assessed by the investigator as possibly being related to 
study treatment. 
The following events will be considered DLTs only if they are associated with treatment 
delay beyond 14 days in initiating Cycle 2, Day 1: 

Grade 4 thrombocytopenia (platelet count <25,000/mm3)

Grade 3 thrombocytopenia with severe bleeding

Grade 4 anemia 

Grade 4 neutropenia (absolute neutrophil count [ANC] 500/L) 
The following events will be considered DLTs regardless of whether they result in a 
treatment delay:

Any treatment-related death

Grade 3 febrile neutropenia lasting for more than 7 days with growth factor support 
and supportive care

Grade 4 febrile neutropenia of any duration 

Grade 3 diarrhea, nausea, or vomiting lasting for 72 hours despite adequate 
treatment and supportive care (e.g., anti-emetics, anti-diarrheals, etc.)

Laboratory TLS lasting for 7 days with best supportive care or clinical TLS 
according to the Howard criteria (Howard et al. 2011)

Treatment related Grade 3 non-hematologic, non-hepatic toxicities lasting for 
72 hours


 
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 
Laboratory abnormalities consistent with Hy's Law will be considered a DLT. Hy's 
Law is defined as AST and/or ALT elevation   3  ULN, in conjunction with an 
elevation in total bilirubin to   2  ULN, without findings of cholestasis (ALP 
within normal limits), in patients for whom no other cause of hepatotoxicity is 
evident. 
 
All study treatment-related adverse events requiring permanent discontinuation of 
any of the study drugs  
 
3.1.4 
Dose-Escalation Rules, Determination of 
Dose-Limiting Toxicities, and Recommended Phase II Dose 
Dose -escalation for venetoclax in the maintenance only (Arm A) as well as in the 
induction and maintenance (Arm B) settings will occur in accordance with the rules listed 
below. 
Arm A (Refer to Figure 3): 
 
A minimum of 3 DLT-evaluable patients will initially be enrolled into each cohort. 
 
If none of the first 3 DLT-evaluable patients experiences a DLT, enrollment of the 
next cohort at the next dose level may proceed. 
 
If 1 of the first 3 DLT-evaluable patients experiences a DLT, the cohort will be 
expanded to 6 patients.  If there are no further DLTs in the first 6 DLT-evaluable 
patients, enrollment of the next cohort at the next dose level may proceed. 
 
If 2 or more of the first 6 DLT-evaluable patients in the cohort experience a DLT, an 
additional 3 patients will be evaluated for DLTs at a lower dose level.  If none of the 
first 3 DLT-evaluable patients experiences a DLT, the MTD in maintenance will have 
been reached. 
 
If 1 of the first 3 DLT-evaluable patients at a lower dose level experiences a DLT, 
this  cohort will be expanded to 6 patients.  If there are no further DLTs in the first 6 
DLT-evaluable patients, the MTD in maintenance will have been reached. 
 
If 2 or more of the first 6 DLT-evaluable patients in the lower dose level cohort 
experience a DLT, the MTD will have been exceeded and dose-escalation in 
maintenance will stop.  
 
If the MTD is exceeded at any dose level, the highest dose at which fewer than 2 of 
6 DLT-evaluable patients (i.e., ൒ 33%) experience a DLT will be declared the MTD. 
If the MTD is not exceeded at any dose level, the highest dose of venetoclax 
(800 mg) administered in maintenance will be declared the MTD for the 
maintenance setting. 
Arm B (Refer to Figure 4): 
 
A minimum of 3 DLT-evaluable patients will initially be enrolled into each cohort. 
 
If none of the first 3 DLT-evaluable patients experiences a DLT, enrollment of the 
next cohort at the next dose level may proceed. 


 
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 
If 1 of the first 3 DLT-evaluable patients experiences a DLT, the cohort will be 
expanded to 6 patients.  If there are no further DLTs in the first 6 DLT-evaluable 
patients, enrollment of the next cohort at the next dose level may proceed. 
 
If 2 or more of the first 6 DLT-evaluable patients in the next cohort at the next dose 
level experience a DLT, the MTD in induction will have been exceeded and dose-
escalation will stop.  
 
If the MTD is exceeded at any dose level, the highest dose at which fewer than 2 of 
6 DLT-evaluable patients (i.e., ൒ 33%) experience a DLT will be declared the MTD. 
If the MTD is not exceeded at any dose level, the highest dose of venetoclax 
(800 mg NC Day 114) administered in induction will be declared the MTD for the 
induction setting. 
If a particular cohort in induction dose-escalation (Arm B) exceeds MTD due to DLTs 
associated with neutropenia or febrile neutropenia without primary prophylactic growth 
factor support, then that cohort level will be tested again with primary prophylactic 
growth factor support.  For example, if venetoclax 400 mg Day 17 exceeds the MTD 
due to DLTs associated with neutropenia or febrile neutropenia without primary 
prophylactic growth factor support, then primary prophylactic growth factor support will 
be implemented in the study and that dose level cohort will be tested again with another 
3  3 cohort.  Of note, primary G-CSF prophylaxis is only mandated during induction and 
not during maintenance therapy.  Once prophylactic growth factor support is instituted, 
then this will be required for further escalation cohorts during all induction cycles. For 
guidance on use of prophylactic growth factor support, please see Appendix 10. 
Patients exhibiting acceptable safety and evidence of clinical benefit (as determined by 
the investigator) may continue to receive study treatment until confirmed objective 
disease progression or unacceptable toxicity, whichever occurs first. 
The Sponsor will review cumulative safety data and make recommendations regarding 
dose-escalation and overall study conduct on the basis of trial safety data to ensure 
patient safety while receiving study treatment.  These include recommendations to open 
or suspend patient enrollment in a given dose-escalation cohort based on the overall 
benefitrisk profile of venetoclax in combination with atezolizumab, carboplatin, and 
etoposide. 
Relevant demographic, adverse event, laboratory, dose administration, and PK data (if 
available) will be reviewed prior to the selection of a RP2D in the maintenance (RP2D-
M) and RP2D in the induction setting (RP2D-I).  The RP2D-I will be based on the MTD 
of venetoclax when combined with standard doses of atezolizumab, carboplatin, plus 
etoposide and the RP2D-M will be based on the MTD of venetoclax when combined with 
standard dose of atezolizumab. Both RP2D-I and RP2D-M will integrate aggregate 
safety data during treatment.  Decision making will be led by the Medical Monitor in 
consultation with the Principal Investigators and a committee composed of at a minimum 


 
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the following Sponsor representatives: statistician, safety scientist, PK scientist, and 
clinical scientist.   
3.1.5 
Dose-Expansion Cohort 
Once the RP2D in the induction and in the maintenance phase has been established from 
the dose-escalation cohorts, additional patients will be enrolled in the dose-expansion 
cohort to further assess the safety and efficacy of venetoclax in combination with 
carboplatin, etoposide and/or atezolizumab.  If the RP2D for venetoclax during induction 
was established, then the dose-expansion cohort will continue to test venetoclax in both 
induction and maintenance.  If significant toxicity and DLTs in induction preclude 
identification of an RP2D for venetoclax in induction treatment, then the safety and 
efficacy of venetoclax will only be investigated in dose-expansion in the maintenance 
setting.  If the maintenance-only cohort is expanded, then prior treatment with 4 
induction cycles of carboplatin and etoposide as well as at least 3 cycles of atezolizumab 
will be required.  If there are concerns about the tolerability of venetoclax during the 
dose-expansion stage, then a lower dose or alternative dosing schedule may be 
explored based on the severity and timing of DLTs as well as the specific adverse 
events encountered.  For example, consideration may be given to enrolling an 
expansion cohort at the next lower dose level (as defined in dose-escalation stage; see 
Section 3.1.2).  Decision making will integrate cumulative safety and efficacy data during 
treatment and will be led by the Medical Monitor in consultation with the Principal 
Investigators and a committee composed of at a minimum the following Sponsor 
representatives: statistician, safety scientist, PK scientist, and clinical scientist.  


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Figure 5
Study Schema:  Dose-Expansion Cohort
DORduration of response; ECOG Eastern Cooperative Oncology Group; ESextensive-stage; INVinvestigator; MTD maximum tolerated 
dose; ORRobjective response rate; PFSprogression-free survival; Q3W every 3 weeks; RECIST v1.1Response Evaluation Criteria in Solid 
Tumors, Version 1.1; RP2D-Irecommended Phase II dose for induction; RP2D-Mrecommended Phase II dose for maintenance; SCLCsmall 
cell lung cancer.


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3.1.6
Treatment after Disease Progression
During the study, patients who meet criteria for disease progression per RECIST v1.1 
and show evidence of clinical benefit may continue treatment at the investigator’s 
discretion, provided that the patients meet all of the following criteria:

Evidence of clinical benefit, as assessed by the investigator

Absence of symptoms and signs (including worsening of laboratory values 
[e.g., new or worsening hypercalcemia]) indicating unequivocal progression of 
disease

No decline in Eastern Cooperative Oncology Group (ECOG) performance status
that can be attributed to disease progression

Absence of tumor progression at critical anatomical sites (e.g., CNS, leptomeningeal 
disease, etc.) that cannot be managed by protocol-allowed medical interventions 
Investigator assessment of overall tumor response at all timepoints will be based only on
RECIST v1.1.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as 6 months after the last patient’s radiographic last 
assessment.  The end of the study is expected to occur 24 months after the last patient 
is enrolled. In addition, the Sponsor may decide to terminate the study at any time.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be 31 to 49 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Patient Population
The current standard of care regimen for the first-line treatment for ES-SCLC in both the 
United States and European Union is atezolizumab plus CE. Durvalumab plus platinum 
chemotherapy and etoposide is also regarded as a preferred therapy (NCCN 2019).  
Despite the survival benefit observed with these regimen, median survival remains at 
approximately 1 year, leaving considerable room for improvement in outcomes.  This 
study will enroll patients with ES-SCLC who are chemotherapy-naive for their extensive-
stage disease, and for whom the experimental therapy can represent a valuable 
treatment option with a reasonable benefit-risk balance.  
This study will enroll patients irrespective of Bcl-2 or PD-L1 expression status. Drug 
development in SCLC poses its own challenges with rapid clinical deterioration often 
precluding trial entry. Patients with SCLC frequently present with symptoms of 
widespread metastatic disease and may experience fast clinical deterioration; therefore, 
there is a need for rapid treatment initiation for these patients.  In addition, tissue sample 
collection for investigational biomarker testing may be difficult in this patient population 
because the amount of tissue available in many cases is limited, therefore prospective 
Bcl-2 biomarker testing will not be performed.  Moreover, as the benefit of atezolizumab 


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plus chemotherapy was observed in all-comer patients in IMpower133, this study will 
enroll patients with ES-SCLC whose disease is unselected for PD-L1 expression.  Pre-
treatment tumor tissue samples will be collected to allow for the analysis of biomarkers 
including but not limited to Bcl-2 and PD-L1 expression with patient outcomes.
3.3.2
Rationale for Venetoclax and/or Atezolizumab
Treatment Beyond Initial Radiographic Progression
In studies of immunotherapeutic agents, CRs, PRs, and SD have each been shown to 
occur after radiographic evidence of an apparent increase in tumor burden.  This initial 
increase in tumor burden caused by immune-cell infiltration in the setting of a T-cell 
response has been termed pseudo-progression (Hales et al. 2010).  In Study 
PCD4989g, evidence of tumor growth followed by a response was observed in several 
tumor types.  In addition, in some responding patients with radiographic evidence of 
progression, biopsies of new lesions or areas of new growth in existing lesions revealed 
immune cells and no viable cancer cells.  
Patients with ES-SCLC experience rapid tumor growth and fast clinical deterioration and 
have an overall poor prognosis.  First-line therapy with atezolizumab plus CE has 
demonstrated high response rates and significant clinical benefit.  However, after 
disease progression, treatment options are limited and such options have shown limited 
efficacy and significant toxicity (see Section 1.2).  Given that the greatest opportunity to 
achieve a clinically significant benefit from therapy is in the front-line setting and given 
the poor efficacy and high toxicity profile of second-line therapies, patients may be 
considered for treatment beyond radiographic disease progression per RECIST v1.1 at 
the discretion of the investigator and after appropriate discussion with the patient, only if 
they meet all of the criteria described in Section 3.1.6.
In addition, conventional response criteria may not adequately assess the activity of 
immunotherapeutic agents because progressive disease (by initial radiographic 
evaluation) does not necessarily reflect therapeutic failure.  Because of the potential for 
pseudo-progression/tumor-immune infiltration, this study will allow patients to remain on 
treatment after apparent radiographic disease progression per RECIST v1.1, provided all 
criteria in Section 3.1.6 are met.  Treatment should be discontinued if clinical 
deterioration due to disease progression occurs at any time or if persistent disease 
growth is confirmed in a follow-up scan.  In addition, patients should be discontinued for 
unacceptable toxicity or for any other signs or symptoms of deterioration attributed to 
disease progression as determined by the investigator after an integrated assessment of 
radiographic data and clinical status (see Section 4.6.1). 
3.3.1
Rationale for Atezolizumab Dose and Schedule
Atezolizumab will be administered at a fixed dose of 1200 mg Q3W (1200 mg on Day 1 
of each 21-day cycle), which is an approved dosage for atezolizumab, as outlined in the 
prescribing information.  Anti-tumor activity has been observed across doses ranging 


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from 1 mg/kg to 20 mg/kg Q3W.  In Study PCD4989g, the MTD of atezolizumab was not 
reached and no DLTs were observed at any dose.  The fixed dose of 1200 mg Q3W 
(equivalent to an average body weightbased dose of 15 mg/kg Q3W) was selected on 
the basis of both nonclinical studies (Deng et al. 2016) and available clinical 
pharmacokinetic, efficacy, and safety data (refer to the Atezolizumab Investigator's 
Brochure for details).
3.3.2
Rationale for Venetoclax Dosing Schedule
Venetoclax has been investigated in multiple trials of hematologic malignancies as well 
as solid tumors at doses ranging from 200 mg to 1200 mg, as a monotherapy and in 
combination with other agents including dexamethasone, rituximab, obinutuzumab, 
bortezomib, and chemotherapy. Venetoclax is approved in the United States and 
European Union as monotherapy for the treatment of adult patients with CLL who have 
received at least one prior therapy. The recommended dose of venetoclax monotherapy 
in this setting is 400 mg QD in a ramp-up schedule (Venclexta U.S. Package Insert) and 
the 400 mg QD dosing is maintained during administration with rituximab. Venetoclax is 
also approved in combination with azacitidine or decitabine or LDAC for the treatment of 
newly-diagnosed AML and dosing is at 400 mg QD when in combination with azacitidine 
or decitabine and 600 mg QD when dosing in combination with LDAC. 
3.3.2.1
Rationale for Venetoclax Dose Selection for Maintenance in 
Phase I Dose-Escalation Portion of the Study
For patients in the maintenance phase venetoclax will be administered in combination 
with atezolizumab at a starting dose of 400 mg continuous QD with potential escalation 
to a second dose level of 800 mg continuous QD (refer to Section 3.1.1). A 400-mg 
venetoclax starting dose is considered acceptable based on limited overlapping toxicities
and low drug-drug interaction (DDI) potential between the two agents; toxicities from 
these two agents are expected to be monitorable and manageable.   
The safety of continuous daily dosing of single agent venetoclax has been evaluated in 
hematologic malignancies.  In Study M12-175, venetoclax was administered as 
monotherapy in patients with relapsed refractory CLL and NHL at doses of 150 mg to 
1200 mg.  The safety profile of venetoclax as monotherapy in NHL was tolerable and 
manageable, with the most common adverse events including nausea, diarrhea, and 
fatigue.
The safety of continuous escalating daily dosing of venetoclax up to a maximum of 
800 mg in combination with atezolizumab and cobimetinib was evaluated in patients with 
relapsed or refractory MM in Study BO39813.  In this study, venetoclax was well 
tolerated in combination with atezolizumab and cobimetinib or cobimetinib alone.  The 
nature and frequencies of adverse events were consistent with known safety profiles of 
the individual agents, and there were minimal overlapping toxicities. Additionally, in a 
study of relapsed and refractory B-lymphomas (R/R NHLs), venetoclax administered in 
combination with atezolizumab and obinutuzumab was well tolerated and preliminary 


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efficacy was shown to be encouraging for a chemo-free regimen in R/R NHLs. 
Neutropenia was observed with the combination and primary prophylactic growth factor 
support was instituted (Herbaux et al. 2019). Treatment and follow-up of these patients 
are currently ongoing.
Furthermore, the safety of an 800 mg dose of venetoclax in SCLC is supported by 
findings in metastatic breast cancer studies where venetoclax was administered in 
combination with either tamoxifen or fulvestrant (Lok et al. 2019; Study WO40181).  In 
these studies, 800 mg QD continuous venetoclax was well tolerated, and the nature and 
frequencies of adverse events were consistent with the known safety profiles of the 
individual agents.  No Grade 5 adverse events or DLTs occurred during the DLT 
observation period. A ramp-up phase was not incorporated into these studies due to 
lower expected TLS risk in solid tumors compared to hematological malignancies. It is a 
well-known fact that TLS is especially common in patients with hematological 
malignancies with rapid cellular turnover rates such as acute lymphocytic leukemia and 
Burkitt lymphoma, but is very rare in patients with solid tumors (Mirrakhimov et al. 2014).
The escalation to 800 mg QD continuous venetoclax in maintenance is planned, as 
patients with solid tumors may require a higher dose of venetoclax when compared with 
the 400 mg QD label dose in hematologic malignancies such as CLL. Cancer cells in 
the tumor compartment may be less sensitive to venetoclax than those circulating in the 
peripheral blood. This is reflected in the lower EC50 values of venetoclax for circulating 
lymphocyte counts (0.00863 μg/mL) compared with tumor size (0.146 g/mL; Freise et 
al. 2016). Possible explanations for this observation include (1) reduced blood flow and 
subsequent less efficient delivery of systemic venetoclax within a tumor; and (2) altered 
signaling interactions between lymphoma cells and the cells of the tumor 
microenvironment.
3.3.2.2
Rationale for Venetoclax Dose Selection for Induction in the 
Phase I Dose-Escalation Portion of the Study
Based on expected overlapping toxicities such as neutropenia, febrile neutropenia, 
anemia, thrombocytopenia, and gastrointestinal adverse events between venetoclax and 
chemotherapy, four NC dose-escalation levels, as well as an option to incorporate 
primary prophylactic treatment with G-CSF, have been selected for dose finding in the 
induction phase. A conservative and gradual approach to dose escalation is proposed, 
with a starting dose of 200 mg Day 17 NC QD, moving to 400 mg Day 17 NC QD, to
800 mg Day 17 NC QD, and to 800 mg Day 114 NC QD (refer to Section 3.1.1).  
The dose finding strategy for the induction phase is supported by data from the VICER 
Study (venetoclax + rituximab, ifosfamide, carboplatin, and etoposide [R-ICE] in R/R 
diffuse large B-cell lymphoma [DLBCL]). In this study, venetoclax was given orally on 
Days 110 of each 21-day cycle; R-ICE was given at standard doses and schedule on 
Days 13. NC venetoclax dosing on Days 110 of a 21-day cycle (10/21) allowed


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manageable and tolerable administration, with escalation of venetoclax doses to 800 mg
in combination with R-ICE (Caimi et al. 2018).
Similar to the maintenance phase, the risk for TLS is expected to be low in solid tumors 
such that venetoclax ramp-up dosing is not required.  Nonetheless, TLS labs will be 
monitored frequently especially in the first cycle and in patients who develop electrolyte 
changes suggestive of TLS will undergo aggressive management and further monitoring 
(refer to Appendix 11 for detailed guidance on TLS prophylaxis). 
3.3.2.3
Rationale for Preferential Venetoclax Dose Modifications in the 
Setting of Overlapping Toxicities
Dose delays and dose modifications as a result of adverse events should proceed on the 
basis of the principle of maintaining the dose intensity of atezolizumab, carboplatin, and 
etoposide. The determination of dose modifications will be made on the basis of the 
investigator’s assessment of ongoing clinical benefit with continuing study treatment in 
consultation with and with the approval of the Medical Monitor.
In the event of high-grade hematologic toxicities such as neutropenia, febrile 
neutropenia, thrombocytopenia (overlapping toxicities for venetoclax and carboplatin 
etoposide), and high-grade gastrointestinal toxicities such as diarrhea (overlapping 
toxicity for venetoclax, atezolizumab, carboplatin, and etoposide), the dose of venetoclax 
should be reduced as per Table 6. The dose of carboplatin and etoposide should be
reduced per standard guidance provided in Table 7. No dose reduction of atezolizumab 
is permitted in the study. 
In each specific portion of study treatment (induction vs. maintenance), no re-escalation 
of venetoclax dose is allowed after dose reduction. The dose level of venetoclax in the 
maintenance portion (RP2D-M) identified in Arm A will not be affected by venetoclax 
dose reductions during the induction phase. The dose of carboplatin and etoposide can 
be re-escalated (even to full dose) with the approval of the Medical Monitor. For more 
details, see Sections 5.1.5 and 5.1.6.
3.3.3
Rationale for Dose Finding Rules
The rules for dose escalation are designed to ensure patient safety while providing an 
opportunity to identify the optimal venetoclax dose and schedule in combination with 
atezolizumab, carboplatin, and etoposide to maximize the benefit-risk profile of the 
combination. Key elements of dose escalation based on a standard 33 design are 
described in Section 3.1.
Rules based on the nature and timing of observed safety events have been 
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3.3.4
Rationale for Biomarker Assessments
SCLC is a heterogeneous disease, with PD-L1 and Bcl-2 expression having been shown 
to vary among patients (Ben-Ezra et al. 1994; Kaiser et al. 1996).  All patients may not 
be equally likely to benefit from treatment with venetoclax and atezolizumab, carboplatin,
and etoposide.  Predictive biomarker samples (tissue and blood) collected prior to 
dosing will be assessed in an effort to identify those patients who are most likely to 
respond to venetoclax and atezolizumab, carboplatin, and etoposide.
Pharmacodynamic biomarkers (tissue and blood) will be assessed to demonstrate 
evidence of biologic activity of venetoclax and atezolizumab, carboplatin, and etoposide
in patients, to support selection of a recommended dose and dosing regimen, and to 
inform potential revisions to the PK sample collection schedule. As these biomarkers 
may also have prognostic value, their potential association with disease progression will 
also be explored.
Bcl-2 expression may have a prognostic role in SCLC, with improved survival in SCLC 
patients being observed in the context of lower Bcl-2 expression, consistent with in vitro 
data. A study evaluating Bcl-2 staining in 140 patients samples using tissue microarray 
indicated that patients with low intensity staining had better OS than those with high 
intensity staining in a Cox regression analysis (HR: 0.55; 95% CI: 0.33 to 0.94; p 0.03;
n 117). The meta-analysis included 510 deaths in 673 cases and showed no 
significant effect of Bcl-2 on survival (HR: 0.91; 95%: CI 0.74 to 1.09). This may be due 
to differences in staining and scoring methods between the studies (Lawson et al. 2010).
Predictive biomarker samples collected prior to dosing will be assessed in an effort to 
identify those patients with Bcl-2-driven pathogenesis who are most likely to respond to 
venetoclax. The study aims to explore if Bcl-2 expression might have predictive or 
prognostic value or may be associated with disease progression in the studied 
population.
Fresh tissue acquisition in some patients with SCLC may not be feasible; consequently, 
assessment of more easily accessible biomarkers in circulation is of high interest. In 
addition to identification of disease-specific, potentially prognostic, or predictive 
biomarkers in predose, baseline blood specimens, on-treatment collection of blood to 
evaluate circulating tumor DNA (ctDNA) and other circulating markers may enable 
identification of biomarkers informing the relationship with established clinical response 
assessments, the monitoring of disease progression, and the identification of markers of 
resistance.
Tumor tissue samples will be analyzed through use of IHC to assess protein expression, 
and/or RNA sequencing to assess gene expression levels. Both tissue and blood 
samples will be analyzed by next-generation sequencing (NGS) to identify somatic 
alterations that are predictive of response to study drug, are associated with 
progression, are associated with acquired resistance to study drug, or can increase the 
knowledge and understanding of disease biology.


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Tissue samples will be collected for DNA extraction to enable whole genome sequencing 
(WGS) or whole exome sequencing (WES) to identify variants that are predictive of 
response to study drug, are associated with progression to a more severe disease state, 
are associated with susceptibility to developing adverse events, can lead to improved 
adverse event monitoring or investigation, or can increase the knowledge and 
understanding of disease biology and drug safety.  Genomics is increasingly informing 
researchers’ 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 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.
Exploratory research on safety biomarkers may be conducted to support future drug 
development.  Research may include further characterization of a safety biomarker or 
identification of safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation.  
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 1842 patients will be enrolled in the dose-escalation cohorts. An 
additional estimated 20 patients will be enrolled in the dose-expansion cohort of this 
study.
4.1.1
Inclusion Criteria
Dose Escalation, Maintenance Arm A

Patients with ES-SCLC who have completed 4-6 cycles of carboplatin and 
etoposide induction chemotherapy, with or without atezolizumab, as their first-line 
therapy for extensive-stage disease and have responded (CR or PR) or have SD
are eligible for the maintenance arm of the study.

All side effects attributed to prior anti-cancer therapy must have resolved to Grade 1 
or baseline.

A maximum of 8 weeks (56 days) is allowed between last chemotherapy dose 
(Cycle 4, Day 3) given in induction and the start of maintenance therapy.


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Dose Escalation, Induction Arm B

Patients with no prior systemic treatment for ES-SCLC are eligible for this study.

ANC 1,500 cells/L without granulocyte colony-stimulating factor support
Dose Expansion, Maintenance-Only

Patients with ES-SCLC who have completed 4 cycles of carboplatin and etoposide 
induction chemotherapy and at least 3 cycles of atezolizumab as their first-line 
therapy for extensive-stage disease and have responded (CR or PR) or have SD are 
eligible for the maintenance arm of the study.
Dose Escalation (Arms A and B) and Dose Expansion

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator's judgment

ECOG performance status of 0 or 1

Patients must be able to swallow pills

Histologically or cytologically confirmed diagnosis of ES-SCLC per the Veterans 
Administration Lung Study Group (VALG) staging system

Patients who received prior chemoradiotherapy for limited-stage SCLC must have 
been treated with curative intent and experienced a treatment-free interval of at 
least 6 months since last chemotherapy, radiotherapy, or chemoradiotherapy cycle 
prior to diagnosis of ES-SCLC

Patients with a history of treated CNS metastases that are currently asymptomatic 
are eligible, provided they meet all of the following criteria:
–
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to 
midbrain, pons, medulla or spinal cord)
–
No ongoing requirement for corticosteroids as therapy for CNS disease
–
No evidence of interim progression between the completion of CNS-directed 
therapy and enrollment
–
Patients with new asymptomatic CNS metastases detected at the screening 
scan must receive radiation therapy and/or surgery for CNS metastases. 
Following treatment, these patients may then be eligible without the need for an 
additional brain scan prior to enrollment, if all other criteria are met.

Measurable disease, as defined by RECIST v1.1. Baseline measurements and 
evaluation of all sites of disease must be obtained 4 weeks prior to enrollment.
–
Previously irradiated lesions can only be considered as measurable disease if 
disease progression has been unequivocally documented at that site since 
radiation and the previously irradiated lesion is not the only site of disease.

Eligible to receive a carboplatin-based chemotherapy regimen


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
Adequate hematologic and end-organ function, defined by the following laboratory 
results obtained within 14 days prior to enrollment: 
–
ANC 1500 cells/L (without granulocyte-colony stimulating factor support
within 7 days prior to Cycle 1, Day 1)
–
Lymphocyte count 500 cells/L
–
Platelet count 100,000 cells/L without transfusion
–
Hemoglobin 9.0 g/dL
Patients may be transfused to meet this criterion. 
–
INR or aPTT 1.5 ULN
This applies only to patients who are not receiving therapeutic 
anticoagulation; patients receiving therapeutic anticoagulation should be on 
a stable dose and with INR 3.5 ULN.
–
AST (SGOT), ALT (SGPT), and alkaline phosphatase   2.5 ULN with the 
following exceptions:
Patients with documented liver metastases: AST and/or ALT
5 ULN
Patients with documented bone or liver metastases: alkaline phosphatase 
5 ULN
–
Serum total bilirubin 1.5 ULN
Patients with known Gilbert disease who have serum bilirubin level 3 
ULN may be enrolled.
–
Albumin 25 g/L (2.5 g/dL)
–
Creatinine clearance (CRCL) 50 mL/min calculated with the use of the 24-
hour CRCL or modified Cockcroft-Gault equation (i.e., estimation of creatinine 
clearance rate [eCCr]) with the use of ideal body mass (IBM) instead of mass:
eCCr = (140age)(weight in kg) (0.85 if female)
72 (serum creatinine in mg/dL)
Or, if serum creatinine is in μmol/L:
eCCr = (140age) IBM (kg) (1.04 if female)
serum creatinine (μmol/L)

Patients must submit a pre-treatment tumor tissue sample. Any available tumor 
tissue sample can be submitted (fresh, paraffin-embedded tissue block, or serial cut 
slides [15 preferred]). The tissue sample should be submitted before or within 
4 weeks after enrollment; however, patients may be enrolled into the study before 
the pre-treatment tumor tissue sample is submitted. If tissue is not available, 
approval from the Medical Monitor is required before enrolling. 

Patients must submit a blood sample for exploratory biomarker research before 
treatment, on-study, and following progression of disease.


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
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use non-hormonal contraceptive methods that result in 
a failure rate of 1% per year during the treatment period and for at least 30 days 
after the final dose of venetoclax, 5 months after the final dose of atezolizumab, or 
6 months after the final dose of carboplatin or etoposide, whichever is longer. 
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.  If 
required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form.

Women who are not postmenopausal (12 months of nontherapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test result 
within 14 days prior to initiation of study drug.  
If a serum pregnancy test has not been performed 14 days prior to dosing, a 
urine pregnancy test must be performed 7 days prior to dosing.  If the test result 
is positive, patient dosing will be postponed until the patient’s status is 
confirmed by a serum pregnancy test.

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partners, 
men must remain abstinent or use a condom plus an additional contraceptive 
method that together result in a failure rate of 1% per year during treatment 
with chemotherapy (i.e., carboplatin and etoposide) and for at least 6 months 
after the final dose of carboplatin or etoposide to avoid exposing the embryo. 
Men must refrain from donating sperm during this same period.


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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, sympotothermal, or postovulation 
methods) are not acceptable methods of contraception. If required per local 
guidelines or regulations, locally recognized acceptable methods of 
contraception and information about the reliability of abstinence will be 
described in the local Informed Consent Form. 
4.1.2
Exclusion Criteria

Use of nonprotocol-specified anti-cancer therapies or other combination partners 
with carboplatin/etoposide during induction

Symptomatic or actively progressing CNS metastases 
Note: Asymptomatic patients with treated (i.e., local CNS-directed therapy) or 
untreated CNS lesions are eligible, provided that all of the following criteria are 
met:
–
Measurable disease, per RECIST v1.1, must be present outside the CNS.
–
The patient has no history of intracranial hemorrhage or spinal cord 
hemorrhage from CNS disease.
–
Metastases are limited to the cerebellum or the supratentorial region (i.e., 
no metastases to the midbrain, pons, medulla, or spinal cord).
–
The patient has no symptoms caused by CNS disease (i.e., no headache, 
nausea, vomiting, convulsion, paralysis, etc.).
–
The patient has no ongoing requirement for anticonvulsants for CNS 
disease.  
–
The patient has no ongoing requirement for dexamethasone/corticosteroids 
for CNS disease (previously untreated patients must also not have any
history of requiring or receiving dexamethasone/corticosteroids for CNS 
disease).
–
For patients with previously treated CNS metastases, there is no evidence 
of interim CNS progression between the completion of CNS-directed 
therapy and enrollment. 
–
For previously untreated patients, there is no evidence of brain edema 
related to CNS disease (e.g., vasogenic edema).
–
For previously untreated patients, a brain magnetic resonance imaging 
(MRI) scan with contrast is required at screening and is the preferred 
modality for all subsequent scheduled follow-up tumor assessments.
Note:  Computed tomography (CT) scan with contrast may be 
acceptable for all subsequent scheduled follow-up tumor assessments
if the following criteria are met.
–
Both brain MRI and CT scan with contrast must be performed at 
screening to assess untreated CNS disease.


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–
The CT scan with contrast can be used to reliably evaluate lesions 
identified on the screening MRI with contrast.
If CT scan with contrast cannot be used to reliably evaluate lesions 
identified on the screening MRI with contrast, then MRI scan with 
contrast must be used at all subsequent scheduled follow-up tumor 
assessments.
The same modality must be used at every tumor assessment.

Pregnant or breastfeeding, or intending to become pregnant during the study
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study drug.

Spinal cord compression not definitively treated with surgery and/or radiation or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for 1 week prior to enrollment

Leptomeningeal disease

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once a month or more frequently)
Patients with indwelling catheters (e.g., PleurX) are allowed regardless of 
drainage frequency.

Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, total 
serum calcium 12 mg/dL, or corrected calcium ULN)

History of malignancy other than SCLC within 5 years prior to enrollment, with the 
exception of those with a negligible risk of metastasis or death (e.g., expected 
5-year OS >90%) treated with expected curative outcome (such as adequately 
treated carcinoma in situ of the cervix, basal or squamous cell cancer of the skin, 
localized prostate cancer treated surgically with curative intent, ductal carcinoma in 
situ treated surgically with curative intent)

History of autoimmune disease, including but not limited to myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid 
syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis 
Patients with a history of autoimmune-mediated hypothyroidism on a stable 
dose of thyroid replacement hormone are eligible for this study. 
Patients with controlled Type I diabetes mellitus on a stable dose of insulin 
regimen are eligible for this study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., no psoriatic arthritis) are permitted 
provided that they meet the following conditions: 
–
Rash must cover less than 10% of body surface area.


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–
Disease is well-controlled at baseline and only requiring low potency topical 
steroids.
–
No acute exacerbations of underlying condition within the last 12 months 
requiring treatment with either psoralen plus ultraviolet A radiation (PUVA), 
methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high 
potency or oral topical steroids 

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive test result for HIV
All patients must be tested for HIV; patients who test positive for HIV will be 
excluded.

Active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface 
antigen [HBsAg] test result at screening) or hepatitis C virus (HCV)
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as the presence of hepatitis B core antibody [HBcAb] and absence of 
HBsAg) are eligible. HBV DNA should be obtained in these patients prior to 
enrollment and should be undetectable. These patients must be willing to 
undergo monthly DNA testing.
Patients positive for HCV antibody are eligible only if polymerase chain reaction
(PCR) is negative for HCV RNA.

Active tuberculosis

Known infection with human T-cell leukemia virus 1

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection 
(excluding fungal infections of nail beds) at study enrollment, or any major episode 
of infection requiring treatment with IV antibiotics or hospitalization (relating to the 
completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1

Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction, or cerebrovascular accident 
within the previous 3 months, unstable arrhythmias, or unstable angina 
Patients with known coronary disease, congestive heart failure not meeting the 
above criteria, or left ventricular ejection fraction <50% must be on a stable 
medical regimen that is optimized in the opinion of the treating physician, in 
consultation with a cardiologist if appropriate. 

Major surgical procedure within 28 days prior to enrollment or anticipation of need 
for major surgical procedure during the course of the study 

Prior allogenic bone marrow transplantation or solid organ transplant 


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
Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk for treatment 
complications

Illnesses or conditions that interfere with their capacity to understand, follow, and/or 
comply with study procedures

Treatment with investigational therapy with therapeutic intent within 28 days prior to 
enrollment

Administration of a live, attenuated vaccine within 4 weeks before enrollment or 
anticipation that such a live attenuated vaccine will be required during the study
Patients must not receive live, attenuated influenza vaccines (e.g. FluMist) 
within 4 weeks prior to enrollment, during treatment, and for 5 months following 
the last dose of atezolizumab or chemotherapy.

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-
PD-1, and anti-PD-L1 therapeutic antibodies

Treatment with systemic immunosuppressive medications (including, but not limited 
to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-tumor necrosis factor [anti-TNF] agents) within 1 week prior to enrollment
Patients who have received acute systemic immunosuppressant medications 
(e.g., use of corticosteroids for nausea, vomiting, or management of or 
premedication for allergic reactions) may be enrolled in the study after 
discussion with and approval by the Medical Monitor. In those patients, the 
need and length of the washout period prior to enrollment will also be 
established in conjunction with the Medical Monitor.
The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic 
hypotension, and low-dose supplemental corticosteroids for adrenocortical 
insufficiency are allowed.

History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins 

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation 

History of allergic reactions to carboplatin or etoposide or to any of its excipients 
(etoposide)

Known hypersensitivity to venetoclax or to any of its excipients


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
Administration of the following agents within 7 days prior to the first dose of study 
drug:
–
Steroid therapy for anti-neoplastic intent (stable steroid mediation not more 
than 10 mg prednisolone per day or an equivalent dose of other 
corticosteroids for controlling CNS metastases is acceptable)
–
Strong or moderate CYP3A inhibitors (see Appendix 6 for examples)
–
Strong or moderate CYP3A inducers (see Appendix 6 for examples)
Additional restrictions for on-study use of CYP3A inhibitors/inducers are outlined 
in Section 4.4.2.

Consumption of grapefruit, grapefruit products, Seville oranges (including
marmalade-containing Seville oranges), or starfruit (carambola) within 3 days before
within 3 days prior to the first dose of study drug

Malabsorption syndrome or other condition that would interfere with 
enteral absorption

Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator’s 
judgment

Inability or unwillingness to swallow a large number of tablets

History of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) or 
active bowel inflammation (e.g., diverticulitis)
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is a non-randomized, open-label study.  After initial written informed consent has 
been obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient's 
identification number and treatment assignment from an interactive voice or web-based 
response system (IxRS).
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMP) for this study are atezolizumab and 
venetoclax. Carboplatin and etoposide are background treatments and are thus 
considered non-investigational medicinal products (NIMPs) in this study.  
Rescue medications pre-medications, and supportive medications such as 
acetaminophen, ibuprofen, diphenhydramine, famotidine, cimetidine and other 
antihistamines, antipyretics, analgesics, corticosteroids, G-CSF, H2-receptor antagonists, 
2-adrenergic agonists are also considered NIMPs in this study.


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4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Atezolizumab 
The atezolizumab Drug Product will be supplied by the Sponsor as a sterile liquid in a 
single-use, 20 mL glass vial.  The vial contains approximately 20 mL (1200 mg) of 
atezolizumab solution.
For information on the formulation and handling of atezolizumab, refer to the 
Atezolizumab Pharmacy Manual and Investigator’s Brochure.
4.3.1.2
Venetoclax
Patients will self-administer venetoclax tablets by mouth daily. Venetoclax is formulated 
as 100-mg tablets; patients may take up to eight 100-mg tablets daily to receive an 
800-mg continual dose. Each dose of venetoclax will be taken with approximately 
240 mL of water within 30 minutes after the patient’s first meal of the day (e.g., 
breakfast). For continuous venetoclax dose (Days 121), patients should continue 
taking venetoclax without a break between cycles.
For information on the formulation and handling of venetoclax, refer to the Venetoclax 
Pharmacy Manual and Investigator’s Brochure.
4.3.1.3
Carboplatin and Etoposide
Carboplatin and etoposide will be used in the commercially available formulation. 
For information on the formulation, packaging, and handling of carboplatin and 
etoposide, refer to the prescribing information for each drug.
4.3.2
Study Treatment Dosage, Administration, Sequence, and 
Compliance
Atezolizumab will be given at fixed dose of 1200 mg by IV infusion every 21 [2] days in 
both induction and maintenance. For more information on the formulation, packaging, 
and handling of atezolizumab, please refer to the prescribing information. 
Carboplatin and etoposide induction therapy will be administered as follows:
During induction, patients will be treated with carboplatin and etoposide chemotherapy.
For information on the formulation, packaging, and handling of these therapies, please 
see the prescribing information for each drug.
Standard doses of each agent will be administered for a total of four 21-day cycles
during induction.

Carboplatin AUC 5 mg/mL min (Calvert formula dosing) IV infusion over 
3060 minutes on Day 1 of each cycle after completion of atezolizumab IV infusion 
with standard anti-emetics per local practice guidelines.


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
Etoposide 100 mg/m2 IV on Days 13 of each cycle. On Day 1 of each cycle, 
etoposide should be administered intravenously over 60 minutes following 
carboplatin administration. On Days 2 and 3 of each cycle, etoposide (100 mg/m2) 
should be administered intravenously over 60 minutes. Premedication should be 
administered according to local standard of care. 
On Day 1 of each cycle, all eligible patients will receive treatment in the following order:
Induction:  atezolizumab carboplatin etoposidevenetoclax
Maintenance:  atezolizumab venetoclax 
On Days 2 and 3, patients will receive etoposide infusions.
Because the effects of corticosteroids on T-cell proliferation have the potential to 
attenuate atezolizumab-mediated anti-tumor immune activity, premedication with 
corticosteroids should be minimized to the extent that is clinically feasible. Secondly, at 
the initiation of the induction phase of dose-escalation Arm B, cohorts will be treated 
without primary prophylactic G-CSF. The administration of secondary prophylactic G-
CSF for high-frequency febrile neutropenia, severe neutropenia, or prolonged 
neutropenia must be discussed and agreed upon between the investigator and the 
Medical Monitor. Please refer to Appendix 10 or administration details, which are in 
accordance with institutional standards and ASCO, NCCN, or ESMO guidelines. Of 
note, if and once primary prophylactic G-CSF is deemed to be necessary as determined 
in the dose-escalation phase (see Section 3.1.2.2), then this requirement will be 
implemented during induction therapy for all subsequent patients.
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure.
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 8.  
Atezolizumab infusions will be administered per the instructions outlined in Table 2.
Cycles in which no chemotherapy is given do not count toward the total number of 
induction chemotherapy cycles.
After the induction phase, patients will begin maintenance therapy with atezolizumab 
plus venetoclax. 
The suggested infusion times for carboplatin and etoposide may be adapted in
accordance with local standard of care.
Any dose modification should be noted on the Study Drug Administration eCRF.  Cases 
of accidental overdose or medication error, along with any associated adverse events, 
should be reported as described in Section 5.3.5.12.


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Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 8.  
Guidelines for dose modification and treatment interruption or discontinuation for 
carboplatin and etoposide are provided in Sections 5.1.5 and 5.1.5.3.
4.3.2.1
Atezolizumab
All patients will receive 1200 mg atezolizumab administered by IV infusion on Day 1 of 
each 21-day cycle.  The atezolizumab dose is fixed and is not dependent on body weight. 
Atezolizumab infusions will be administered per the instructions outlined in Table 2.
No dose modification for atezolizumab is allowed.  Guidelines for treatment interruption 
or discontinuation are provided in Appendix 10 and Appendix 13.  Guidance on study 
drug administration in the context of management of specific adverse events is provided 
in Section 5.
For further details on dose preparation, storage, and administration instructions for 
atezolizumab, please refer to the pharmacy manual and/or the Atezolizumab
Investigator’s Brochure.
4.3.2.2
Venetoclax
At the start of each cycle, patients will be supplied with sufficient venetoclax tablets for 
that cycle. A drug diary will be provided to the patient to record oral administration of 
doses, including the date and time of dosing.  Patients will be instructed to return empty 
bottles or unused tablets.
The investigator is responsible for monitoring patient compliance by monitoring the 
patient diary and counting unused tablets.  Patient compliance with the assigned daily 
dose of study medication will be assessed by standard pill counts.  Previously distributed 
bottles will be returned to the clinic and tablets counted.  Any discrepancy will be 
resolved with the patient at each clinic visit and documented in the patient record.
Each dose of venetoclax will be taken orally once daily with approximately 240 mL of 
water within approximately 30 minutes after the completion of breakfast or patient’s first 
meal of the day.  Patients should self-administer venetoclax at approximately the same 
time each morning.  On days that PK sampling is required, the patient’s first meal of the 
day and all study treatment doses should occur in the clinic to ensure accurate timing of 
the PK sampling.  On those days, the time of each dose of venetoclax will be recorded to 
the nearest minute.
A meal containing approximately 30% of the total caloric content from fat is 
recommended to ensure adequate absorption of venetoclax.  The following is an 
example of a breakfast that contains approximately 520 Kcal and has 30% of the total 
caloric content of the meal from fat that is, approximately 17 grams of fat:  one box 


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cereal (3040 g), skim milk (240 mL), one boiled egg, one slice of toast (15 g) with 
1 tablespoon of margarine (14 g).  The toast and margarine may be replaced with one
medium croissant or two large pancakes.  If there is a substantial period of time between 
the patient’s regular time of breakfast and their venetoclax dosing in the clinic on PK 
sampling days, the patients may have a low-fat snack in the morning.  The patients must 
be instructed not to take their study treatment with the snack and to take their study 
treatments in the clinic after a meal.
Venetoclax tablets should be swallowed whole and never be chewed, cut, or crushed.  If 
vomiting occurs within 15 minutes after taking venetoclax and all expelled tablets are still 
intact, another venetoclax dose should be taken, and the second dose should be noted 
in the drug diary. If tablets are not intact or if vomiting occurs more than 15 minutes after 
taking venetoclax, no replacement dose is to be taken. In cases where a dose of 
venetoclax is missed or forgotten, the patient should take the dose with food as soon as 
possible, ensuring that the dose is taken within 8 hours of the missed dose.  Otherwise, 
the dose should not be taken. 
Following the administration of atezolizumab and an observation period (see Table 2), 
patients will receive venetoclax.
Guidance on study drug administration in the context of management of specific adverse 
events is provided in Section 5.


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Table 2
Administration of First and Subsequent Atezolizumab Infusions
First Infusion
Subsequent Infusions
Atezolizumab 
infusion
No premedication is allowed for 
the first infusion of atezolizumab.
Record the patient’s vital signs 
(pulse rate, respiratory rate, 
blood pressure, and 
temperature) within 60 minutes 
prior to starting the infusion of 
atezolizumab.
Infuse atezolizumab over 
60 (15) minutes.
If clinically indicated, vital signs 
should be measured every 
15 (5) minutes during the 
infusion and at 30 (10) minutes 
after the infusion.
Patients should be informed 
about the possibility of delayed 
post-infusion symptoms and 
instructed to contact their study 
physician if they develop such 
symptoms.
If the patient experienced an IRR during 
any previous infusion of atezolizumab, 
premedication with an antihistamine 
and/or antipyretic may be administered for 
Cycle2 and beyond at the discretion of 
the treating physician.
Record the patient’s vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) within 30 minutes before 
starting the infusion of atezolizumab.
If the patient tolerated the first infusion of 
atezolizumab well without infusion-
associated adverse events, the next 
infusion of atezolizumab may be infused 
over 30 (10) minutes.
If no reaction occurs, continue subsequent 
infusions of atezolizumab over 30 (10) 
minutes.
Continue to record vital signs within 
30 minutes before starting the infusion of 
atezolizumab.
Record vital signs during the infusion of 
atezolizumab if clinically indicated.
Observation 
period after 
infusion of 
atezolizumab
After the infusion of 
atezolizumab, the patient begins 
a 60minute observation period.
Record the patient’s vital signs 
(pulse rate, respiratory rate, 
blood pressure, and 
temperature) at 30 (10) 
minutes after the infusion of 
atezolizumab.
If the patient tolerated the first or a 
subsequent infusion of atezolizumab 
(without premedication) well without 
infusion-associated adverse events, the 
observation period after the next and 
following infusions may be reduced to 30 
minutes.
If the patient experienced infusion-
associated adverse events in the previous 
infusion, the observation period should be 
60 minutes.
If clinically indicated, record the patient’s 
vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) at 
15 (10) minutes after the infusion of 
atezolizumab.
IRRinfusion-related reaction.
Guidelines for medical management of infusion-related reactions (IRRs) are provided in
Appendix 13.


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4.3.2.3
Atezolizumab/Venetoclax
The following rules apply as long as neither atezolizumab nor venetoclax has been 
permanently discontinued: 

Treatment cycles will normally begin with dosing of atezolizumab on Day 1 of each 
21-day cycle.  If atezolizumab is delayed for related toxicity, it is recommended that 
the venetoclax is also delayed. However, if venetoclax is delayed for related 
toxicity, atezolizumab may be continued, if considered appropriate at the discretion 
of the investigator.  

In case of delays in dosing of one study drug (atezolizumab or venetoclax) for 
drug-related toxicity while the other study drug (atezolizumab or venetoclax) is given 
as planned, it is recommended that the study drug being delayed be administered at 
the next scheduled infusion (i.e., at the next scheduled 21-day cycle).
Carboplatin and/or etoposide may be administered as planned in the event that 
atezolizumab and/or venetoclax dose(s) are delayed.  If carboplatin and/or etoposide 
doses must be delayed, atezolizumab and/or venetoclax may be administered as 
planned.
Guidelines for treatment interruption or discontinuation are provided in Sections 4.6.1
and 5.1.5.
4.3.2.4
Carboplatin and Etoposide
Carboplatin
During the induction phase, carboplatin will be administered after completion of 
atezolizumab by IV infusion over 3060 minutes to achieve an initial target AUC of 
5 mg/mL/min (Calvert formula dosing) with standard anti-emetics per local practice 
guidelines.  Because the effects of corticosteroids on T-cell proliferation have the 
potential to attenuate atezolizumab-mediated anti-tumor immune activity, premedication 
with corticosteroids should be minimized to the extent that is clinically feasible (see 
Section 4.4.2).  Carboplatin infusion times may be adapted in accordance with local 
standard of care.
The carboplatin dose of AUC 5 will be calculated using the Calvert formula 
(Calvert et al. 1989):
Calvert Formula
Total dose (mg)(target AUC)(glomerular filtration rate [GFR]25)
NOTE:  The GFR used in the Calvert formula to calculate AUC-based dosing should 
not exceed 125 mL/min.


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For the purposes of this protocol, the GFR is considered to be equivalent to the CRCL.  
The CRCL is calculated by institutional guidelines or by the method of Cockcroft and 
Gault (1976) using the following formula:
CRCL
(140age)(wt)
(0.85 if female)
72Scr
Where:
CRCLcreatinine clearance in mL/min
agepatient's age in years 
wtpatient’s weight in kg
Scrserum creatinine in mg/dL
NOTE: For patients with an abnormally low serum creatinine level, estimate the GFR 
through use of a minimum creatinine level of 0.8 mg/dL or cap the estimated GFR at 
125 mL/min.
If a patient’s GFR is estimated based on serum creatinine measurements by the isotope 
dilution mass spectroscopy method, the U.S. Food and Drug Administration (FDA) 
recommends that physicians consider capping the dose of carboplatin for desired 
exposure (AUC) to avoid potential toxicity due to overdosing. On the basis of the Calvert 
formula described in the carboplatin label, the maximum doses can be calculated as 
follows:
Maximum carboplatin dose (mg)target AUC (mgmin/mL)(GFR25 mL/min)
The maximum dose is based on a GFR estimate that is capped at 125 mL/min for 
patients with normal renal function.  No higher estimated GFR values should be used.
For a target AUC5, the maximum dose is 5 x (12525) 5150750 mg.
For a target AUC4, the maximum dose is 4 x (12525)4150600 mg.
Refer to the FDA’s communication regarding carboplatin dosing with use of the following 
Web site for more details:
http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/
ucm228974.htm
Guidelines for treatment interruption or discontinuation are provided in Sections 4.6.1
and 5.1.5.
Etoposide
During the induction phase, on Day 1 of each cycle, etoposide (100 mg/m2) will be 
administered by IV infusion over 60 minutes following carboplatin administration.  On 
Days 2 and 3 of each cycle, etoposide (100 mg/m2) will be administered by IV infusion 
over 60 minutes.  Premedication should be administered according to local standard of
care.  Because the effects of corticosteroids on T-cell proliferation have the potential to 
attenuate atezolizumab-mediated anti-tumor immune activity, premedication with 


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corticosteroids should be minimized to the extent that is clinically feasible (see 
Section 4.4.2).  Etoposide infusion times may be adapted in accordance with local 
standard of care.
Guidelines for treatment interruption or discontinuation are provided in Sections 4.6.1
and 5.1.5.
Refer to the local prescribing information for material on potential drug interactions 
between etoposide or carboplatin and concomitant medications.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site will acknowledge receipt of IMPs supplied by the Sponsor using the IxRS to confirm 
the shipment condition and content.  Any damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to Atezolizumab and Venetoclax
The Sponsor will offer continued access to Roche IMPs venetoclax and atezolizumab
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 IMPs venetoclax and atezolizumab 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 IMPs venetoclax and atezolizumab 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)


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
The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for breast cancer

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
breast cancer  

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
4.4
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS
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 7 days prior to initiation of 
study drug to the study completion/treatment discontinuation visit.  All such medications 
should be reported to the investigator and recorded on the Concomitant Medications 
eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Oral contraceptives with a failure rate of 1% per year (see Section 4.1.1)

Hormone-replacement therapy

Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable
dose or low-molecular-weight heparin)

Inactivated influenza vaccinations

Megestrol acetate administered as an appetite stimulant 

Mineralocorticoids (e.g., fludrocortisone)

Corticosteroids administered for chronic obstructive pulmonary disease (COPD) or 
asthma

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency
o
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are 
eligible for the study after Medical Monitor confirmation has been 
obtained.


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
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below:
In patients without documentation of progression of disease, it is strongly 
encouraged to maximize supportive care for symptomatic management and 
avoid radiotherapy that will interfere with the assessment of target lesions.
Treatment with venetoclax and atezolizumab may be continued during palliative 
radiotherapy.
Definitive radiotherapy with curative intent (not palliative) is not permitted.
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab infusions only, at the discretion of the 
investigator.
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Sections 4.4.2 and 4.4.3) as clinically indicated, per local 
standard practice.  Patients who experience infusion-associated symptoms may be 
treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2-
receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local 
standard practice.  Serious infusion-associated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists; see Appendix 8).
4.4.2
Prohibited and Cautionary Therapy
Use of the following concomitant therapies is prohibited as described below:

Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent (see 
Section 4.1.2), and during study treatment, until disease progression is documented 
and the patient has discontinued study treatment, with the exception of palliative 
radiotherapy and local therapy under certain circumstances (see Section 4.4.1 for 
details).

Investigational therapy is prohibited within 21 days prior to initiation of study 
treatment and during study treatment.

Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during atezolizumab and/or venetoclax treatment, and 
for 5 months after the final dose of atezolizumab and at least 28 days after the final 
dose of venetoclax.


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
Systemic immunostimulatory agents (including, but not limited to, interferons and
IL-2) are prohibited within 4 weeks or 5 drug-elimination half-lives (whichever is 
longer) prior to initiation of study treatment and during study treatment because 
these agents could potentially increase the risk for autoimmune conditions when 
given in combination with atezolizumab.

Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited 
during study treatment because these agents could potentially alter the efficacy and 
safety of atezolizumab.

Systemic corticosteroids and TNF-inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab.  Therefore, in situations in 
which systemic corticosteroids or TNF-inhibitors would be routinely administered, 
alternatives, including antihistamines, should be considered.  If the alternatives are 
not feasible, systemic corticosteroids and TNF-inhibitors may be administered at 
the discretion of the investigator. Systemic corticosteroids are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy (refer to Appendix 13 for details).  
o
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are 
eligible for the study after Medical Monitor confirmation has been 
obtained.
o
Patients who received mineralocorticoids (e.g., fludrocortisone), 
corticosteroids for COPD or asthma, or low-dose mineralocorticoids for 
orthostatic hypotension or low-dose mineralocorticoids and 
corticosteroids for adrenal insufficiency are eligible for the study.
Some additional therapies are prohibited only for specific study phases, or are allowed 
with caution, restrictions, and/or dose adjustments.  These are described in Table 3 and 
are to be implemented after relevant exclusion criteria for these medications are met 
(see Section 4.1.2).
Of particular note, venetoclax is a substrate of CYP3A and therefore venetoclax 
exposure can be impacted by concomitant strong and moderate of CYP3A inducers and 
inhibitors.  
Relevant restrictions and dosing recommendations for concurrent CYP3A 
inhibitors/inducers are described in Table 3 and Table 4.
After discontinuation of a moderate or strong CYP3A inhibitor that led to a venetoclax 
dose reduction as per the following guidelines, the investigator should wait for 3 days 
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Table 4
Venetoclax Dose Reductions for Strong and Moderate CYP3A 
Inhibitors
Venetoclax Assigned
Dose (mg)
Venetoclax Reduced Dose (mg)
Strong CYP3A Inhibitors
Moderate CYP3A Inhibitors
200
Consult with Medical Monitor
100
400
100
(70 for posaconazole in U.S. and 
countries with USPI-based approval)
200
600
300
800
200
400
U.S.United States; USPI United States Prescribing Information.
Appendix 6 contains examples of CYP3A4 inhibitors/inducers and P-gp 
substrates/inhibitors. Additional examples of these classes of medications are provided 
at the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm
The above lists of medications are not necessarily comprehensive; the investigator 
should also consult the prescribing information for any concomitant medication when 
determining the DDI potential.    
In addition, the investigator should contact the Medical Monitor if questions arise 
regarding medications not listed.  A decision may be made to allow the use of prohibited 
medications on a case by case basis, following discussion with the Medical Monitor and 
assessment of the benefitrisk ratio.
Patients who require the use of any therapies when they are prohibited (unless an 
allowance is made after consultation with the Medical Monitor) will be discontinued from 
study treatment and followed for safety outcomes for 4 weeks after the last dose of study 
treatment or until initiation of another subsequent anti-cancer therapy, whichever comes 
first.
Refer to the local prescribing information for information on potential drug interactions 
between etoposide or carboplatin and concomitant medications.
4.4.2.1
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential DDIs are generally unknown.  However, 
herbal therapies not intended for the treatment of cancer (see Section 4.4.2 may be 
used during the study at the discretion of the investigator.


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4.4.3
Prohibited Food
Use of the following foods is prohibited for at least 3 days prior to initiation of treatment, 
throughout venetoclax administration and for 28 days after last dose of study treatment.

Constituents of these foods have been shown to inhibit CYP3A4, the major enzyme 
responsible for the metabolism of venetoclax. Consumption of these foods could 
lead to increased venetoclax exposure:
–
Grapefruit
–
Grapefruit products
–
Seville oranges (including marmalade-containing Seville oranges)
–
Star fruit (carambola)
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1
and Appendix 2. All activities should be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
Screening tests and evaluations will be performed within 28 days prior to Day 1 of 
Cycle 1.  Results of standard of care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to Day 1 of Cycle 1 may be used; such tests 
do not need to be repeated for screening.
All treatment visits must occur 3 days from the scheduled date unless otherwise noted 
(see Appendix 1 and Appendix 2).  All assessments will be performed on the day of the 
specified visit unless a time window is specified.  Assessments scheduled on the day of 
study treatment administration (Day 1) of each cycle should be performed prior to study 
treatment infusion unless otherwise noted.
If scheduled dosing and study assessments are precluded because of a holiday, 
weekend, or other event, then dosing may be postponed to the soonest following date, 
with subsequent dosing continuing on a 21-day schedule.  If treatment was postponed 
for fewer than 3 days, the patient can resume the original schedule.
The following assessments may be performed 96 hours before Day 1 of each cycle:

ECOG performance status

Limited physical examination

Local laboratory tests
Screening assessments performed 96 hours before Day 1 of Cycle 1 are not required 
to be repeated on Day 1 of Cycle 1.


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4.5.1
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 at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History, Baseline Conditions, Concomitant Medication,
and Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
and use of alcohol and drugs of abuse, 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 7 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.
4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline 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 Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure, and temperature.  Record abnormalities observed at baseline 
on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, 
record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
Vital signs should be measured within 60 minutes prior to each atezolizumab infusion 
and, if clinically indicated, during or after the infusion.  In addition, vital signs should be 




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Further investigations such as bone scans and CT scans of the neck should also be 
performed if clinically indicated.  At the investigator’s discretion, other methods of 
assessment of measurable disease as per RECIST v1.1 may be used.
Tumor assessments performed as standard-of-care prior to obtaining informed consent 
and within 28 days of Cycle 1, Day 1 may be used rather than repeating tests.  All known 
sites of disease, including measurable and/or non-measurable disease, must be 
documented at screening and re-assessed at each subsequent tumor evaluation.  
At subsequent (post-screening) tumor assessments, patients with a history of treated 
brain metastases at screening are not required to undergo brain scans unless clinically 
indicated (e.g., in patients with neurological symptoms).  The same radiographic 
procedure used to assess disease sites at screening should be used throughout the 
study (e.g., the same contrast protocol for CT scans).  
For patients with previously untreated CNS metastases, a brain MRI scan with contrast
is required at screening and is the preferred modality for all subsequent scheduled 
follow-up tumor assessments.  Note:  CT scan with contrast may be acceptable for all 
subsequent scheduled follow-up tumor assessments if the following criteria are met: (1) 
Both brain MRI and CT scan with contrast must be performed at screening to assess 
untreated CNS disease, and (2) The CT scan with contrast can be used to reliably 
evaluate lesions identified on the screening MRI with contrast.  If CT scan with contrast
cannot be used to reliably evaluate lesions identified on the screening MRI with contrast, 
then MRI scan with contrast must be used at all subsequent scheduled follow-up tumor 
assessments.  The same modality must be used at every tumor assessment.
Untreated CNS disease must be recorded in the Tumor Assessment eCRF per RECIST 
1.1 at screening as well as at subsequent scheduled follow-up tumor assessments.
Patients will undergo tumor assessments at baseline and at every 6 weeks (7 days) for 
48 weeks following Day 1 of Cycle 1 regardless of treatment delays.  After the 
completion of the Week 48 tumor assessment, tumor assessment will be required every 
9 weeks (7 days) regardless of treatment delays, until radiographic disease 
progression per RECIST v1.1 (or loss of clinical benefit for patients who continue study 
treatment after disease progression per RECIST v1.1), withdrawal of consent, death, or 
study termination by the Sponsor, whichever occurs first (see Section 3.1.6).  At the 
investigator’s discretion, scans may be performed at any time if progressive disease or 
loss of clinical benefit is suspected. Patients who continue treatment beyond 
radiographic disease progression per RECIST v1.1 will undergo tumor assessments at 
the frequency described above, which is every 6 weeks (7 days) for 48 weeks following 
Cycle 1, Day 1 and then every 9 weeks (7 days) thereafter, until study treatment is 
discontinued.


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Response will be assessed by the investigator on the imaging modalities detailed above, 
using RECIST v1.1 (see Appendix 5).  The investigator’s assessment of overall tumor 
response at all timepoints should only be based on RECIST v1.1.  Assessments should 
be performed by the same evaluator if possible to ensure internal consistency across 
visits.  Results must be reviewed by the investigator before dosing at the next cycle.
Study treatment may be continued as long as patients are experiencing clinical benefit 
as assessed by the investigator in the absence of unacceptable toxicity or symptomatic 
deterioration attributed to disease progression after an integrated assessment of 
radiographic data, biopsy results (if available), and clinical status.  Patients who meet 
criteria for disease progression per RECIST v1.1 will be permitted to continue study
treatment if they meet all of the criteria specified in Section 3.1.6.
Patients who discontinue treatment for reasons other than radiographic disease 
progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will continue 
scheduled tumor assessments at the frequency described above until radiographic 
disease progression per RECIST v1.1, withdrawal of consent, death, or study 
termination by Sponsor, whichever occurs first. Patients who start a new anti-cancer 
therapy in the absence of radiographic disease progression per RECIST v1.1 will 
continue tumor assessments at the frequency described above until radiographic 
disease progression per RECIST v1.1, withdrawal of consent, death, or study 
termination by the Sponsor, whichever occurs first.
Investigator assessment of overall tumor response at all timepoints will be only based on 
RECIST v1.1.
4.5.6
Other Disease-Specific Assessments
Tumor samples from the primary tumor (or metastatic site, in the absence of primary 
site) are to be assessed for expression of Bcl-2 and other markers of lung cancer biology 
(i.e., EGFR, ROS, ALK, other Bcl-2 family members, etc.), mutations in cancer-related 
genes assessed by NGS of DNA, and expression of cancer-related genes assessed by 
quantification of RNA.

Bcl-2 expression status will be determined by central laboratory testing using the 
Ventana Bcl-2 IHC assay.  Bcl-2 high is defined as ≥50% of tumor cells stained with 
an intensity of IHC 2+ or 3+, and Bcl-2 low is defined as ≥50% stained with an 
intensity of IHC 0 or 1+, and <50% stained an intensity of IHC 2+ or 3+.
4.5.7
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count with 
differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other 
cells], and platelet count)


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
Chemistry panel (serum):  glucose, BUN or urea, sodium, magnesium, potassium, 
chloride, bicarbonate, total CO2 (if assessed), total bilirubin, ALT, AST, alkaline 
phosphatase, total protein, and albumin
TLS laboratory assessments include serum creatinine, uric acid, potassium, 
calcium, phosphorus, and LDH.

Coagulation:  INR and aPTT

Thyroid function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) (or 
total T3 for sites where free T3 is not performed), and free thyroxine (also known as 
T4)

Epstein-Barr virus (EBV) serology (EBV IgM, EBV IgG, and/or EBNA) and/or EBV 
PCR
If the patient has positive serology for EBV IgG and/or Epstein-Barr nuclear 
antigen, then EBV IgM testing and/or EBV PCR is required prior to enrollment
for consideration of eligibility.

HIV serology

HBV serology:  HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb 
test is positive) HBV DNA
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection.  

HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection.

Pregnancy test
All women of childbearing potential will have a serum pregnancy test at 
screening.  Urine pregnancy tests will be performed at specified subsequent 
visits.  If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test.
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).

Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); dipstick 
permitted
The following samples will be sent to the Sponsor, one or several central laboratories, or 
a designee for analysis using a validated assay:

Plasma samples for venetoclax PK analysis

Serum samples for atezolizumab analysis


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
Serum samples for atezolizumab immunogenicity analysis

Plasma samples for carboplatin analysis

Plasma samples for etoposide analysis
Note:  Alternative PK and ADA assessments may be explored if there is substantial
difficulty in obtaining the timepoints listed in Appendix 3. Depending on the results from 
interim PK and ADA analyses, the frequency of PK and ADA sampling may be reduced 
or halted later in the study.

Blood samples for exploratory research on biomarkers and biomarker assay 
development

Archival or newly collected tumor tissue sample obtained at baseline for 
determination of Bcl-2 expression and for exploratory research on biomarkers and 
biomarker assay development:
For baseline Bcl-2 and Bcl-2 family protein expression, formalin-fixed paraffin-
embedded (FFPE) samples prepared from resections, core needle, excisional, 
incisional, punch, or forceps biopsies. If these sample types are not available, 
any type of specimen (including fine-needle aspiration, cell pellet specimens 
(e.g., from pleural effusion and lavage samples) is acceptable.
For baseline expression of transcripts for Bcl-2 family members and other
apoptotic genes, FFPE samples prepared from resections, core needle, 
excisional, incisional, punch, or forceps biopsies. If these sample types are not 
available, any type of specimen (including fine-needle aspiration, cell pellet 
specimens [e.g., from pleural effusion and lavage samples], and/or ctDNA 
samples are acceptable.
A representative FFPE tumor specimen in a paraffin block (preferred) or at least 
15 slides containing unstained, freshly cut, serial sections must be submitted 
along with an associated pathology report prior to study enrollment.  If less than 
15 slides are available, the patient may still be eligible for the study, after 
Medical Monitor approval has been obtained.

Tumor tissue sample obtained at the time of progression, if deemed clinically 
feasible, for exploratory research on biomarkers and biomarker assay development
Biopsies at the time of progression should be performed within 40 days after 
progression or prior to the next anti-cancer therapy, whichever is sooner. 
Samples collected via resection, core needle biopsy, or excisional, incisional, 
punch, or forceps biopsy are preferred.
Exploratory biomarker research may include, but will not be limited to, Bcl-2 family 
members, ctDNA analysis, analysis of genes or gene signatures associated with 
apoptosis, tumor immunobiology, T-cell receptor repertoire, or circulating biomarkers.
Research may involve extraction of DNA, cell-free DNA, or RNA; analysis of mutations, 
single nucleotide polymorphisms, and other genomic variants; and genomic profiling 
through use of NGS of a comprehensive panel of genes.  DNA extracted from blood may 
be compared with DNA extracted from tissue to identify somatic variants by 


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distinguishing germline variants from somatic variants. NGS methods may include WGS 
or WES of tissue and blood samples, but WGS or WES of blood samples will be 
performed only at participating sites (see Section 4.5.9).
Screening blood and tumor tissue 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.
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 4.5.11), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exceptions:

Serum samples collected for PK or immunogenicity analysis may be needed for 
additional pharmacokinetics (e.g., PK biomarkers or relevant 
analytes/catabolites/metabolites) and immunogenicity characterization and for PK or 
immunogenicity assay development and validation; therefore, these samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed.

Blood, plasma, serum, and tumor tissue samples collected for biomarker research
and biomarker assay development will be destroyed no later than 5 years after the 
final Clinical Study Report has been completed, with the exception of tissue samples 
that undergo WGS or WES, which will be stored until they are no longer needed or 
until they are exhausted However, the storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health 
authority requirements).

For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or no later than the time of final closure of the study database, 
whichever occurs first.  For patients who are not enrolled, remaining archival tissue 
blocks will be returned to the site no later than 6 weeks after eligibility determination.
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, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 


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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.
4.5.8
Electrocardiograms
An ECG is required at screening and when clinically indicated.  ECGs for each patient 
should be obtained from the same machine wherever possible.  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.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF.
4.5.9
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites)
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
or WES to identify variants that are predictive of response to study drug, are associated 
with progression to a more severe disease state, are associated with acquired 
resistance to study drug, are associated with susceptibility to developing adverse events, 
can lead to improved adverse event monitoring or investigation, or can increase the 
knowledge and understanding of disease biology and drug safety.  DNA extracted from 
blood may be compared with DNA extracted from tissue to identify somatic variants by 
distinguishing germline variants from somatic variants. The samples may be sent to one 
or more laboratories for analysis.
Collection and submission of blood samples for WGS or WES is contingent upon the 
review and approval of the exploratory research by each site's Institutional Review Board 
or Ethics Committee (IRB/EC) and, if applicable, an appropriate regulatory body.  If a 
site has not been granted approval for WGS or WES, this section of the protocol 
(Section 4.5.9) will not be applicable at that site.
Genomics is increasingly informing researchers’ 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 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.  


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Blood samples collected for WGS or WES are to be stored until they are no longer 
needed or until they are exhausted.  However, the storage period will be in accordance 
with the IRB/EC-approved Informed Consent Form and applicable laws (e.g., health 
authority requirements).
Refer to Section 4.5.7 for details on use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker analyses.
4.5.10
Optional Tumor Biopsies
Consenting patients may undergo an optional tumor biopsy (if deemed clinically feasible 
by the investigator) anytime during treatment and/or during the survival follow-up phase.  
Preferred sample types include FFPE samples prepared from resections, core needle, 
excisional, incisional, punch, or forceps biopsies.  If these sample types are not available, 
any type of specimen (including fine-needle aspiration, cell pellet specimens [e.g., from 
pleural effusion and lavage samples]) is acceptable.  
The Informed Consent Form will contain a separate section that addresses optional 
biopsies.  A separate, specific signature will be required to document a patient's 
agreement to undergo optional biopsies.  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 Optional Biopsy Sample Informed Consent eCRF.
Samples may be used for exploratory biomarker research as described in Section 4.5.7.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Refer to Section 4.5.7 for details on duration of sample storage, use 
of samples after patient withdrawal, confidentiality standards for data, and availability of
data from biomarker analyses.
4.5.11
Optional Samples for Research Biosample Repository
4.5.11.1
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


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
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
4.5.11.2
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 each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.11) 
will not be applicable at that site.
4.5.11.3
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 Bcl-2, diseases, or drug 
safety:

Blood samples collected at predose

Additional archival tumor tissue samples (e.g., from an earlier biopsy) collected at 
screening

Tumor tissue samples from biopsies performed at the investigator's discretion 
during the study

Leftover blood, serum, plasma, PBMC, and tumor tissue samples (with the 
exception of remaining archival tissue blocks, which will be returned to sites) and 
any derivatives thereof (e.g., DNA, RNA, proteins, peptides), including leftover 
tissue samples from medically indicated procedures (e.g., bronchoscopy, 
esophagogastroduodenoscopy, colonoscopy) performed at the investigator's 
discretion during the course of the study
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via WGS, 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.


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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
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).
4.5.11.4
Confidentiality
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 study 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.
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.
4.5.11.5
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.


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4.5.11.6
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 site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address:
global_rcr-withdrawal@roche.com
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.
4.5.11.7
Monitoring and Oversight
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.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must discontinue study treatment if they experience any of the following:

Symptomatic deterioration attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results if 
available, and the patient’s clinical status

Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient’s potential response to therapy and severity of the event

Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment

Use of another nonprotocol-specified anti-cancer therapy (see Section 4.4.2)


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
Pregnancy

Radiographic disease progression per RECIST v1.1 (unless treating beyond 
radiographic progression; see below)
However, to better accommodate standard clinical practice which is guided by the fact 
that patients with ES-SCLC whose disease progresses after first-line treatment have 
limited treatment options and such options also have limited efficacy and significant 
toxicity, patients may be considered for treatment beyond radiographic progression per 
RECIST v1.1 at the discretion of the investigator and after appropriate discussion with 
the patient, only if all of the following criteria are met:

Evidence of clinical benefit as assessed by the investigator

No decline in ECOG performance status that can be attributed to disease 
progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions
Treatment should be discontinued if clinical deterioration due to disease progression 
occurs at any time or if persistent disease growth is confirmed in a follow-up scan.  In 
addition, patients should be discontinued for unacceptable toxicity or for any other signs 
or symptoms of deterioration attributed to disease progression as determined by the 
investigator after an integrated assessment of radiographic data and clinical status.
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 will return to the clinic for a treatment discontinuation visit 30 days after the 
final dose of study treatment (see Appendix 1).  The visit at which response assessment 
shows progressive disease may be used as the treatment discontinuation visit.  Patients 
who discontinue study treatment for any reason other than progressive disease or loss 
of clinical benefit will continue to undergo tumor response assessments and PRO 
assessments as outlined in the schedule of activities (see Appendix 1 and Appendix 2).
After treatment discontinuation, information on survival follow-up and new anti-cancer 
therapy will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 months until death (unless the patient withdraws consent or the 
Sponsor terminates the study) (see Appendix 1 and Appendix 2).  Information on 
subsequent anti-cancer therapies will include systemic therapies (e.g., chemotherapy, 
targeted therapy, hormonal therapy, or CIT), surgery (e.g., resection of metastatic 
disease), and radiation procedures (e.g., radiotherapy to a tumor lesion).


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4.6.2
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 or site closure

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 appropriate eCRF.  If a patient requests to be withdrawn from the study, 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.
4.6.3
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.
4.6.4
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 International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)


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5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is based on clinical experience with venetoclax
as well as atezolizumab plus carboplatin and etoposide in completed and ongoing 
studies.  The anticipated important safety risks are outlined below (see 
Sections 5.1.15.1.4).  
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.  Administration of venetoclax and atezolizumab plus 
carboplatin etoposide will be performed in a monitored setting in which there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  Guidelines for managing patients who experience 
anticipated adverse events, including criteria for dosage modification and treatment 
interruption or discontinuation, are provided in Appendix 10, Appendix 11, Appendix 12,
and Appendix 13.  Refer to Sections 5.25.7 for details on safety reporting (e.g., adverse 
events, pregnancies) for this study.
5.1.1
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs and immune-
mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, 
myasthenic syndrome or myasthenia gravis, meningoencephalitis, myocarditis, nephritis, 
and myositis.  Immune-mediated reactions may involve any organ system and may lead 
to hemophagocytic lymphohistiocytosis and macrophage activation syndrome.  Refer to 
Appendix 13 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure 
for a detailed description of anticipated safety risks for atezolizumab.  
5.1.2
Risks Associated with Etoposide
Etoposide is known to cause bone marrow suppression including myelosuppression, 
anemia, thrombocytopenia, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), 
hepatotoxicity, and alopecia.  Etoposide-based chemotherapy is considered to be 
moderately emetogenic.  Etoposide carries a risk of secondary hematologic malignancy.  
Patients will be monitored for etoposide-related adverse events.
For more details regarding the safety profile of etoposide, refer to the etoposide 
prescribing information.
5.1.3
Risks Associated with Carboplatin
Carboplatin is known to cause bone marrow suppression including myelosuppression, 
anemia, and thrombocytopenia.  Carboplatin-based chemotherapy is considered to be 
moderately emetogenic.  Patients will be monitored for carboplatin-related adverse 
events.


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For more details regarding the safety profile of carboplatin, refer to the carboplatin 
prescribing information.
5.1.4
Risks Associated with Venetoclax
Clinical experience gained thus far with venetoclax has demonstrated that it is generally 
well tolerated, and toxicities appear to be mostly manageable and/or reversible; see the 
Venetoclax Investigator’s Brochure for more information. 
On the basis of clinical data to date, the following known and potential risks with 
venetoclax are described below.  Guidelines around the management of these risks 
through dose and schedule modifications are described in Section 5.1.5.1.
5.1.4.1
Tumor Lysis Syndrome
Available data suggest that in patients with non-CLL, with the exception of those with 
mantle cell lymphoma, the risk of TLS is low with venetoclax. Due to different biology 
between ES-SCLC and hematological malignancies, the risk of TLS is considered to be 
low in patients with ES-SCLC. 
Nevertheless, patients should be advised to remain well hydrated for the first week of 
study drug administration. Although not mandatory, at the discretion of the investigator, a 
prophylactic oral agent (e.g., allopurinol 300 mg QD) may be initiated in patients who are 
deemed to be at the risk of TLS in order to reduce the uric acid level. Laboratory values 
obtained before the dose of venetoclax are to be used to determine whether a patient 
developed a change related to TLS. Laboratory results of the 24-hour postdose must be 
reviewed before receiving the dose of venetoclax for that day. Patients who develop 
electrolyte changes suggestive of TLS should undergo aggressive management and 
further monitoring per Appendix 11.
Patients with TLS should be treated as per institutional practice and local guidelines, 
including correction of electrolyte abnormalities and monitoring of renal function and fluid 
balance. Recommendations for initial management of electrolyte imbalances and 
prevention of TLS are provided in Appendix 11. In some cases, dialysis may be 
indicated. Guidelines for defining TLS are provided in Appendix 9.
5.1.4.2
Neutropenia
Neutropenia is an important identified risk for venetoclax. Clinical data from the 
oncology studies suggest that the neutropenia adverse events are observed among 
subjects who receive venetoclax as a single agent or in combination with other
therapeutic agents, with higher frequency observed in some combination studies. 
Serious adverse events of neutropenia or neutropenia events that lead to 
discontinuations are few across the entire venetoclax oncology program. Neutropenia 
management guidelines are provided in Table 10 and Appendix 12. Granulocyte colony 
stimulating factors are permitted according to local practice, and patients will be 
monitored and treated promptly in case of infection.


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5.1.4.3
Serious Infections
Serious infection is an important identified risk for venetoclax. Infections have been 
reported in the oncology clinical studies; however, these events are confounded by 
the underlying disease, comorbidities, and other immunosuppressive medications. To 
date, no clear relationship has been noted between serious infectious events and 
neutropenia. The types of infectious events observed generally have been consistent 
with those anticipated in the elderly population of heavily pretreated subjects with 
hematologic malignancies and are similar across all indications. Infections are closely 
monitored in venetoclax program across all indications. Patients should be advised to 
report fever and should be assessed for further management as per standard medical 
practice. In the oncology studies, recommendations are included in the protocol 
regarding the need for anti-infective prophylaxis per standard of care (e.g., NCCN for 
oncology subjects).
5.1.4.4
Other Hematological Effects
Anemia has been reported across oncology studies investigating venetoclax, with a 
higher frequency in some studies in which venetoclax is combined with other 
reference therapies; however, most of the events were non-serious and confounded 
by disease factors and prior therapies.
Thrombocytopenia adverse events have been reported in oncology studies 
investigating venetoclax, with a higher frequency in those studies in which venetoclax 
was combined with other chemotherapeutic agents. However, most of the events were 
non-serious and assessment of these events is confounded by the patients' 
underlying hematologic malignancy disease state, prior therapies, and preexisting 
thrombocytopenia, including autoimmune thrombocytopenia in several patients.
Lymphopenia has been observed in nonclinical studies and in the phase I clinical 
study conducted in heavily pretreated patients with CLL and NHL. While opportunistic 
infections have been reported in the clinical program, data are confounded by the 
patients’ underlying disease and prior therapies. Patients in this study who develop 
lymphopenia are potentially at risk for atypical infections. As such, prophylaxis against 
varicella zoster virus and Pneumocystis jiroveci pneumonia should be considered and 
implemented (if applicable) as per local institutional practice
5.1.4.5
Reproductive System Effects and Pregnancy
This study enrolls both male and female patients.  The effect of Bcl-2 inhibition on 
pregnancy has not been fully characterized. In animal studies, venetoclax resulted in 
increased post implantation loss, and decreased fetal body weights were observed in 
the mouse embryo-fetal development study at the highest dosage administered. 
Venetoclax was not teratogenic. Two human pregnancies have been reported in the 
clinical program with venetoclax so far, including one pregnancy of a partner; in both 
cases, a live infant with no neonatal complication, congenital anomalies, or birth 
defects was delivered. 


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In nonclinical studies, venetoclax has shown a potential to cause reproductive and 
embryo-fetal developmental toxicities as single agent. No reproductive or teratogenicity 
studies in animals have been conducted with atezolizumab. The PD-L1/PD-1 signaling 
pathway is well established as essential in maternal/fetal tolerance and embryo-fetal 
survival during gestation. Administration of atezolizumab is expected to have an adverse 
effect on pregnancy and poses a risk to the human fetus, including embryo lethality.
Consequently, both venetoclax and atezolizumab should not be administered to 
pregnant women, and they must be discontinued if a patient becomes pregnant. 
Additionally, patients are advised to remain abstinent (i.e., refrain from heterosexual 
intercourse) or use non-hormonal contraceptive methods with a failure rate of <1% per 
year during the treatment period and for 30 days after the last dose of study drug. 
Please refer to Section 4.1.1 for further details on study eligibility and contraceptive 
requirements for patients.
5.1.4.6
Treatment-Emergent Malignancies (Second Primary 
Malignancies)
Events of second primary malignancies have been reported across the venetoclax 
hematologic oncology program. However, no causal association with the venetoclax 
administration has been confirmed, and no pattern has been observed. The overall 
observed incidence rate of malignancy in the venetoclax clinical trial programs were 
comparable to that reported in the general population. The second primary 
malignancies will be closely monitored in this study.
5.1.5
Dose Modification
Reasons for dose modifications including dose delays, the supportive measures taken, 
and the outcomes will be documented in the patient's chart and recorded on the eCRF.  
The severity of adverse events will be graded according to NCI CTCAE v5.0.0.

When several toxicities with different grades of severity occur at the same time, 
the dose modifications should be according to the highest grade observed.

If, in the opinion of the investigator, a toxicity is considered to be due solely to one 
component of the study treatment and the dose or administration of that component 
is delayed or modified, the dose or administration of the other study treatment 
components do not require modification and may be administered if there is no 
contraindication.

When treatment is temporarily interrupted because of toxicity caused by 
atezolizumab, carboplatin, or etoposide, the treatment cycles should be restarted 
such that the atezolizumab infusions remain synchronized and aligned with the 
chemotherapy schedule.

If, in the opinion of the investigator, a toxicity is considered to be due solely to 
one chemotherapy drug, the dose of the other chemotherapy drug does not 
require modification.  




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If a patient must be tapered off steroids used to treat adverse events, atezolizumab may 
be withheld for additional time beyond 105 days from the last dose until steroids are 
discontinued or reduced to prednisone dose (or dose equivalent) 10 mg/day.  The 
acceptable length of interruption will depend on agreement between the investigator and 
the Medical Monitor.
Dose interruptions for reason(s) other than adverse events, such as surgical procedures, 
may be allowed with Medical Monitor approval.  The acceptable length of interruption will 
depend on agreement between the investigator and the Medical Monitor.
5.1.5.3
Chemotherapy Dose Modifications, Treatment Delays, or 
Treatment Discontinuation and Management of Specific 
Adverse Events
Dose modifications for carboplatin and etoposide are permitted for toxicity according to 
the prescribing information and local standard of care.  
Dose modification guidelines are provided below.  
Treatment with carboplatin or etoposide should be discontinued if a patient experiences 
any hematologic or non-hematologic Grade 3 or Grade 4 toxicity after two dose 
reductions or treatment is delayed for more than 63 days due to toxicities. 
Hematologic Toxicity
At the start of each cycle, the ANC should be 1500/L and the platelet count should be 
100,000/L.  Treatment should be delayed for up to 63 days to allow sufficient time for 
recovery.  Growth factors may be used in accordance with American Society of Clinical 
Oncology (ASCO) and NCCN guidelines (Smith et al. 2006; NCCN 2019) or as per 
institutional guidelines.  Upon recovery, dose adjustments at the start of a subsequent 
cycle will be made on the basis of the lowest platelet and neutrophil values from the 
previous cycle (see Table 7). Increased frequency of lab assessments (e.g., neutrophil 
and platelet counts) on Cycle 1, Day 8 and Cycle 1, Day 15 are used to better 
characterize the impact of and response to treatment. Since such assessments are not 
routinely performed, they will not be used for dose modifications for subsequent cycles.
Therefore, Cycle 2 dose adjustments will be based on assessments performed after 
Cycle1, Day 21.
In the event that dose adjustments are needed for both ANC and platelets, patients are 
to receive the lower dose.






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5.1.6.3
Management of Potential Overlapping Toxicities
The main overlapping toxicities based on the individual safety profile of venetoclax and 
atezolizumab, carboplatin, and etoposide are expected to be hematologic toxicities such 
as neutropenia, febrile neutropenia, and thrombocytopenia (in the case of venetoclax, 
etoposide and carboplatin); and gastrointestinal toxicities such as diarrhea, nausea, and 
vomiting (in the case of venetoclax, atezolizumab, etoposide and carboplatin). 
Table 10 below provides management guidelines for specific overlapping toxicities with 
venetoclax, atezolizumab and carboplatin etoposide. Nevertheless, the attribution and 
management of certain adverse events that have been associated with each agent 
separately (e.g., hepatotoxicity, skin and gastrointestinal toxicity) may be unclear when 
the agents are administered together.  It is theoretically possible that allergic or 
inflammatory adverse events associated with carboplatin and etoposide (e.g., dermatitis, 
infusion-associated symptoms) could be exacerbated by the immunostimulatory activity 
of atezolizumab. 
Toxicities should initially be managed according to the recommendations in 
Sections 5.1.5.15.1.5.3, Table 10, Appendix 12, and Appendix 13 with dose holds and 
modifications (if applicable) applied to the component of the study drug judged to be the 
primary cause.  For severe (Grade 3) or persistent Grade 12 diarrhea, an endoscopic 
evaluation should be considered.  Additional tests, such as autoimmune serology or 
biopsies, may be used to determine a possible immunogenic etiology for adverse events 
listed above.  If, in the opinion of the investigator, atezolizumab is a potential inciting 
factor, the dose of atezolizumab may be held for a maximum of 105 days beyond the 
last infusion (see Section 5.1.5.2).  Exceptions require Medical Monitor approval.  
Prompt symptomatic management is appropriate for mild immune-mediated adverse 
events.  In severe cases, immune-mediated toxicities may be acutely managed with 
systemic corticosteroids or TNF-inhibitors.  These cases should be discussed with the 
Medical Monitor.










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
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 treatment

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

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 treatment

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).


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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 5.3.5.7)

Suspected transmission of an infectious agent by the study treatment, 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 study treatment is suspected.

Pneumonitis

Colitis

Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency,
hyperthyroidism, and hypophysitis

Hepatitis, including AST or ALT 10ULN

Systemic lupus erythematosus

Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis

Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, influenza-like illness, and systemic inflammatory response syndrome

Nephritis

Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)

Myositis

Myopathies, including rhabdomyolysis

Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Vasculitis

Autoimmune hemolytic anemia

Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis)

Tumor Lysis Syndrome

Grade 4 thrombocytopenia


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
Grade 4 Febrile neutropenia
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study treatment, 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 treatment, all adverse events will be reported until 30 days after 
the last dose of study drug or until initiation of new systemic anti-cancer therapy, 
whichever occurs first, and serious adverse events and adverse events of special 
interest will continue to be reported until 90 days after the final dose of study treatment
or until initiation of new systemic anti-cancer therapy, whichever occurs first.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 11 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.






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based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.


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5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
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 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 


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It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3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 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 5.3.5.2, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified adverse event reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of SCLC 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 treatment, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).
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 


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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.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of SCLC
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.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., 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 (e.g., for study treatment
administration or performance of an efficacy measurement for the study)


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
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 SCLC
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
5.3.5.12
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}

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, 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 
atezolizumab or venetoclax 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.


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
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.
In addition, all special situations associated with atezolizumab or venetoclax, 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.


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
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.
5.3.5.13
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management.
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 treatment:

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


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Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Medical Monitor/Roche Medical Responsible:
 M.D.
Mobile Telephone No.:
Alternate Medical Monitor Contact Information 
Medical Monitor/Roche Medical Responsible:
 M.D., Ph.D.
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
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 Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Treatment Initiation
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported until 90 days after the final dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 


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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 after the reporting period are 
provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 30 days after the final
dose of venetoclax, 5 months after the final dose of atezolizumab, or 6 months after the 
final dose of carboplatin or etoposide, whichever occurs last.  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 email 
address provided to investigators.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study treatment 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.  
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 
30 days after the final dose of venetoclax, 5 months after the final dose of atezolizumab, 
or 6 months after the final dose of carboplatin or etoposide, whichever occurs last.  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 email 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 treatment.  When permitted by the site, 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.


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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 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the
event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study treatment 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, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.




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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
6.1
DETERMINATION OF SAMPLE SIZE
The estimated sample size of the dose-escalation phase follows from the dose-
escalation rules of a standard 3+3 algorithm. It is anticipated that enrollment of two 
cohorts of 36 patients each in the maintenance phase, as well as up to five cohorts of 
36 patients each in the induction phase, for a total of 1842 patients, will be required to 
establish the RP2D for maintenance (RP2D-M) and the RP2D for the induction setting 
(RP2D-I) during the dose-escalation phase.
A sample of 20 patients will be sufficient to provide adequate precision for the point 
estimates. Assuming an observed ORR of 80% for the induction plus maintenance 
setting (Arm B), with 20 patients, the lower bound of the two-sided 80% CI will rule out 
a probability of response of 63%. Assuming an observed ORR of 5% for the 
maintenance-only setting (Arm A), with 20 patients, the lower bound of the two-sided 
80% CI will rule out a probability of response of 0%.
An 80% CI for true underlying ORR values of 0.05, 0.1, 0.7, 0.75, and 0.8 are provided 
in Table 13.  
Table 13 Operating Characteristics for Proposed Study Design for Several 
Possible True Underlying Overall Response Rate
True Underlying ORR
5%
10%
70%
75%
80%
80% confidence interval for true 
ORR 
(1%, 18%) (3%, 24%) (53%, 83%) (59%, 87%)
(64%, 
91%)
a Confidence intervals are based on the assumption that the point estimate is equal to the 
true underlying value of the objective response rate (ORR) in each column.
For a given adverse event with a true rate of 10%, 5%, or 1%, the probability of 
observing at least one such event in a cohort of 20 patients is 87.8%, 64.2%, and 18.2%, 
respectively.  Table 14 describes exact 90% CIs for a range of observed proportions of 
adverse events based on a sample size of 20 patients.




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Study treatment exposure (such as treatment duration, total dose received, and number 
of cycles and dose modifications) will be summarized with descriptive statistics.
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to NCI CTCAE v5.0.  All adverse events, serious adverse events, adverse 
events leading to death, adverse events of special interest, and adverse events leading 
to study treatment discontinuation that occur on or after the first dose of study treatment 
(i.e., treatment-emergent adverse events) will be summarized by mapped term, 
appropriate thesaurus level, and severity grade.  For events of varying severity, the 
highest grade will be used in the summaries.  Deaths and cause of death will be 
summarized.
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse 
oximetry, and temperature), and ECG data will be displayed by time, with grades
identified where appropriate.  Additionally, a shift table of selected laboratory tests will be 
used to summarize the baseline and maximum postbaseline severity grade.  Changes in 
vital signs and ECGs will be summarized.
6.5
EFFICACY ANALYSES
The analysis population for the efficacy analyses will consist of all enrolled patients in 
the dose-expansion cohort, with patients grouped according to their assigned dose 
levels and treatment schedules.  
6.5.1
Primary Efficacy Endpoint
The primary efficacy objective for the Phase Ib dose-expansion cohort is to evaluate the 
preliminary efficacy of venetoclax in combination with atezolizumab as maintenance 
therapy or venetoclax in combination with atezolizumab, carboplatin, and etoposide as
induction therapy followed by venetoclax plus atezolizumab as maintenance therapy on 
the basis of the following endpoint:

ORR, defined as the proportion of patients with a CR or PR on two consecutive 
occasions 4 weeks apart, as determined by the investigator according to 
RECIST v1.1 criteria.
Patients with no disease assessments for any reason will be classified as non-
responders. An estimate of ORR with 90% exact CI will be presented using the method 
of Pearson Clopper. 


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6.5.2
Secondary Efficacy Endpoints
The secondary efficacy objective for the Phase Ib dose-expansion cohort is to evaluate 
the preliminary efficacy of venetoclax in combination with atezolizumab as maintenance 
therapy or venetoclax in combination with atezolizumab, carboplatin, and etoposide as
induction therapy or venetoclax and atezolizumab as maintenance therapy on the basis 
of the following endpoints:

DOR

PFS

OS

PFS rate at 6 months

OS rate at 1 year
6.5.2.1
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 the investigator according to RECIST v1.1 criteria.  Data for patients without the 
occurrence of disease progression or death as of the clinical data cutoff will be censored 
at the time of the last tumor assessment.
The Kaplan-Meier approach will be used to estimate median DOR. The Kaplan-Meier 
curve of time to DOR will be provided. Only patients achieving a CR or PR will be 
included in the assessment of DOR.
6.5.2.2
Progression-Free Survival
PFS after enrollment is defined as the time from enrollment to the first occurrence of 
disease progression or relapse or death from any cause (whichever occurs first), as 
determined by the investigator according to RECIST v1.1 criteria.  Data for patients 
without the occurrence of disease progression or death as of the clinical data cutoff date 
will be censored at the time of last tumor assessment (or the time of enrollment plus 
1 day if no tumor assessment was performed after the baseline visit).
The Kaplan-Meier approach will be used to estimate median PFS. The Kaplan-Meier 
curve of time to PFS will be provided. 
6.5.2.3
Overall Survival
OS after enrollment is defined as the time from enrollment to death from any cause. 
Data for patients who are alive at the time of the analysis data cutoff will be censored at 
the last date they were known to be alive. Data from patients without postbaseline
information will be censored at the date of enrollment plus 1 day.
OS will be analyzed using the same methodology as PFS (see Section 6.5.2.2).


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6.5.2.4
Progression-Free Survival Rate at 6 Months
PFS rate at 6 months, defined as the proportion of patients who have not experienced 
disease progression, relapse, or death from any cause at 6 months, as determined by 
the investigator according to RECIST 1.1 criteria. 
The PFS rate at 6 months will be estimated using the Kaplan-Meier methodology. A 
two-sided 90% CI of the PFS rate at 6 months will be presented based on Greenwood’s 
method of estimating the variance of the KM estimate. 
6.5.2.5
Overall Survival Rate at 1 Year
OS rate at 1 year, defined as the proportion of patients who have not experienced death 
from any cause at 1 year timepoint.
The OS rate at 1 year will be analyzed using the same methodology as the PFS rate at 
6 months (see Section 6.5.2.4).
6.6
PHARMACOKINETIC ANALYSES
Individual PK concentration data will be tabulated and summarized (e.g., mean, standard 
deviation, coefficient of variation, median, minimum, and maximum) after appropriate 
grouping.  PK parameters may also be calculated as data allow (e.g., Cmax, AUC, 
clearance, volume of distribution, half-life, etc.) and tabulated and/or summarized after 
appropriate grouping.  Population PK analyses of concentration data (with or without the 
PK data from other studies) may be conducted as appropriate. Potential PK DDIs may 
be assessed by comparison of PK for agents administered in this study with relevant 
historical data. Potential correlations between exposure and response (e.g., PD, 
efficacy, ECG, and safety endpoints) may also be explored, if warranted.  
The results of Population PK analyses and exploratory exposure-response analyses 
may be reported separately from the Clinical Study Report.  At the discretion of the 
Sponsor, all analyses may be extended to include relevant biotransformation products of 
the study treatments administered in this study.
6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment.  
The numbers and proportions of ADA positive patients (for atezolizumab) and ADA
negative patients (for atezolizumab) at baseline (baseline prevalence) and after drug 
administration (postbaseline incidence) will be summarized by treatment group.  When 
determining postbaseline incidence, patients are considered to be ADA positive if they 
are ADA negative or have missing data at baseline but develop an ADA response 
following study drug exposure (treatment-induced ADA response), or if they are ADA 
positive at baseline and the titer of one or more postbaseline samples is at least 0.60 
titer unit greater than the titer of the baseline sample (treatment-enhanced ADA 


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response).  Patients are considered to be ADA negative if they are ADA negative or 
have missing data at baseline and all postbaseline samples are negative, or if they are 
ADA positive at baseline but do not have any postbaseline samples with a titer that is at 
least 0.60 titer unit greater than the titer of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, efficacy, and PK endpoints may be 
analyzed and reported via descriptive statistics.
6.8
BIOMARKER ANALYSES
Although no formal statistical analysis of exploratory biomarkers will be performed, data 
may be analyzed in the context of this study and in aggregate with data from other 
studies in effort to understand the association of these markers with study treatment 
response. Results will be presented in a separate report.  
6.9
INTERIM ANALYSIS
None planned.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor's standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.


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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
SOURCE DATA DOCUMENTATION
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, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
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.
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.


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7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, 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 such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
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 


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consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
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.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
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 


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also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study 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 9.5).
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 for each study site, 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 9.5).


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8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (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 
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.


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9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
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 1012 sites globally will participate to enroll approximately 62 patients.  
Screening and enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker analyses, and PK analyses), as specified in 
Section 4.5.7.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected.
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 healthcare 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 
Trials Data 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.


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In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.7
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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Appendix 1: Schedule of Activities: Dose-Escalation Maintenance Only (Arm A) and Dose-Expansion Maintenance Only (cont.)
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ADAanti-drug antibody; C Cycle; CT computed tomography; DDay; ECOGEastern Cooperative Oncology Group; eCRFelectronic Case 
Report Form; EBVEpstein-Barr virus; FFPEformalin-fixed paraffin-embedded; HBcAbhepatitis B core antibody; HBsAghepatitis B surface 
antigen; HBVhepatitis B virus; HCVhepatitis C virus; MRImagnetic resonance imaging; PCIprophylactic cranial irradiation; 
PCRpolymerase chain reaction; PDpharmacodynamic; PD-L1programmed deathligand 1; PKpharmacokinetic; PCIprophylactic cranial 
irradiation; RBRRoche Biosample Repository; RECIST Response Evaluation Criteria in Solid Tumors; SCLC small cell lung cancer; 
TLStumor lysis syndrome; TSHthyroid-stimulating hormone.
a Assessments should be performed before study drug infusion unless otherwise noted.
b Cycle 1 must be performed within 5 days after the patient is enrolled. Screening assessments performed 96 hours before Cycle 1, Day 1 are 
not required to be repeated for Cycle 1, Day 1. In addition, ECOG performance status, limited physical examination, and local laboratory tests 
may be performed 96 hours before Day 1 of each cycle.
c Day 2, Day 8, and Day 15 assessments are not necessary during the dose-expansion phase, with the exception of PK sampling (refer to
Appendix 4).
d A pre-treatment tumor tissue (archival or freshly obtained) sample should be submitted before or within 4 weeks after enrollment. This specimen 
must be accompanied by the associated pathology report. Although any available tumor tissue sample can be submitted, it is strongly 
encouraged that representative tumor specimens in paraffin blocks (preferred) or 15 (or more) serial, freshly cut, unstained slides be submitted.
e Vital signs include pulse rate, respiratory rate, systolic and diastolic blood pressure, and temperature. Vital signs should be recorded as 
described in Section 4.5.4.
f Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.
g ECG recordings will be obtained when clinically indicated.
h Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, lymphocytes, eosinophils,
monocytes, basophils, and other cells), and platelet count.
i At screening, the patient must have adequate hematologic and end-organ function defined by laboratory test results obtained within 14 days prior 
to enrollment.
j Serum chemistry includes BUN or urea, sodium, potassium, magnesium, chloride, bicarbonate or total CO2 if considered standard of care in the 
region, glucose, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin.  
k TLS assessment frequency during the dose-expansion phase will be determined based on a comprehensive review of data in the dose-escalation
phase. TLS labs include serum creatinine, calcium, phosphorous, uric acid, potassium, and LDH. If the screening assessments were done within 
3 days prior to Cycle 1 Day 1, there is no need to repeat the TLS panel at Cycle 1 Day 1. Refer to Appendix 9 and Appendix 11 for further 
instructions.
l Serum pregnancy test within 14 days before Cycle 1, Day 1.
m Urine pregnancy tests; if a urine pregnancy test result is positive, it must be confirmed by a serum pregnancy test.
n Total T3 will be tested only at sites where free T3 is not performed.


Appendix 1: Schedule of Activities: Dose-Escalation Maintenance Only (Arm A) and Dose-Expansion Maintenance Only (cont.)
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o Thyroid function testing (TSH, free T3, free T4) collected on Day 1 of Cycles 1, 4, 8, and 12, and every fourth cycle thereafter.
p All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the study. Patients with 
active hepatitis B (chronic or acute; defined as having a positive HBsAg test result at screening) will be excluded from the study. Patients with 
past or resolved HBV infection (defined as the presence of HBcAb and absence of HBsAg) are eligible; HBV DNA should be obtained in these 
patients prior to enrollment. Patients with HCV will be excluded from the study; patients who test positive for HCV antibody are eligible only if 
PCR is negative for HCV RNA.
q Urinalysis by dipstick (specific gravity, pH, glucose, protein, ketones, and blood). Urinalysis is required at screening and will be obtained when
clinically indicated.
r For atezolizumab, the initial dose will be administered over 60 (15) minutes. If the first infusion is well tolerated, subsequent infusions may be 
administered over 30 (10) minutes (see Section 4.3.2.1).  Venetoclax is administered QD for 21 days as described in Section 3.1.2; also see 
Section 4.3.2.2.
s During the maintenance phase, PCI is permitted as per local standard of care and will be reported on the Prophylactic Cranial Irradiation eCRF.
t CT scans (with oral/IV contrast unless contraindicated) or MRI scans of the chest and abdomen. A CT or MRI scan of the pelvis is required at 
screening and as clinically indicated or as per local standard of care at subsequent response evaluations. A CT (with contrast) or MRI scan of the 
head must be done at screening to evaluate CNS metastasis in all patients.
u Perform every 6 weeks (7 days) for 48 weeks following Cycle 1, Day 1 and then every 9 weeks (7 days) thereafter, after completion of the 
Week 48 tumor assessment, regardless of treatment delays, until radiographic disease progression per RECIST v1.1, withdrawal of consent, 
death, or study termination by the Sponsor, whichever occurs first. Patients who continue treatment beyond radiographic disease progression 
per RECIST v1.1 will undergo tumor assessments at the frequency described above until study treatment is discontinued.
v If the patient discontinued study treatment for any reason other than radiographic disease progression per RECIST v1.1 (e.g., toxicity, 
symptomatic deterioration), tumor assessments will continue at the same frequency as would have been followed if the patient had remained on 
study treatment (i.e., every 6 weeks [7 days] for 48 weeks following Cycle 1, Day 1 and then every 9 weeks [7 days] thereafter) until 
radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first, 
even if the patient starts another anti-cancer therapy after study treatment discontinuation, unless consent is withdrawn.
w Optional tumor biopsy at radiographic disease progression, if clinically feasible, preferably within 40 days of radiographic progression or prior to 
start of the next anti-cancer therapy, whichever occurs first.
x All serious adverse events and adverse events of special interest, regardless of relationship to study drug, will be reported until 90 days after the 
last dose of study drug or initiation of new systemic anti-cancer therapy after the last dose of study drug, whichever occurs first. All other adverse 
events, regardless of relationship to study drug, will be reported until 30 days after the last dose of study drug or initiation of new systemic anti-
cancer therapy after the last dose of study drug, whichever occurs first. After this period, all deaths should continue to be reported. In addition, 
the Sponsor should be notified if the investigator becomes aware of any serious adverse event or adverse event of special interest that is 
believed to be related to prior exposure to study treatment. These events should be reported through use of the Adverse Event eCRF.
y From 7 days before screening until the treatment discontinuation visit. All such medications should be reported to the investigator and recorded 
on the Concomitant Medications eCRF.


Appendix 1: Schedule of Activities: Dose-Escalation Maintenance Only (Arm A) and Dose-Expansion Maintenance Only (cont.)
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z Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits every 3 months or more frequently 
until death, loss to follow-up, or study termination by the Sponsor, whichever occurs first. All patients will be periodically contacted for survival 
and new anti-cancer therapy information unless the patient requests to be withdrawn from follow-up (this request must be documented in the 
source documents and signed by the investigator). If the patient withdraws from the study, study staff may use a public information source (e.g., 
county records), when permissible, to obtain information about survival status only.












Appendix 2: Schedule of Activities: Dose-Escalation Induction + Maintenance (Arm B) and Dose-Expansion Induction Maintenance
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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b Cycle 1 must be performed within 5 days after the patient is enrolled. Screening assessments performed 96 hours before Cycle 1, Day 1 are 
not required to be repeated for Cycle 1, Day 1. In addition, ECOG performance status, limited physical examination, and local laboratory tests 
may be performed 96 hours before Day 1 of each cycle.
c Day 2, Day 8, and Day 15 assessments are not necessary during the dose-expansion phase, with the exception of PK sampling (refer to
Appendix 4).
d A pre-treatment tumor tissue (archival or freshly obtained) sample should be submitted before or within 4 weeks after enrollment. This specimen 
must be accompanied by the associated pathology report. Although any available tumor tissue sample can be submitted, it is strongly 
encouraged that representative tumor specimens in paraffin blocks (preferred) or 15 (or more) serial, freshly cut, unstained slides be submitted.
e Vital signs include pulse rate, respiratory rate, systolic and diastolic blood pressure, and temperature. Vital signs should be recorded as described
in Section 4.5.4.
f Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.
g ECG recordings will be obtained when clinically indicated.
h Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, lymphocytes, eosinophils,
monocytes, basophils, and other cells), and platelet count.
i At screening, the patient must have adequate hematologic and end-organ function defined by laboratory test results obtained within 14 days prior 
to enrollment.
j Serum chemistry includes BUN or urea, sodium, potassium, magnesium, chloride, bicarbonate or total CO2 if considered standard of care in the 
region, glucose, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin.  
k TLS assessment frequency during the dose-expansion phase will be determined based on a comprehensive review of data in the dose-escalation 
phase. TLS labs include serum creatinine, calcium, phosphorous, uric acid, potassium, and LDH. If the screening assessments were done within 
3 days prior to Cycle 1 Day 1, there is no need to repeat the TLS panel at Cycle 1 Day 1. Refer to Appendix 9 and Appendix 11 for further 
instructions.
l Serum pregnancy test within 14 days before Cycle 1, Day 1.
m Urine pregnancy tests; if a urine pregnancy test result is positive, it must be confirmed by a serum pregnancy test.
n Total T3 will be tested only at sites where free T3 is not performed.
o Thyroid function testing (TSH, free T3, free T4) collected on Day 1 of Cycles 1, 4, 8, and 12, and every fourth cycle thereafter.
p All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the study. Patients with 
active hepatitis B (chronic or acute; defined as having a positive HBsAg test result at screening) will be excluded from the study. Patients with 
past or resolved HBV infection (defined as the presence of HBcAb and absence of HBsAg) are eligible; HBV DNA should be obtained in these 
patients prior to enrollment. Patients with HCV will be excluded from the study; patients who test positive for HCV antibody are eligible only if 
PCR is negative for HCV RNA.
q Urinalysis by dipstick (specific gravity, pH, glucose, protein, ketones, and blood). Urinalysis is required at screening and will be obtained when
clinically indicated.
r For atezolizumab, the initial dose will be administered over 60 (15) minutes. If the first infusion is well tolerated, subsequent infusions may be 
administered over 30 (10) minutes. For carboplatin and etoposide, study drug will be administered as described.


Appendix 2: Schedule of Activities: Dose-Escalation Induction + Maintenance (Arm B) and Dose-Expansion Induction Maintenance
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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s During the maintenance phase, PCI is permitted as per local standard of care and will be reported on the Prophylactic Cranial Irradiation eCRF.
t CT scans (with oral/IV contrast unless contraindicated) or MRI scans of the chest and abdomen. A CT or MRI scan of the pelvis is required at 
screening and as clinically indicated or as per local standard of care at subsequent response evaluations. A CT (with contrast) or MRI scan of the 
head must be done at screening to evaluate CNS metastasis in all patients.
u Perform every 6 weeks (7 days) for 48 weeks following Cycle 1, Day 1 and then every 9 weeks (7 days) thereafter, after completion of the 
Week 48 tumor assessment, regardless of treatment delays, until radiographic disease progression per RECIST v1.1, withdrawal of consent, 
death, or study termination by the Sponsor, whichever occurs first. Patients who continue treatment beyond radiographic disease progression per 
RECIST v1.1 will undergo tumor assessments at the frequency described above until study treatment is discontinued.
v If the patient discontinued study treatment for any reason other than radiographic disease progression per RECIST v1.1 (e.g., toxicity, 
symptomatic deterioration), tumor assessments will continue at the same frequency as would have been followed if the patient had remained on 
study treatment (i.e., every 6 weeks [7 days] for 48 weeks following Cycle 1, Day 1 and then every 9 weeks [7 days] thereafter) until 
radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first, 
even if the patient starts another anti-cancer therapy after study treatment discontinuation, unless consent is withdrawn.
w See Appendix 3, Table 2.
x
Optional tumor biopsy at radiographic disease progression, if clinically feasible, preferably within 40 days of radiographic progression or prior to 
start of the next anti-cancer therapy, whichever occurs is sooner.
y Phone call from the site to the patient to assess adverse events as described in Section 5.2.1. The rationale for this phone call is to characterize 
the impact of and response to treatment, such assessments allow follow-up that is more frequent than the visit, which is every 3 weeks, will be 
useful in management.
z All serious adverse events and adverse events of special interest, regardless of relationship to study drug, will be reported until 90 days after the 
last dose of study drug or initiation of new systemic anti-cancer therapy after the last dose of study drug, whichever occurs first. All other adverse 
events, regardless of relationship to study drug, will be reported until 30 days after the last dose of study drug or initiation of new systemic anti-
cancer therapy after the last dose of study drug, whichever occurs first. After this period, all deaths should continue to be reported. In addition, the 
Sponsor should be notified if the investigator becomes aware of any serious adverse event or adverse event of special interest that is believed to 
be related to prior exposure to study treatment. These events should be reported through use of the Adverse Event eCRF.
aa From 7 days before screening until the treatment discontinuation visit. All such medications should be reported to the investigator and recorded 
on the Concomitant Medications eCRF.
bb Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits every 3 months or more frequently 
until death, loss to follow-up, or study termination by the Sponsor, whichever occurs first. All patients will be periodically contacted for survival and
new anti-cancer therapy information unless the patient requests to be withdrawn from follow-up (this request must be documented in the source 
documents and signed by the investigator). If the patient withdraws from the study, study staff may use a public information source (e.g., county 
records), when permissible, to obtain information about survival status only.
cc On Day 1 of each cycle, patients will receive treatment in the following order: 1) atezolizumab, 2) carboplatin, 3) etoposide, and 4) venetoclax. On 
Days 2 and 3, patients will receive etoposide infusions. Refer to Section 4.3.2 for specific details. Venetoclax is administered QD for 7 or 14 days 
as described in Section 3.1.2.




Appendix 3: Schedule of Pharmacokinetic and Immunogenicity Sampling (cont.)
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Record exact date and time of venetoclax dosing on the day of and the day prior to the date of PK sampling.  Patients should record doses taken at 
home in a dosing diary.
Record the date and time of administration of atezolizumab on the day of PK sampling.
Record exact date and time of all PK sample collections.
Sample collection times are relative to the administration of the study drug being measured.
a Only one sample will be taken at Treatment Discontinuation.  Patients may need to discontinue treatment in either the induction or the 
maintenance phase.  Therefore, this sample appears in both Table 1 and Table 2 of Appendix 3.










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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) 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 clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor 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 positron emission tomography 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 the 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 
used 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 should 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 


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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 CR 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 


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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
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not all evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial 
response; SDstable disease.
Table 2
Criteria for Overall Response at a Single Timepoint:  Patients 
with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a "Non-CR/non-PD" is preferred over "stable disease" for non-target 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some trials; thus, assigning "stable disease" 
when no lesions can be measured is not advised.


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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 
"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.
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.  






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Appendix 7
Preexisting Autoimmune Diseases and Immune Deficiencies
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias where the
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Contact the Medical Monitor regarding any 
uncertainty over autoimmune exclusions.
Autoimmune Diseases and Immune Deficiencies
Acute disseminated
encephalomyelitis
Addison disease
Ankylosing spondylitis
Antiphospholipid antibody
syndrome
Aplastic anemia
Autoimmune hemolytic 
anemia
Autoimmune hepatitis
Autoimmune
hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune 
thrombocytopenic purpura
Behçet disease
Bullous pemphigoid
Chronic fatigue syndrome
Chronic inflammatory
demyelinating
polyneuropathy
Churg-Strauss syndrome
Crohn disease 
Dermatomyositis
Diabetes mellitus type 1
Dysautonomia
Epidermolysis bullosa 
acquisita
Gestational pemphigoid
Giant cell arteritis
Goodpasture syndrome
Grave’s disease
Guillain-Barré syndrome
Hashimoto disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki disease
Lambert-Eaton myasthenia
syndrome
Lupus erythematosus
Lyme disease, chronic
Meniere syndrome
Mooren ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus
syndrome
Optic neuritis
Ord thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodosa
Polyarthritis
Polyglandular autoimmune
syndrome
Primary biliary cirrhosis
Psoriasis
Reiter syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren syndrome
Stiff-Person syndrome
Takayasu arteritis
Ulcerative colitis
Vitiligo
Vogt-Koyanagi-Harada 
disease
Wegener granulomatosis


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Appendix 8
Anaphylaxis Precautions
These guidelines are intended as a reference and should not supersede pertinent local
or institutional standard operating procedures.
REQUIRED EQUIPMENT AND MEDICATION
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion:

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1.
Stop the study treatment infusion.
2.
Call for additional medical assistance.
3.
Maintain an adequate airway.
4.
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible.
5.
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge.
6.
Continue to observe the patient and document observations.


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Appendix 9
Guidelines for Defining Tumor Lysis Syndrome
All tumor lysis syndrome events should be graded per the National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 5.0 criteria.
Howard et al. (2011) defined laboratory tumor lysis syndrome as the presence of two or 
more electrolyte changes above or below the thresholds described above occurring 
during the same 24-hour period within 3 days before the start of therapy or 7 days after 
the start of therapy.  For the purposes of this study, this window applies to the initiation 
of any study therapy and each dose -escalation of venetoclax.  Furthermore, this 
assessment assumes that a patient has or will receive adequate hydration 
(alkalinization) and a hypouricemic agent(s).
Table 1
Howard Definition of Laboratory Tumor Lysis Syndrome
Laboratory Assessment
Range
Uric acid
476 mol/L (8.0 mg/dL)
Potassium
6.0 mmol/L (6.0 mEq/L)
Phosphorous
1.5 mmol/L (4.5 mg/dL)
Corrected calcium
1.75 mmol/L (7.0 mg/dL) or ionized calcium 1.12 (0.3 mmol/L) a
Note:  Howard et al. (2011) defined laboratory tumor lysis syndrome as the presence of two or 
more electrolyte changes above or below the thresholds described above occurring during the 
same 24-hour period within 3 days before the start of therapy or 7 days afterward. For the 
purposes of this study, this window applies to the initiation of any study therapy and each dose
escalation of venetoclax. Furthermore, this assessment assumes that a patient has or will receive
adequate hydration (± alkalization) and a hypouricemic agent(s).
a The corrected calcium level in mg/dL is the measured calcium in mg/dL(0.8[4-albumin in g/dL






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Appendix 11
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome
FIRST DOSE OF VENETOCLAX 

Within the first 24 hours after the first dose, if any laboratory criteria below are met, 
the patient should be hospitalized for monitoring and the investigator notified.  No 
additional venetoclax doses should be administered until resolution.  A rapidly rising 
serum potassium level is a medical emergency. 

Nephrology (or acute dialysis service) must be consulted/contacted on admission
(per institutional standards to ensure emergency dialysis is available). 

Intravenous (IV) fluids (e.g., D5 1/2 normal saline) should be initiated at a rate of at 
least 1 mL/kg/h rounded to the nearest 10 mL (target 150200 mL/hr; 
not 50 mL/hr).  Modification of fluid rate should also be considered for individuals
with specific medical needs. 

Monitor for symptoms or signs of tumor lysis syndrome (e.g., fever, chills, 
tachycardia, nausea, vomiting, diarrhea, diaphoresis, hypotension, muscle aches, 
weakness, paresthesias, mental status changes, confusion, and seizures).  If any 
clinical features are observed, recheck potassium, phosphorus, uric acid, calcium, 
and creatinine within 1 hour STAT. 

Vital signs should be taken at time of all blood draws or any intervention. 

The management recommendations below focus on the minimum initial responses
required.  If a diagnosis of tumor lysis syndrome is established, ongoing intensive 
monitoring and multidisciplinary management will be as per institutional protocols. 
In addition to the recommendations for patients receiving first dose of venetoclax: 

For potassium increase 0.5 mmol/L from baseline, or any value 5.0 mmol/L, 
recheck potassium, phosphorus, uric acid, calcium, and creatinine within 1 hour 
STAT and follow first guideline. 

For phosphorus increase of 0.5 mg/dL AND 4.5 mg/dL, administer phosphate
binder and recheck potassium, phosphorus, uric acid, calcium, and creatinine within 
1 hour STAT. 




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Appendix 13
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
may not have an immediate therapeutic effect, and in severe cases, immune-mediated
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, or other immunosuppressive agents. 
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  In patients who have met 
the criteria for permanent discontinuation, resumption of atezolizumab may be 
considered if the patient is deriving benefit and has fully recovered from the immune-
mediated event.  Patients can be re-challenged with atezolizumab only after approval 
has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor. 
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will have CT scans of the 
chest performed at every tumor assessment.  
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  Management guidelines for pulmonary events are provided in Table 1.


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
Page 193 of 214 Protocol GO41864, Version 2
Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis
Event
Management
Pulmonary 
event, Grade 1 

Continue atezolizumab and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.
Pulmonary 
event, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c

For recurrent events, treat as a Grade 3 or 4 event.
Pulmonary 
event, Grade 3 
or 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Bronchoscopy or BAL is recommended.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
BALbronchoscopic alveolar lavage.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
Page 194 of 214 Protocol GO41864, Version 2
HEPATIC EVENTS
Immune-mediated hepatitis has been associated with the administration of 
atezolizumab.  Eligible patients must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases, and liver function will be 
monitored throughout study treatment.  Management guidelines for hepatic events are 
provided in Table 2.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.
Table 2
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1

Continue atezolizumab.

Monitor LFTs until values resolve to within normal limits or to 
baseline values. 
Hepatic event, 
Grade 2
All events:

Monitor LFTs more frequently until return to baseline values. 
Events of 5 days’ duration:

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
LFTliver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
Page 195 of 214 Protocol GO41864, Version 2
Table 2
Management Guidelines for Hepatic Events (cont.)
Event
Management
Hepatic event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury. 

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
LFTliver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 3.
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
Page 196 of 214 Protocol GO41864, Version 2
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate treatment 
with corticosteroids equivalent to 12 mg/kg/day oral prednisone. 

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Diarrhea or 
colitis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist for evaluation and confirmatory biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
Page 197 of 214 Protocol GO41864, Version 2
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.)
Event
Management
Diarrhea or 
colitis, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Refer patient to GI specialist for evaluation and confirmation biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab.  Management guidelines for 
endocrine events are provided in Table 4.
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., 
TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
MRI of the brain (with detailed pituitary sections) may help to differentiate primary 
pituitary insufficiency from primary adrenal insufficiency.


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
Page 198 of 214 Protocol GO41864, Version 2
Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.
Symptomatic 
hypothyroidism

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.
Asymptomatic 
hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:

Continue atezolizumab.

Monitor TSH every 4 weeks.
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism

Withhold atezolizumab.

Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.

Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-mediated hyperthyroidism.
c
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or
an appropriate delegate) and the Medical Monitor. 


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
Page 199 of 214 Protocol GO41864, Version 2
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Symptomatic adrenal 
insufficiency, 
Grade 24 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform appropriate imaging.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b

If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical 
Monitor. c
Hyperglycemia, 
Grade 1 or 2 

Continue atezolizumab.

Investigate for diabetes.  If patient has Type 1 diabetes, treat 
as a Grade 3 event.  If patient does not have Type 1 diabetes, 
treat as per institutional guidelines.

Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4

Withhold atezolizumab.

Initiate treatment with insulin.

Monitor for glucose control.

Resume atezolizumab when symptoms resolve and glucose 
levels are stable.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or
an appropriate delegate) and the Medical Monitor. 


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
Page 200 of 214 Protocol GO41864, Version 2
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

Initiate hormone replacement if clinically indicated.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c

For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

Initiate hormone replacement if clinically indicated.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
Page 201 of 214 Protocol GO41864, Version 2
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.
Table 5
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 

Continue atezolizumab.

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Ocular event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to ophthalmologist.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone.  

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
Page 202 of 214 Protocol GO41864, Version 2
IMMUNE-MEDIATED MYOCARDITIS
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab.  Immune-mediated myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not limited 
to, laboratory (e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, 
dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from 
infection (commonly viral, e.g., in a patient who reports a recent history of 
gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6.


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
Page 203 of 214 Protocol GO41864, Version 2
Table 6
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated
myocarditis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Consider treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Immune-mediated
myocarditis, Grade 3-4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over1 month.
ECMOextracorporeal membrane oxygenation; VAD ventricular assist device.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
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INFUSION-RELATED REACTIONS
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) with Cycle 1 of 
atezolizumab may receive premedication with antihistamines or antipyretics/analgesics 
(e.g., acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited in 
treating atezolizumab-associated IRRs because of its potential for causing 
agranulocytosis.
Guidelines for medical management of IRRs during Cycle 1 are provided in Table 7.  For 
subsequent cycles, IRRs should be managed according to institutional guidelines.
Table 7
Management Guidelines for Infusion-Related Reactions
Event
Management
IRR, Grade 1 

Reduce infusion rate to half the rate being given at the time of 
event onset.

After the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate.

If the infusion is tolerated at the reduced rate for 30 minutes after 
symptoms have resolved, the infusion rate may be increased to 
the original rate.
IRR, Grade 2

Interrupt atezolizumab infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic medication, glucocorticoids, 
epinephrine, bronchodilators, oxygen, IV fluids).

After symptoms have resolved to baseline, resume infusion at half 
the rate being given at the time of event onset.

For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or analgesics 
and monitor closely for IRRs.
IRR, Grade 3 or 4

Stop infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic medication, glucocorticoids, 
epinephrine, bronchodilators, oxygen, IV fluids).

Permanently discontinue atezolizumab and contact Medical 
Monitor. a
IRRinfusion-related reaction.
a Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
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PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of 
atezolizumab.  The differential diagnosis of acute abdominal pain should include 
pancreatitis.  Appropriate workup should include an evaluation for ductal obstruction, as 
well as serum amylase and lipase tests.  Management guidelines for pancreatic events, 
including pancreatitis, are provided in Table 8.
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase 
elevation, Grade 2
Amylase and/or lipase 1.52.0ULN:

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone.
Asymptomatic with amylase and/or lipase 2.05.0ULN:

Treat as a Grade 3 event.
Amylase and/or lipase 
elevation, Grade 3 or 4

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Monitor amylase and lipase every other day.

If no improvement, consider treatment with corticosteroids 
equivalent to 12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


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Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
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Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-mediated
pancreatitis, Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
Immune-mediated
pancreatitis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
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DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash were mild in severity and self limited, with or without pruritus.  A 
dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy should 
be considered unless contraindicated.  Management guidelines for dermatologic events 
are provided in Table 9.
Table 9
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 

Continue atezolizumab.

Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 

Continue atezolizumab.

Consider patient referral to dermatologist.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if 
event does not improve.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist.

Initiate treatment with corticosteroids equivalent to 10 mg/day 
oral prednisone, increasing dose to 12 mg/kg/day if event does 
not improve within 4872 hours.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Dermatologic 
event, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
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NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic workup is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 10.
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-
mediated
neuropathy, 
Grade 1

Continue atezolizumab.

Investigate etiology.
Immune-
mediated
neuropathy, 
Grade 2 

Withhold atezolizumab for up to 12 weeks after event onset. a

Investigate etiology.

Initiate treatment as per institutional guidelines.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Immune-
mediated
neuropathy, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c 

Initiate treatment as per institutional guidelines.
Myasthenia 
gravis and 
Guillain-Barré
syndrome (any 
grade)

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.

Consider initiation of corticosteroids equivalent to 12 mg/kg/day 
oral or IV prednisone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
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IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-mediated meningoencephalitis should be 
suspected in any patient presenting with signs or symptoms suggestive of meningitis or 
encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, motor 
or sensory dysfunction, and altered or depressed level of consciousness.  
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from 
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or 
progression of malignancy, or secondary to a paraneoplastic process.  
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted.
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 11.
Table 11 Management Guidelines for Immune-Mediated
Meningoencephalitis
Event
Management
Immune-mediated
meningoencephalitis, 
all grades

Permanently discontinue atezolizumab and contact Medical Monitor. a

Refer patient to neurologist.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of 
atezolizumab.  Eligible patients must have adequate renal function.  Renal function, 
including serum creatinine, should be monitored throughout study treatment.  Patients 
with abnormal renal function should be evaluated and treated for other more common 


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etiologies (including prerenal and postrenal causes, and concomitant medications such 
as non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if 
clinically indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment.
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 12.
Table 12 Management Guidelines for Renal Events 
Event
Management
Renal event,
Grade 1

Continue atezolizumab.

Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values.
Renal event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to renal specialist.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Renal event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. 

Refer patient to renal specialist and consider renal biopsy.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
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IMMUNE-MEDIATED MYOSITIS
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13.
Table 13 Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-
mediated 
myositis, Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.
Immune-
mediated 
myositis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
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Table 13 Management Guidelines for Immune-Mediated Myositis (cont.)
Immune-
mediated 
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c

For recurrent events, treat as a Grade 4 event.
Immune-
mediated
myositis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Atezolizumab—F. Hoffmann-La Roche Ltd
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HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS).  
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
–
Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants 4 weeks old)
–
Platelet count 100109/L (100,000/L)
–
ANC 1.0109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard deviations 
above age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count 181109/L (181,000/L)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 14.


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Table 14 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH 
or MAS

Permanently discontinue atezolizumab and contact Medical Monitor.

Consider patient referral to hematologist.

Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines.

Consider initiation of IV corticosteroids and/or an immunosuppressive 
agent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
HLHhemophagocytic lymphohistiocytosis; MASmacrophage activation syndrome.
REFERENCES
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:4819.