Conditions: Multiple Myeloma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 49
Healthy volunteers: no

Brief summary:
This open-label, randomized, multicenter, triple-arm Phase Ib/II study is designed to assess the efficacy, safety, tolerability, and pharmacokinetics of cobimetinib administered as a single agent (Arm A), cobimetinib plus venetoclax (Arm B), and cobimetinib plus venetoclax plus atezolizumab (Arm C) in participants with relapsed and refractory multiple myeloma. Two successive cohorts will evaluate the safety of cobimetinib plus venetoclax and that of cobimetinib plus venetoclax plus atezolizumab in the selected population during the safety run-in phase of the study. Once the dose levels have demonstrated acceptable safety during this phase, randomization will begin for all treatment arms (Arms A, B, and C).

Detailed description:

Arms:
arm 1: Participants will receive the standard single-agent cobimetinib dose of 60 milligrams (mg) (3 tablets of 20 mg each) orally (PO) daily on Days 1-21 of each 28-day cycle until disease progression. Upon progression, participants will be allowed to receive treatment with cobimetinib and atezolizumab at the recommended Phase II dose of cobimetinib 60 mg PO on Days 1-21 plus atezolizumab intravenous (IV) infusion at a fixed dose of 840 mg on Day 1 and Day 15 of each 28-day cycle. Treatment will continue until the participant has disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurs first. arm 2: Participants will receive cobimetinib PO daily on Days 1-21 of each 28-day cycle plus venetoclax PO daily on Days 1-28 of each 28-day cycle, at the dose level identified in the safety run-in phase. Treatment will continue until the participant has disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurs first. arm 3: Participants will receive cobimetinib PO daily on Days 1-21 of each 28-day cycle plus venetoclax PO daily on Days 1-28 of each 28-day cycle, at the dose level identified in the safety run-in phase plus atezolizumab IV infusion at a fixed dose of 840 mg on Day 1 and Day 15 of each 28-day cycle. Treatment will continue until the participant has disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurs first. arm 4: Participants will receive cobimetinib (on Day 1-21) plus venetoclax (on Day 1-28) at escalated doses, in 28-day cycles, to identify the dose level with acceptable safety. arm 5: Participants will receive cobimetinib (on Day 1-21) plus venetoclax (on Day 1-28) at escalated doses and atezolizumab (on Day 1 and Day 15) at a fixed dose of 840 mg IV, in 28-day cycles, to identify the dose level with acceptable safety.

Interventions: intervention 1: Cobimetinib intervention 2: Venetoclax intervention 3: Atezolizumab
Intervention descriptions: intervention 1: Cobimetinib will be administered as per the schedule specified in the respective arm. intervention 2: Venetoclax will be administered as per the schedule specified in the respective arm. intervention 3: Atezolizumab will be administered as per the schedule specified in the respective arm.

Protocol document:
Prot_SAP_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
Protocol BO39813, Version 7
PROTOCOL
TITLE:
A PHASE Ib/II STUDY OF COBIMETINIB 
ADMINISTERED AS SINGLE AGENT AND IN 
COMBINATION WITH VENETOCLAX, WITH OR 
WITHOUT ATEZOLIZUMAB, IN PATIENTS WITH 
RELAPSED AND REFRACTORY MULTIPLE MYELOMA
PROTOCOL NUMBER:
BO39813
VERSION NUMBER:
7
EUDRACT NUMBER:
2017-000830-68
IND NUMBER:
Not applicable
NCT NUMBER:
NCT03312530
TEST PRODUCTS:
Cobimetinib (RO5514041)
Venetoclax (GDC-0199, ABT-199, RO5537382)
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic date stamp below
 
18-Feb-2021 20:55:24
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
2/Protocol BO39813, Version 7
PROTOCOL HISTORY
Protocol
Version
Date Final
7
See electronic date stamp on title page
6
24 January 2020
5
27 March 2019
4
20 September 2018
3
2 March 2018
2
10 August 2017
1
18 April 2017


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
3/Protocol BO39813, Version 7
PROTOCOL AMENDMENT, VERSION 7:
RATIONALE
Protocol BO39813 has been amended to implement changes to align the cobimetinib 
and atezolizumab risk language with the current Cobimetinib Investigator’s Brochure and
Atezolizumab Investigator's Brochures, respectively.  Changes to the protocol, along 
with a rationale for each change, are summarized below:

The list of approved indications for atezolizumab has been updated to include 
hepatocellular carcinoma and melanoma (Section 1.7.1).

Language has been added to clarify the use of investigational medicinal product 
accountability.  Language has been added to indicate that sites can confirm that 
appropriate temperature conditions have been maintained during investigational 
medicinal product transit either by time monitoring (shipment arrival date and time) 
or temperature monitoring (Section 4.3.3).

Immunosuppressive medications have been removed from the prohibited therapy 
section (4.4.5) and added to the cautionary therapy for atezolizumab-treated 
patients section (4.4.2) to align with atezolizumab management guidelines in 
Appendix 7 that permit use of immunosuppressive medications for the treatment of 
corticosteroid-refractory immune-mediated adverse events.

Photosensitivity (when administered with vemurafenib) and pneumonitis have been 
re-added as identified risks associated with cobimetinib (Section 5.1.1.1). 
Additionally, diarrhea classification has been updated to an identified risk associated 
with cobimetinib (Section 5.1.1.1).

The list of identified risks for atezolizumab have been revised to include severe 
cutaneous adverse reactions (SCARs; Section 5.1.3).

Guidelines for the management of atezolizumab-associated dermatologic adverse 
events have been revised to provide guidance SCARs of Stevens-Johnson 
syndrome and toxic epidermal necrolysis in Section 5.1.5.5 (and Table 10) of the 
protocol.

To address a request by the
 
 the management guidelines for infusion-related 
reactions (IRRs) associated with atezolizumab have been updated to include 
guidelines for cytokine release syndrome (CRS) to align with the definition, grading, 
and management of CRS reflected in a recent publication (Lee et al. 2019) 
(Section 5.1.5.15 and Table 4 of Appendix 8).

To address a request by the 
, hemophagocytic lymphohistiocytosis
(HLH) and macrophage activation syndrome (MAS) have replaced systemic 
inflammatory response syndrome on the list of atezolizumab-associated adverse 
events of special interest (Section 5.2.3).  

Language has been added to indicate that the Informed Consent Form will instruct 
female patients to inform the investigator if they become pregnant (Section 5.4.3.1).

Language regarding investigator reporting of pregnancies has been clarified
(Section 5.4.3.2).


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
4/Protocol BO39813, Version 7

The name of a Roche policy on data sharing has been corrected (Section 9.5).

Appendix 7 has been revised to indicate that caution should be used when 
considering atezolizumab for patients who have previously experienced a severe or 
life-threatening skin adverse reaction while receiving another immunostimulatory 
anti-cancer agent.

The adverse event management guidelines for IRR and CRS have been updated to 
ensure COVID-19 is included in the differential diagnosis (Appendix 8).

To address a request by the 
, the management guidelines for HLH 
and MAS have been modified to indicate that HLH should be considered when CRS 
presentation is atypical or prolonged, to add anticytokine therapy as an option for 
treating HLH or MAS, and to suggest that published guidelines should be followed 
for HLH or MAS events that do not respond to treatment within 24 hours 
(Table 10 of Appendix 8).
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.


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
5/Protocol BO39813, Version 7
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14
PROTOCOL SYNOPSIS .................................................................................... 15
1.
BACKGROUND .......................................................................................... 28
1.1
Background on Multiple Myeloma.......................................... 28
1.2
The MAPK Signaling Pathway and Regulation of 
the Immune Tumor Microenvironment................................... 28
1.3
The Anti-Apoptotic Signalling Pathway.................................. 29
1.4
The Programmed T-Cell Death Ligand Pathway ................... 30
1.5
Background on Cobimetinib................................................... 31
1.5.1
Summary of Nonclinical Studies with Cobimetinib................. 31
1.5.2
Summary of Clinical Study with Cobimetinib 
Monotherapy.......................................................................... 31
1.5.2.1
Clinical Pharmacokinetics of Cobimetinib.............................. 33
1.6
Background on Venetoclax.................................................... 34
1.6.1
Summary Nonclinical Studies with Venetoclax...................... 34
1.6.2
Summary of Clinical Data for Venetoclax .............................. 35
1.6.3
Venetoclax Clinical Pharmacology and 
Pharmacokinetics .................................................................. 37
1.6.4
Clinical Safety Data for Venetoclax ....................................... 38
1.7
Background on Atezolizumab................................................ 39
1.7.1
Summary of Nonclinical Studies with 
Atezolizumab......................................................................... 39
1.7.2
Clinical Experience with Atezolizumab 
Monotherapy.......................................................................... 40
1.7.2.1
Ongoing Clinical Studies........................................................ 40
1.7.2.2
Clinical Safety of Atezolizumab ............................................. 40
1.7.3
Atezolizumab Clinical Pharmacology and 
Pharmacokinetics .................................................................. 41
1.7.3.1
Clinical Activity of Atezolizumab ............................................ 42
1.8
Clinical Experience of Cobimetinib Plus 
Atezolizumab......................................................................... 43
1.9
Clinical Data of Cobimetinib Plus Venetoclax........................ 44
1.10
Study Rationale and Benefit–Risk Assessment..................... 45


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6/Protocol BO39813, Version 7
1.10.1
Rationale for Evaluating Cobimetinib in Relapsed 
and Refractory Multiple Myeloma .......................................... 45
1.10.2
Rationale for Evaluating Cobimetinib and 
Venetoclax, and Cobimetinib with Venetoclax 
and Atezolizumab in Relapsed/Refractory 
Multiple Myeloma................................................................... 47
2.
OBJECTIVES AND ENDPOINTS ............................................................... 49
3.
STUDY DESIGN......................................................................................... 51
3.1
Description of the Study......................................................... 51
3.1.1
Overview of the Study Design ............................................... 51
3.1.1.1
Safety Run-In Phase ............................................................. 52
3.1.1.2
Randomization Phase............................................................ 53
3.2
End of Study and Length of Study......................................... 56
3.3
Patient Numbers and Assignment to 
Treatment Groups ................................................................. 56
3.4
Rationale for Study Design.................................................... 56
3.4.1
Rationale for the Triple-Arm Design ...................................... 56
3.4.2
Rationale for the Safety Run-In Phase .................................. 57
3.4.3
Rationale for Cobimetinib Dose and Schedule ...................... 58
3.4.4
Rationale for Venetoclax Dose and Schedule ....................... 58
3.4.5
Rationale for Atezolizumab Dose and Schedule.................... 58
3.4.6
Rationale for Patient Population ............................................ 59
3.4.7
Rationale for Blood and Bone Marrow Sampling 
for Biomarker Assessments................................................... 60
3.4.8
Rationale for Pharmacokinetic Collection .............................. 60
4.
MATERIALS AND METHODS .................................................................... 61
4.1
Patients.................................................................................. 61
4.1.1
Inclusion Criteria.................................................................... 61
4.1.2
Exclusion Criteria................................................................... 62
4.2
Method of Treatment Assignment and Blinding..................... 65
4.3
Study Treatment.................................................................... 65
4.3.1
Formulation, Packaging, and Handling.................................. 66
4.3.1.1
Cobimetinib............................................................................ 66
4.3.1.2
Venetoclax............................................................................. 66


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4.3.1.3
Atezolizumab......................................................................... 66
4.3.2
Dosage, Administration, and Compliance.............................. 66
4.3.2.1
Cobimetinib............................................................................ 66
4.3.2.2
Venetoclax............................................................................. 67
4.3.2.3
Atezolizumab......................................................................... 68
4.3.3
Investigational Medicinal Product Accountability ................... 69
4.3.4
Post-Trial Access to Cobimetinib, Venetoclax, 
and Atezolizumab.................................................................. 70
4.4
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 71
4.4.1
Permitted Therapy................................................................. 71
4.4.2
Cautionary Therapy for Atezolizumab-Treated 
Patients.................................................................................. 72
4.4.3
Cautionary Therapy for Cobimetinib-Treated 
Patients.................................................................................. 72
4.4.4
Cautionary Therapy for Venetoclax-Treated 
Patients.................................................................................. 73
4.4.5
Prohibited Therapy ................................................................ 74
4.5
Study Assessments ............................................................... 75
4.5.1
Informed Consent Forms and Screening Log........................ 75
4.5.2
Medical History and Demographic Data ................................ 75
4.5.3
Physical Examinations........................................................... 76
4.5.4
Vital Signs.............................................................................. 76
4.5.5
Tumor and Response Evaluations......................................... 77
4.5.5.1
Extramedullary Disease......................................................... 79
4.5.5.2
Skeletal Survey...................................................................... 79
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 80
4.5.7
Left Ventricular Ejection Fraction........................................... 84
4.5.8
Electrocardiograms................................................................ 84
4.5.9
Ophthalmic Examination........................................................ 85
4.5.10
Optional Samples for Research Biosample 
Repository ............................................................................. 85
4.5.10.1
Overview of the Research Biosample Repository.................. 85


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
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4.5.10.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 86
4.5.10.3
Sample Collection.................................................................. 86
4.5.10.4
Confidentiality........................................................................ 87
4.5.10.5
Consent to Participate in the Research 
Biosample Repository............................................................ 87
4.5.10.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 87
4.5.10.7
Monitoring and Oversight....................................................... 88
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 88
4.6.1
Study Treatment Discontinuation........................................... 88
4.6.2
Patient Discontinuation from Study........................................ 89
4.6.3
Study Discontinuation............................................................ 89
4.6.4
Site Discontinuation............................................................... 90
5.
ASSESSMENT OF SAFETY....................................................................... 90
5.1
Safety Plan ............................................................................ 91
5.1.1
Risks Associated with Cobimetinib........................................ 91
5.1.1.1
Important Identified Risks Associated with 
Cobimetinib............................................................................ 91
5.1.1.2
Potential Risks Associated with Cobimetinib ......................... 93
5.1.1.3
Other Risks with Cobimetinib................................................. 94
5.1.2
Risks Associated with Venetoclax ......................................... 96
5.1.3
Risks Associated with Atezolizumab ..................................... 98
5.1.4
Anticipated Overlapping Adverse Events for 
Cobimetinib, Venetoclax, and Atezolizumab.......................... 98
5.1.5
Management of Patients Who Experience 
Specific Adverse Events...................................................... 101
5.1.5.1
Cytopenias........................................................................... 102
5.1.5.2
Infections ............................................................................. 103
5.1.5.3
Tumor Lysis Syndrome........................................................ 104
5.1.5.4
Hepatotoxicity...................................................................... 104
5.1.5.5
Dermatologic Toxicity .......................................................... 107
5.1.5.6
CPK Elevations and Rhabdomyolysis.................................. 108
5.1.5.7
Visual Disorders .................................................................. 109


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5.1.5.8
Gastrointestinal Events........................................................ 113
5.1.5.9
Colitis................................................................................... 115
5.1.5.10
Cardiac Adverse Events ...................................................... 117
5.1.5.11
Hemorrhage......................................................................... 119
5.1.5.12
Pancreatitis.......................................................................... 119
5.1.5.13
Pulmonary Events, Including Pneumonitis........................... 120
5.1.5.14
Neurologic Disorders ........................................................... 121
5.1.5.15
Infusion-Related Reactions and Cytokine-
Release Syndrome ............................................................. 121
5.1.5.16
Endocrine Events ................................................................ 121
5.1.5.17
Immune-Mediated Adverse Events...................................... 122
5.1.5.18
Immune-Mediated Myocarditis............................................. 122
5.1.5.19
Immune-Mediated Meningoencephalitis .............................. 122
5.1.5.20
Immune-Mediated Nephritis................................................. 122
5.1.5.21
Other Unspecified Adverse Events...................................... 122
5.1.5.22
Immune-Mediated Myositis.................................................. 125
5.2
Safety Parameters and Definitions ...................................... 125
5.2.1
Adverse Events ................................................................... 125
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 126
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 126
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 128
5.3.1
Adverse Event Reporting Period ......................................... 128
5.3.2
Eliciting Adverse Event Information..................................... 129
5.3.3
Assessment of Severity of Adverse Events ......................... 129
5.3.4
Assessment of Causality of Adverse Events ....................... 129
5.3.5
Procedures for Recording Adverse Events.......................... 130
5.3.5.1
Infusion-Related Reactions.................................................. 130
5.3.5.2
Diagnosis versus Signs and Symptoms............................... 130
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................. 131
5.3.5.4
Persistent or Recurrent Adverse Events.............................. 131


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
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5.3.5.5
Abnormal Laboratory Values ............................................... 131
5.3.5.6
Abnormal Vital Sign Values ................................................. 132
5.3.5.7
Abnormal Liver Function Tests............................................ 133
5.3.5.8
Deaths ................................................................................. 133
5.3.5.9
Preexisting Medical Conditions............................................ 134
5.3.5.10
Lack of Efficacy or Worsening of Multiple 
Myeloma.............................................................................. 134
5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 134
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 135
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 135
5.4.1
Emergency Medical Contacts.............................................. 136
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 136
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 136
5.4.2.2
Events That Occur after Study Drug Initiation...................... 136
5.4.3
Reporting Requirements for Pregnancies............................ 137
5.4.3.1
Pregnancies in Female Patients.......................................... 137
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 137
5.4.3.3
Abortions ............................................................................. 138
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 138
5.5
Follow-Up of Patients after Adverse Events ........................ 138
5.5.1
Investigator Follow-Up......................................................... 138
5.5.2
Sponsor Follow-Up .............................................................. 138
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 139
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 139
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 139
6.1
Determination of Sample Size ............................................. 140
6.2
Summaries of Conduct of Study.......................................... 140
6.3
Summaries of Demographic and Baseline 
Characteristics..................................................................... 141


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6.4
Efficacy Analyses ................................................................ 141
6.4.1
Primary Efficacy Endpoint.................................................... 141
6.4.2
Secondary Efficacy Endpoints............................................. 141
6.4.3
Exploratory Efficacy Endpoints............................................ 141
6.5
Safety Analyses................................................................... 142
6.6
Pharmacokinetic Analyses................................................... 142
6.7
Immunogenicity Analyses.................................................... 143
6.8
Exploratory Biomarker Analyses.......................................... 143
7.
DATA COLLECTION AND MANAGEMENT ............................................. 143
7.1
Data Quality Assurance....................................................... 143
7.2
Electronic Case Report Forms............................................. 144
7.3
Source Data Documentation................................................ 144
7.4
Use of Computerized Systems ............................................ 145
7.5
Retention of Records........................................................... 145
8.
ETHICAL CONSIDERATIONS.................................................................. 145
8.1
Compliance with Laws and Regulations .............................. 145
8.2
Informed Consent................................................................ 146
8.3
Institutional Review Board or Ethics Committee.................. 147
8.4
Confidentiality...................................................................... 147
8.5
Financial Disclosure ............................................................ 148
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 148
9.1
Study Documentation .......................................................... 148
9.2
Protocol Deviations.............................................................. 148
9.3
Site Inspections ................................................................... 148
9.4
Administrative Structure....................................................... 149
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 149
9.6
Protocol Amendments ......................................................... 150
10. REFERENCES ......................................................................................... 151


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
12/Protocol BO39813, Version 7
LIST OF TABLES
Table 1
Summary of Clinical Studies with Venetoclax in Patients with 
Multiple Myeloma........................................................................ 37
Table 2
Objectives and Corresponding Endpoints................................... 49
Table 3
Administration of First and Subsequent Atezolizumab 
Infusions...................................................................................... 69
Table 4
Proposed Non-Inherited Biomarkers for Exploratory 
Research..................................................................................... 83
Table 5
Gastrointestinal Prophylaxis Guidelines...................................... 95
Table 6
Recommended Doses of Cobimetinib in Arm A, Arm B, and 
Arm C........................................................................................ 101
Table 7
Recommended Doses of Venetoclax in Arm B and Arm C ....... 102
Table 8
Recommended Dose Modifications for Hematological 
Toxicities................................................................................... 103
Table 9
Guidelines for the Management of Hepatotoxicity..................... 105
Table 10
Guidelines for the Management of Dermatologic Events .......... 107
Table 11
Guidelines for the Management of Grade 3 or Higher 
Elevations in CPK and Rhabdomyolysis ................................... 109
Table 12
National Cancer Institute Common Terminology Criteria for 
Adverse Events v4.0 Eye DisordersOther, Specify ............... 110
Table 13
Guidelines for Managing Ocular Toxicity .................................. 111
Table 14
Guidelines for Managing Gastrointestinal Toxicity .................... 113
Table 15
Guidelines for the Management of Atezolizumab-Induced 
Colitis ........................................................................................ 115
Table 16
Guidelines for the Management of Congestive Heart 
Failure/Reduction in Left Ventricular Ejection Fraction ............. 118
Table 17
Guidelines for the Management of Hemorrhage ....................... 119
Table 18
Guidelines for Managing Pulmonary Events, Including 
Pneumonitis .............................................................................. 120
Table 19
Dose Modifications Recommendations for Cobimetinib............ 123
Table 20
Guidelines for the Management of Unspecified Related 
Adverse Events Grade 3 or Higher Other Than Laboratory 
Abnormalities ............................................................................ 124
Table 21
Guidelines for Grade 3 and Higher Unspecified Laboratory 
Abnormality Adverse Events..................................................... 125
Table 22
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 129
LIST OF FIGURES
Figure 1
Study Design Schema ................................................................ 51


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
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LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 156
Appendix 2
Schedule of Pharmacokinetic and Immunogenicity Samples.... 162
Appendix 3
Guidelines for the Determination of Prior Lines of Therapy ...... 164
Appendix 4
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 165
Appendix 5
International Myeloma Working Group Uniform Response 
Criteria (2016)........................................................................... 166
Appendix 6
Anaphylaxis Precautions........................................................... 169
Appendix 7
Preexisting Autoimmune Diseases and Immune Deficiencies... 170
Appendix 8
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 171


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
14/Protocol BO39813, Version 7
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE Ib/II STUDY OF COBIMETINIB 
ADMINISTERED AS SINGLE AGENT AND IN 
COMBINATION WITH VENETOCLAX, WITH OR 
WITHOUT ATEZOLIZUMAB, IN PATIENTS WITH 
RELAPSED AND REFRACTORY MULTIPLE MYELOMA
PROTOCOL NUMBER:
BO39813
VERSION NUMBER:
7
EUDRACT NUMBER:
2017-000830-68
IND NUMBER:
Not applicable
NCT NUMBER:
NCT03312530
TEST PRODUCTS:
Cobimetinib (RO5514041)
Venetoclax (GDC-0199, ABT-199, 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 to the Sponsor or their designee.


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
15/Protocol BO39813, Version 7
PROTOCOL SYNOPSIS
TITLE:
A PHASE Ib/II STUDY OF COBIMETINIB ADMINISTERED AS 
SINGLE AGENT AND IN COMBINATION WITH VENETOCLAX, 
WITH OR WITHOUT ATEZOLIZUMAB, IN PATIENTS WITH 
RELAPSED AND REFRACTORY MULTIPLE MYELOMA
PROTOCOL NUMBER:
BO39813
VERSION NUMBER:
7
EUDRACT NUMBER:
2017-000830-68
IND NUMBER:
Not applicable
NCT NUMBER:
NCT03312530
TEST PRODUCT:
Cobimetinib (RO5514041)
Venetoclax (GDC-0199, ABT-199, RO5537382)
Atezolizumab (RO5541267)
PHASE:
Phase Ib/II
INDICATION:
Multiple Myeloma
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will assess the efficacy, safety, tolerability, and pharmacokinetics of cobimetinib 
administered as a single agent, cobimetinib plus venetoclax, and cobimetinib plus venetoclax 
plus atezolizumab in patients with relapsed and refractory multiple myeloma (R/R MM).  Specific 
objectives and corresponding endpoints are outlined below.
Primary Objective
Corresponding Endpoints
To evaluate the preliminary safety and 
tolerability and the preliminary efficacy of 
cobimetinib administered as single agent 
(Arm A), cobimetinibvenetoclax (Arm B), 
and cobimetinib venetoclax 
atezolizumab (Arm C)
Incidence, nature, and severity of adverse events, 
graded according to NCI CTCAE, v4.0; laboratory data
ORR (sCR, CR, VGPR, PR) as determined by the 
investigator using the IMWG response criteria in the 
safety population and biomarker-selected population
Secondary Efficacy Objective
Corresponding Endpoints
To further evaluate the efficacy of 
cobimetinib administered as single agent 
(Arm A), cobimetinibvenetoclax (Arm B), 
and cobimetinibvenetoclax 
atezolizumab (Arm C)
CBR defined as MR or better
PFS defined as the time from randomization to the first 
occurrence of disease progression or relapse as 
determined by the investigator using the IMWG criteria 
or death from any cause during the study, whichever 
occurs first
DOR applies to patients achieving at least a PR, and 
is measured from the first observation of PR to the 
time of disease progression; deaths not due to 
progression will be censored
OS defined as the time from randomization until death 
from any cause


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Exploratory Efficacy Objective
Corresponding Endpoint
To evaluate the time elapsed before 
requiring the start of further anti-myeloma 
treatment 
Time to next treatment defined as the time between 
the start date of the current treatment line and the start 
date of the next treatment line, death or last follow-up
Pharmacokinetic Objective
Corresponding Endpoints
To characterize the pharmacokinetics of 
cobimetinib (Arm A), to characterize the 
pharmacokinetics of cobimetinib and 
venetoclax when administered together 
(Arm B), and to characterize the 
pharmacokinetics of cobimetinib, 
venetoclax, and atezolizumab when 
administered together (Arm C)
Plasma concentration of cobimetinib and venetoclax 
at specified timepoints
Serum concentration of atezolizumab at specified 
timepoints
Immunogenicity Objective
Corresponding Endpoint
To evaluate the immune response to 
atezolizumab administered in Arm C
Incidence of ADAs during the study relative to the 
prevalence of ADAs at baseline
Exploratory Immunogenicity Objective
Corresponding Endpoint
To evaluate the potential effects of ADAs
Correlation between ADA status and efficacy, safety, 
or PK endpoints
Exploratory Biomarker Objectives
Corresponding Endpoints
To identify biomarkers that are predictive 
of response to cobimetinib, venetoclax, 
and atezolizumab, such as RAS 
mutation, t(11;14) translocation, Bcl-2 
family proteins, and pretreatment 
immune contexture
Identification and profiling of biomarkers 
associated with disease biology; the 
mechanisms of action of cobimetinib 
alone (Arm A), cobimetinib venetoclax 
(Arm B), or cobimetinib venetoclax 
atezolizumab (Arm C); mechanism of 
resistance to drugs in all the arms; 
pharmacodynamics; prognosis and 
improvement of diagnostic assays 
Determine impact of MRD 
measurements with patient response and 
survival
The effect of treatment with cobimetinib, venetoclax, 
and atezolizumab on markers of MAPK pathway 
activity, apoptosis, immune infiltration and activation 
Determine impact of MRD measurements with 
patient responses and survival
Relationship between biomarkers in blood and bone 
marrow (may include somatic mutations) and 
efficacy, safety, pharmacokinetics, immunogenicity, 
or other biomarker endpoints.
ADAanti-drug antibody; CBRclinical benefit rate; CRcomplete response; DORduration of 
response; IMWG International Myeloma Working Group; MAPK mitogen-activated protein 
kinase; MRminimal response; MRDminimal residual disease; NCI CTCAE v4.0 National
Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0; ORRoverall
response rate; OSoverall survival; PFS progression-free survival; PKpharmacokinetic; 
PRpartial response; sCR stringent complete response; VGPRvery good partial response.
Study Design
Description of Study
This is an open-label, randomized, multicenter, triple-arm Phase Ib/II study designed to assess 
the efficacy, safety, tolerability, and pharmacokinetics of cobimetinib administered as a single 
agent (Arm A), cobimetinib plus venetoclax (Arm B), and cobimetinib plus venetoclax plus 
atezolizumab (Arm C) in patients with R/R MM. 
Two successive cohorts will evaluate the safety of cobimetinib plus venetoclax (n 6) and that 
of cobimetinib plus venetoclax plus atezolizumab (n 6) in the selected population during the 


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safety run-in phase of the study.  Once the dose levels have demonstrated acceptable safety 
during this phase, randomization will begin for all treatment arms (Arms A, B, and C).
Safety Run-In Phase
Cobimetinib plus Venetoclax Safety Run-In Cohort
The cobimetinib plus venetoclax safety run-in cohort will enroll 6 patients with a starting dose of 
cobimetinib 40 mg orally (PO) daily on Days 121, plus venetoclax 800 mg PO daily on 
Days 128 of each 28-day cycle.  This combination is currently being evaluated in an ongoing 
Phase Ib/II study (Study GH29914, a multi-arm study with venetoclax in combination with 
cobimetinib and venetoclax in combination with idasanutlin in patients aged 60 years with R/R 
acute myeloid leukemia (AML) who are not eligible for cytotoxic therapy). In that study, 
cobimetinib 40 mg plus escalating doses of venetoclax (400, 600, and 800 mg) have been 
explored as part of the dose-escalation phase.
The study team will evaluate the safety and tolerability data from the first cycle of treatment for 
patients in the cobimetinib plus venetoclax safety run-in cohort in accordance with the following 
rules:

If 2 of 6 (33%) evaluable patients experience a dose-limiting toxicity (DLT), cobimetinib 
40 mg plus venetoclax 800 mg will be considered to have acceptable safety.

If 2 of 6 (33%) evaluable patients experience a DLT, then one or more sequential 
cohorts of 6 additional evaluable patients will be enrolled and treated with cobimetinib 
40 mg plus lower doses of venetoclax (600 mg 400 mg 200 mg) until 2 of 
6 evaluable patients experience a DLT.
This same approach with respect to the management of patients treated with cobimetinib 40 mg 
plus venetoclax 800 mg will be used for the evaluation of cohorts of patients treated with 
cobimetinib at 40 mg and lower doses of venetoclax at (600 mg 400 mg 200 mg).  If the 
dose of venetoclax reaches 200 mg, then if necessary, the dose of cobimetinib may be reduced 
to a final dose of 20 mg.  After the last patient has been enrolled and completed the DLT period 
in the safety run-in cohort of the cobimetinib plus venetoclax combination, patient enrolment in 
the cobimetinib plus venetoclax plus atezolizumab safety run-in cohort can start provided that 
the treatment is considered to have acceptable safety.
Cobimetinib plus Venetoclax plus Atezolizumab Safety Run-In Cohort
Once the dose level of cobimetinib plus venetoclax is considered safe in the safety run-in 
cohort, a cohort of 6 evaluable patients will then be treated with cobimetinib plus venetoclax 
plus atezolizumab.  Cobimetinib PO and venetoclax PO will be administered at the selected 
dose for the randomization phase of the study with atezolizumab IV at the fixed dose of 840 mg 
on Day 1 and Day 15 (3 days) of each 28-day cycle (note: Cycle 1 of the safety run-in phase 
does not include the 3-day window).  For this cohort, a staggered design will be adopted for the 
first 3 patients.  One patient will be enrolled and dosed in the initial dose cohort.  Afterwards, 
patients will be enrolled sequentially once the prior patient has completed the first cycle with an 
acceptable safety.  If no DLTs are observed in the first 3 patients, 3 more patients will be 
enrolled simultaneously.  If a DLT is observed in 1 of the first 3 patients, the following 3 patients 
will be enrolled consecutively after the completion of the first cycle of the prior patient.
Once the last patient has completed the first cycle of therapy, patient enrollment will be put on 
hold until the study team has completed the evaluation of the safety and tolerability data of the 
cobimetinib plus venetoclax plus atezolizumab safety run-in phase of the study in accordance 
with the following rules:

Cobimetinib plus venetoclax plus atezolizumab will be considered safe if 2 evaluable 
patients experience a DLT during the first cycle of treatment.

If 2 of 6 (33%) evaluable patients experience a DLT, then one or more sequential 
cohorts of 6 additional evaluable patients will be enrolled and treated with cobimetinib 
40 mg plus lower doses of venetoclax (600 mg 400 mg 200 mg) until 2 of 
6 evaluable patients experience a DLT.


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
If 2 of 6 (33%) evaluable patients experience a DLT with the new lower dose level, this 
would be the selected dose for the randomization phase of the study.

If 2 of 6 (33%) evaluable patients experience a DLT, 6 additional patients will be 
enrolled and assessed for DLTs at lower dose levels. 
For initial dose reductions at the starting dose, cobimetinib and atezolizumab will remain fixed 
with dose reductions for venetoclax if needed in sequential decrements of 200 mg. If the dose 
of venetoclax reaches 200 mg, then if needed, the dose of cobimetinib may be reduced from the 
starting dose of 40 mg to a final dose of 20 mg.  
Definition of Evaluable Patients in the Safety Run-In Cohorts 
During the safety run-in phase of the study, patients will be evaluable if they have completed 
at least 70% of the protocol-planned dose for each individual drug.  If a significant decrease 
(70%) in the intended relative dose intensity is due to safety reasons, the toxicity will be 
considered a DLT.  If the significant decrease (70%) in the intended relative dose intensity is 
due to unrelated adverse events or to progressive disease (PD), then the patient will be 
replaced.
An interim analysis for safety will be performed prior to the randomization phase to assess data 
from all safety run-in cohorts.  The analysis will assess the DLTs during the DLT period and the 
tolerability of the study treatments for patients who have received more than one cycle of study 
therapy.  The interim analysis will be completed after the last evaluable patient in Arm C (triplet 
regimen) has concluded the first cycle. 
Randomization Phase
After the safety run-in phase and prior to patient randomization (1:2:2 for Arms A:B:C), a 
biomarker assessment for the translocation t(11;14) will be performed to allow randomization of 
a representative MM population and to ensure that approximately 20% of patients in each arm 
have MM with a t(11;14).  See the protocol for patient assignment to study arms. 
Approximately 12 patients will be randomized to the cobimetinib single-agent arm (Arm A) and 
will receive the standard single-agent cobimetinib dose of 60 mg PO daily on Days 121 of each 
28-day cycle.  Upon progression, patients will be allowed to receive treatment with cobimetinib 
and atezolizumab at the recommended Phase II dose of cobimetinib 60 mg PO from Day 1 to 
Day 21 plus atezolizumab IV at a fixed dose of 840 mg on Day 1 and Day 15 (3 days) of each 
28-day cycle.  This combination at the above-indicated doses is currently being explored in 
multiple clinical studies including a Phase III clinical trial in patients with metastatic colorectal 
cancer (CRC; Study GO30182).
Arm B (cobimetinib plus venetoclax) will randomize approximately 24 patients to receive 
cobimetinib plus venetoclax at the dose level identified in the safety run-in phase.
Arm C will randomize approximately 24 patients to receive cobimetinib plus venetoclax at the 
dose level identified in the safety run-in phase plus atezolizumab IV at a fixed dose of 840 mg 
on Day 1 and Day 15 (3 days) of each 28-day cycle.
The study drugs will be administered on 28-day cycles as follows: 
Arm A:  Cobimetinib

Cobimetinib 60 mg PO daily on Days 121 

Upon progression, patients in Arm A are allowed to receive treatment with:

Cobimetinib 60 mg PO daily on Days 121

Atezolizumab 840 mg IV infusion on Day 1 and Day 15 (3 days)
Arm B:  Cobimetinib Venetoclax  

Cobimetinib 40 mg PO daily on Days 121

Venetoclax 800 mg PO daily on Days 128
Arm C:  Cobimetinib Venetoclax Atezolizumab

Cobimetinib (dose to be determined in Arm B) PO daily on Days 121

Venetoclax (dose to be determined in Arm B) PO daily on Days 128

Atezolizumab 840 mg IV on Day 1 and Day 15 (3 days)


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Treatment will continue until the patient has disease progression as defined by the International 
Myeloma Working Group (IMWG) consensus criteria, unacceptable toxicity, death, patient or 
physician decision to withdraw, or pregnancy, whichever occurs first.
All patients will be closely monitored for safety and tolerability during all cycles of therapy, at the 
treatment discontinuation visit, and during the follow-up period.  A treatment discontinuation visit 
will take place within 30 (7) days after the last dose of study drug.  After PD and study 
treatment discontinuation, the required follow-up information will be collected via telephone calls 
and/or clinic visits every 3 months until death, withdrawal of consent, the patient is lost to 
follow-up, or study termination by the Sponsor, whichever occurs first. 
Any toxicity associated with, or possibly associated with cobimetinib and/or venetoclax 
administration should be managed with supportive care and/or dose interruptions (maximum 
allowable length of treatment interruption is 28 days) and/or dose reductions.  If the investigator 
considers that the patient could derive clinical benefit from the study treatment after an 
interruption longer than 28 days, study treatment may continue after discussion with the Medical 
Monitor.  Toxicity due to atezolizumab administration will be managed by supportive care and/or 
dose interruptions.  No dose modification of atezolizumab is allowed in this study.
A DLT will be defined as any of the following adverse events related to study treatment 
occurring during the DLT period which corresponds to the first cycle of study treatment 
(from Cycle 1 Day 1 to Cycle 1 Day 28):

Any treatment-related death

Grade 4 hematologic toxicity lasting 7 days or higher (except leukopenia or lymphopenia)

Treatment-related non-hematologic toxicity Grade 3 (according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 4.0 [NCI CTCAE v4.0]) 
except for the following:

Grade 3 fatigue, asthenia, fever, anorexia, or constipation

Grade 3 nausea, vomiting, or diarrhea that responds to maximal supportive care within 
72 hours 

Grade 3 rash that resolves to Grade 1 within 7 days with maximal supportive care

Grade 3 laboratory abnormality that is asymptomatic and deemed to be not clinically 
significant by the investigator

A patient who receives less than 70% of the protocol-planned dose for each individual drug 
due to drug-related toxicity
If any of the DLT toxicities occur and are assessed as related to study treatment by the 
investigator, the study treatment will be halted immediately for the individual patient, and a 
thorough investigation and safety analysis will be conducted.
NCI CTCAE v4.0 will be used to characterize the toxicity profile of the study treatments on all 
patients.
Anti-myeloma response will be evaluated according to IMWG criteria.  Disease evaluations will 
include biochemical disease assessments, skeletal survey, bone marrow aspirate, and biopsy.  
Investigators will assess anti-myeloma response every cycle, regardless of any dose delays.  
Patients who discontinue treatment for reasons other than disease progression (e.g., for 
toxicity) will continue to have tumor assessments as scheduled until confirmed disease 
progression per IMWG criteria, withdrawal of consent, initiation of a new anti-cancer therapy, 
study termination by the Sponsor, or death, whichever occurs first.
Number of Patients
Approximately 72 patients with R/R MM (across the three arms) will be recruited into this study, 
from approximately 25 centers worldwide.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years


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
Able to comply with the study protocol, in the investigator’s judgment

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2

Life expectancy of at least 12 weeks

Documented MM as defined by the below criteria:

Monoclonal plasma cells in the bone marrow 10% or presence of a biopsy-proven 
plasmacytoma

Measurable disease as defined by any of the following: 
Serum M-protein level 1.0 g/dL or urine monoclonal protein (M-protein) level 
200 mg/24 hours; or 
Light chain MM:  Serum Ig free light chain (FLC) 10 mg/dL and abnormal serum 
Ig kappa/lambda FLC ratio

Received 3 to 5 prior lines of therapy for MM, including a proteasome inhibitor (PI) and an 
immunomodulatory drug (IMiD)

A line of therapy consists of 1 complete cycle of a single agent, a regimen consisting 
of a combination of several drugs, or a planned sequential therapy of various drugs 
(e.g., induction therapy followed by stem cell transplantation [SCT] is considered 1 line 
of therapy) 

Achieved a response (minimal response [MR] or better) to at least one prior regimen

Documented evidence of PD (as defined by the IMWG criteria) on or after their last prior 
therapy, or patients who were intolerant to their last prior therapy
Note:  There is no required time period between last prior therapy and 
documented evidence of PD.

Toxicities resulting from previous therapy (including peripheral neuropathy) that must be 
resolved or stabilized to Grade 1

Laboratory values as follows:

Hemoglobin level 7.5 g/dL (5 mmol/L) (without growth factor support)

Platelet count 50,000/mm3 or 30,000 if bone marrow plasma cell 50% (without 
transfusion support)

Absolute neutrophil count 1000/mm3 (without growth factor support)

AST and ALT 2.5 the upper limit of normal (ULN)

Total bilirubin 1.5 ULN

Adequate renal function as demonstrated by a calculated creatinine clearance of 
40 mL/min; determined via urine collection for 24-hour creatinine clearance or by the 
Cockcroft-Gault formula 

For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two contraceptive measures, and agreement to refrain 
from donating eggs, as defined below:

A woman is considered to be of childbearing potential if she is post-menarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).

Women must remain abstinent or use two contraceptive methods with a failure rate of 
1% per year during the treatment period and for at least 3 months after the final dose 
of cobimetinib, 1 month after the final dose of venetoclax, and 5 months after the final 
dose of atezolizumab.  Women must refrain from donating eggs 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, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception.


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
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.

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 female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 3 months 
after the last dose of cobimetinib 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, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Anti-myeloma treatment within 14 days or 5 pharmacokinetic (PK) half-lives of the 
treatment, whichever is longer, before the date of randomization

Completion of autologous stem cell transplant within 100 days prior to the date of 
randomization

Prior allogeneic stem cell transplant as well as prior solid organ transplant

Spinal cord compression not definitively treated with surgery and/or radiation

Prior treatment with MEK inhibitors, Bcl-2 inhibitors, or immune checkpoint inhibitor 
therapies including antiCTLA-4, antiPD-1 or antiPD-L1

Treatment with systemic immunostimulatory agents (including, but not limited to, CD137 
agonists or interferon and interleukin 2) within 28 days or 5 half-lives of the drug (whichever 
is longer) prior to initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-
TNFagents) within 14 days prior to initiation of study treatment, or anticipation of need 
for systemic immunosuppressive medication during the course of the study, with the 
following exceptions:

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 
approval has been obtained. 

Surgical procedure (including open biopsy, surgical resection, or any other major surgery) 
or significant traumatic injury within 28 days prior to enrollment, or anticipation of need for 
major surgical procedure during the course of the study

Prior radiation therapy within 14 days prior to study enrollment and/or persistence of 
radiation-related adverse effects

Minor surgical procedure within 7 days (including placement of a vascular access device)

History or evidence of retinal pathology on ophthalmic examination that is considered a risk 
factor for neurosensory retinal detachment/central serous chorioretinopathy, retinal vein 
occlusion (RVO), or neovascular macular degeneration:

History of serous retinopathy

History of RVO

Evidence of ongoing serous retinopathy or RVO at baseline

Left ventricular ejection fraction below institutional lower limit of normal

History of clinically significant cardiovascular dysfunction including the following:

Inadequately controlled hypertension (defined as systolic blood pressure 150 mmHg 
and/or diastolic blood pressure 100 mmHg that is treated or untreated)


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
Prior history of hypertensive crisis or hypertensive encephalopathy

Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
arterial thrombosis) within 6 months of study enrollment 

History of stroke or transient ischemic attack within 6 months prior to enrollment

History of myocardial infarction within 6 months prior to first dose of study drug in 
Cycle 1

New York Heart Association Class III or IV cardiac disease

Unstable arrhythmias, or unstable angina 

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Any previous venous thromboembolism Grade3 within 12 months of study enrollment

INR 1.5 and aPTT 1.5 upper limit of normal within 7 days prior to study enrollment

History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of 
bleeding

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins (for patients in Arm C only)

History of other malignancy that could affect compliance with the protocol or interpretation 
of results

Patients with a history of curatively treated basal or squamous cell carcinoma of the 
skin or in situ carcinoma of the cervix are allowed.

Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, or multiple 
sclerosis (see the protocol for a more comprehensive list of autoimmune diseases and 
immune deficiencies), with the following exceptions:

Patients with a history of autoimmune-related hypothyroidism who are on thyroid 
replacement hormone are eligible for the study.

Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for the study.

Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met:
Rash must cover 10% of body surface area.
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids
There is no occurrence of acute exacerbations of the underlying condition 
requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the 
previous 12 months

Uncontrolled serious medical or psychiatric illness

History of malabsorption or other condition that would interfere with absorption of study 
drugs

Active tuberculosis

Severe infection within 28 days prior to initiation of study treatment, including, but not 
limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia

Treatment with therapeutic oral or IV antibiotics within 14 days prior to initiation of study 
treatment


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
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study. 

Positive test results for hepatitis B (hepatitis B surface antigen and/or total hepatitis B core 
antibody [HBcAb]) or hepatitis C virus (HCV) antibody

Patients positive for HBcAb are eligible only if polymerase chain reaction (PCR) is 
negative for hepatitis B virus DNA.

Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.

Known history of HIV seropositivity

Treatment with a live, attenuated influenza vaccine (e.g., FluMist) within 28 days  prior to 
Cycle 1 Day 1, at any time during the study, and for at least 5 months after the last dose of 
study drug (for patients in Arm C only)

Received strong CYP3A inhibitors (such as ketoconazole and clarithromycin), moderate 
CYP3A inhibitors (such as fluconazole, ciprofloxacin, and verapamil) strong CYP3A 
inducers (such as carbamazepine and phenytoin), and moderate CYP3A inducers (such as 
efavirenz, modafinil) within 7 days prior to the initiation of study treatment

The following foods/supplements are prohibited at least 7 days prior to initiation of and 
during study treatment:

St John’s wort or hyperforin (potent CYP3A enzyme inducer)

Grapefruit juice (potent CYP3A enzyme inhibitor)

Pregnant or lactating, or intending to become pregnant during the study

Women of childbearing potential must have a negative serum pregnancy test within 
7 days prior to initiation of study drug
End of Study
The end of this study is defined as when all patients randomized have been followed until death, 
withdrawal of consent, lost to follow-up, or the Sponsor decides to end the trial, whichever 
occurs first.
Length of Study
The total length of the study, from first patient in until end of follow-up, is expected to be 
approximately 24 months.
Investigational Medicinal Products
Test Products (Investigational Drugs)
The investigational medicinal products for this study are cobimetinib, venetoclax, and 
atezolizumab.
Cobimetinib will be supplied by the Sponsor as tablets.  The 20-mg cobimetinib drug product is 
a film-coated, white, round, immediate-release tablet.  Cobimetinib will be packaged in blister 
packs.  Cobimetinib should not be stored above 25°C (77°F).  If the study drug is stored outside 
of the permitted temperature ranges, quarantine the affected supply and contact the study 
monitor.
Venetoclax (GDC-0199/ABT-0199) is manufactured by AbbVie, Inc. and will be supplied by the 
Sponsor as oral film-coated tablets of 100-mg strength.  Venetoclax tablets will be packaged in 
high-density polyethylene plastic bottles to accommodate the study design.  Venetoclax tablets 
must be stored at 15°C25°C (59°F77°F). 
Atezolizumab will be supplied by the Sponsor as sterile liquid in 20-mL glass vials.  The vial is 
designed to deliver 20 mL (1200 mg) of atezolizumab solution, but may contain more than the 
stated volume to enable delivery of the entire 20 mL volume.  Extraction of 14 mL of 
atezolizumab solution from a 1200 mg per vial contains 840-mg dose.


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Statistical Methods
Primary Analysis
The primary efficacy objective of this study is to evaluate the anti-myeloma activity of 
cobimetinib administered as a single agent (Arm A), cobimetinib in combination with venetoclax 
(Arm B), and cobimetinib in combination with venetoclax and atezolizumab (Arm C) based on 
the overall response rate (ORR) as determined by the investigator using the IMWG response 
criteria.  ORR is defined as a stringent complete response, complete response, very good 
partial response, or partial response and will be analyzed in the efficacy population and in 
biomarker-selected sub-populations (e.g., MAPK activation, t[11;14]).  For Arm A, ORR will also 
be analyzed separately in the cobimetinib single-agent arm and for those patients who are 
treated with cobimetinib plus atezolizumab upon disease progression.
Descriptive statistics will be used to evaluate the incidence, nature and severity of adverse 
events, graded according to the NCI CTCAE v4.0.
Determination of Sample Size
Design considerations were not made with regard to power or to control the type I error, but to 
obtain preliminary efficacy, safety, tolerability, and PK information of cobimetinib as a single 
agent (Arm A), cobimetinib plus venetoclax (Arm B), and cobimetinib plus venetoclax plus 
atezolizumab (Arm C) in patients with R/R MM.
Approximately 72 patients are anticipated to be recruited in this study:  approximately 
12 patients in the safety run-in cohorts, 12 patients in Arm A, 24 patients in Arm B, and 
24 patients in Arm C. 
If patients must be replaced or additional cohorts are enrolled during the safety run-in, the total 
sample size for this study may increase and the study team may enroll 6 additional patients 
(in each safety run-in cohort, if necessary) at a reduced dose level.  Depending on the outcome 
of the review of the clinical data from the additional 6 patients, the study team will determine if 
the expansion stage can initiate with this lower combination dose.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
14/14
14 days on/14 days off
21/7
21 days on/7 days off
ACTH
adrenocorticotropic hormone
ADA
anti-drug antibody, also known as anti-therapeutic 
antibody (ATA)
ALP
alkaline phosphatase
AML
acute myeloid leukemia
AUC
area under the concentration–time curve
BCRP
breast cancer resistance protein
BH
Bcl-2 homologue
BOR
best overall response
CL
clearance
CLL
chronic lymphocytic leukemia
Cmax
maximum observed concentration at steady state
Cmin
minimum concentration under steady-state conditions 
within a dosing interval
CR
complete response
CRC
colorectal cancer
CT
computed tomography
Ctrough
target trough concentration
DLT
dose-limiting toxicity
DOR
duration of response
EC
Ethics Committee
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
ERK
extracellular signal-regulated kinase
FDA
(U.S. ) Food and Drug Administration
FISH
fluorescence in situ hybridization
FLC
free light chain
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


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Abbreviation
Definition
HLH
hemophagocytic lymphohistiocytosis
IC
immune cell
ICH
International Council for Harmonisation
IL-2
interleukin 2
IMiD
immunomodulatory drug 
IMP
investigational medicinal product
IMWG
International Myeloma Working Group
IND
Investigational New Drug (application)
IRB
Institutional Review Board
IRR
infusion-related reaction
Ki
inhibitor constant
LFT
liver function test
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MAPK
mitogen-activated protein kinase
MAS
macrophage activation syndrome
MHC
major histocompatibility complex
MM
multiple myeloma
M-protein
monoclonal protein
MR
minimal response
MRD
minimal residual disease
MRI
magnetic resonance imaging
MTD
maximum-tolerated dose
mUC
metastatic urothelial carcinoma
MUGA
multiple-gated acquisition (scan)
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
NGS
next-generation sequencing
NHL
non-Hodgkin lymphoma
NSCLC
nonsmall cell lung cancer
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival


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Abbreviation
Definition
Pgp
P-glycoprotein 1
PI
proteasome inhibitor
PK
pharmacokinetic
PO
oral
popPK
population pharmacokinetics
PR
partial response
Q2W
every 2 weeks
Q3W
every 3 weeks
QD
once per day
RBR
Research Biosample Repository
R/R
relapsed and refractory
RVO
retinal vein occlusion
sCR
stringent complete response
SCT
stem cell transplant
SD
stable disease
sFLC
serum free light chain
SIFE
serum immunofixation electrophoresis
SLL
small lymphocytic leukemia
SPEP
serum protein electrophoresis
t1/2
elimination half-life
T4
thyroxine
T3
triiodothyronine
TC
tumor cell
TGF
transforming growth factor-β
TIL
tumor-infiltrating lymphocyte
TLS
tumor lysis syndrome
Tregs
T regulatory cells 
TSH
thyroid-stimulating hormone
UC
urothelial carcinoma
UIFE
urine immunofixation electrophoresis
ULN
upper limit of normal
UPEP
urine protein electrophoresis
VGPR
very good partial response
Vss
volume of distribution under steady-state conditions
WES
whole exome sequencing
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON MULTIPLE MYELOMA
Multiple myeloma (MM) is a B-cell neoplasm characterized by the clonal expansion of 
malignant plasma cells in the bone marrow leading often to an excessive production of 
monoclonal proteins (M-proteins). The expansion of malignant plasma cells and the 
accumulation of the M-protein lead to the end-organ damage that characterizes
evolution of the disease.  MM represents 15% of all hematologic cancers. There are 
approximately 86,000 new cases of MM annually worldwide (Becker 2011). 
Treatment of MM consists of combination regimens based on proteasome inhibitors 
(PIs), immunomodulatory drugs (IMiDs), and corticosteroids administered in different 
lines of therapy. Recent advances in the treatment of MM have included a new 
generation of PIs (e.g., carfilzomib) and IMiDs (e.g., pomalidomide), and more recently,
monoclonal antibodies such as daratumumab and elotuzumab, which target the CD38 
and the signaling lymphocytic activation molecule F7 (SLAMF7) (Nooka et al. 2015).  
These new therapeutic options have prolonged the life expectancy of patients with MM.  
However despite these advances, MM is still an incurable disease, and new 
combinations with novel mechanisms of action are necessary.
Several drugs that target central mechanisms of malignant plasma cell biology (such as 
the mitogen-activated protein kinase [MAPK] pathway and the prosurvival protein Bcl-2) 
and the immune system, such as the PD-L1 antibody, are currently being explored in 
nonclinical and clinical settings.
1.2
THE MAPK SIGNALING PATHWAY AND REGULATION OF THE 
IMMUNE TUMOR MICROENVIRONMENT 
The MAPK signaling cascade is a key intracellular signaling network that transduces 
multiple proliferative and differentiating signals from the extracellular environment to the 
nucleus of cells to activate cellular growth and differentiation.  Signaling through the 
MAPK pathway plays a significant role in normal cellular regulation (Johnson and 
Lapadat 2002; Roberts and Der 2007).  Given the central role played by the MAPK 
pathway in normal cellular proliferation, abnormal regulation of this pathway could lead 
or contribute to uncontrolled proliferation, invasion, metastasis, and angiogenesis as well 
as diminished apoptosis.  Constitutive activation of the MAPK pathway occurs frequently
in solid tumors as well as in MM (Heuck et al. 2016) because of somatic mutations that 
activate additional downstream pathways.  This is the case for RAS or RAF mutations, 
which activate the MAPK pathway and thereby perpetuate uncontrolled proliferative 
signals.
The MAPK pathway has also been implicated in regulation of the tumor 
microenvironment.  Blocking the MAPK pathway in in vitro cell lines has shown to 
increase antigen expression and enhance reactivity to antigenspecific T lymphocytes 
(Boni et al. 2010).  In patients with melanoma treated with a combination of BRAF and 


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MEK inhibitors, an increased number of intra-tumoral lymphocytes (CD4and 
CD8T cells) were observed compared to pretreatment biopsy samples 
(Kakavand et al. 2015).  Furthermore, pretreatment biopsies with increased 
tumor-infiltrating lymphocytes (TILs) demonstrated a larger increase in TILs and PD-1 
expression after treatment with a BRAF inhibitor and a MEK inhibitor 
(Cooper et al. 2015; Kakavand 2015; Liu et al. 2015).  
Additionally, up-regulation of the MAPK pathway inhibits the immune cell function 
through the down-expression of major histocompatibility complex (MHC) antigens that 
impairs the tumor antigen presentation to the immune effector cells.  MAPK inhibition 
upregulates the expression of cell-surface MHC antigens (Liu et al. 2015) and increases 
immune effector cells in the tumor, thus enabling the immune system to attack the 
tumor.
The MAPK pathway is also associated with the production of transforming growth 
factor-beta (TGFβ) by malignant cells, which through paracrine signaling has been linked 
to the induction of CD4CD25FoxP3T regulatory cells (Tregs) implicated in the 
tumor immune escape mechanism. Although not essential for the generation of Tregs,
there is accumulating evidence that the TGFβ proteins are essential for the function and 
survival of induced Treg cells (Hossain et al. 2015).
Inhibition of the MAPK pathway has focused on the suppression of targets, such as 
MEK1 and MEK2, within this signaling network.  There are multiple upstream activating 
signals but multiple pathways exist to bypass their inhibition and still activate 
extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK2).  ERK1 and ERK2 can 
only be activated and phosphorylated by MEK1 and MEK2, which therefore render 
MEK1 and MEK2 as key signaling nodes for therapeutic inhibition of the MAPK pathway.
Cobimetinib is a potent and highly selective non-ATP competitive inhibitor of MEK. 
Cobimetinib inhibits the phosphorylation of ERK1/2 and causes inhibition of proliferation 
and induction of apoptosis in BRAF mutant melanoma cell lines. 
1.3
THE ANTI-APOPTOTIC SIGNALLING PATHWAY
Resistance to cell death is a hallmark of the cancer cell and a relevant biological feature 
that gives the tumor cells a competitive advantage over normal cells.  The equilibrium of 
pro- and anti-apoptotic signals is disrupted in malignant diseases.  Bcl-2, along with 
closely related proteins (Bcl-xL, Bcl-w, Mcl-1, A1) are inhibitors of apoptosis, acting 
in large part by binding to and thereby suppressing the proapoptotic triggering 
Bcl-2 homologue (BH)3 proteins (Bid, Bad, Bim, Bik, Bmf, Noxa, Puma, and Hrk;
Taylor et al. 2008). 
Bcl-2 family proteins are crucial regulators of MM cell survival and therefore represent
attractive therapeutic targets (Punnoose et al. 2016).  Venetoclax is a potent and
selective small-molecule Bcl-2-selective BH3 mimetic.  Venetoclax induces cell death in 


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MM cell lines in vitro and primary MM samples ex vivo.  Certain genetic subtypes of 
MM cells are particularly sensitive to venetoclax, including those bearing the recurrent 
chromosomal translocation t(11;14), which results in a high ratio of Bcl-2 to Mcl-1 and 
resistance to apoptosis (Kumar et al. 2015). 
1.4
THE PROGRAMMED T-CELL DEATH LIGAND PATHWAY
Encouraging clinical data in the field of tumor immunotherapy have demonstrated that 
therapies focused on enhancing T-cell responses against malignant diseases can result 
in significant survival benefit in patients with disseminated disease (Hodi and Dranoff 
2010; Kantoff et al. 2010).  Therefore, immune modulation represents a promising new 
strategy for cancer therapy that may result in improved anti-tumor activity.
PD-L1 is commonly expressed in many human tumors (e.g., lung, ovarian, melanoma, 
and colon carcinoma), and its overexpression has been associated with poor prognosis 
in some cancers (Thompson et al. 2006; Hamanishi et al. 2007; Ozaki and Honjo 2007; 
Hino et al. 2010).  In a large number of patients with plasma cell dyscrasias including 
MM it has been shown that PD-L1 is commonly and broadly expressed on the patients’ 
plasma cells (Yousef et al. 2015), while the expression of the PD-L1 receptor, PD-1, is 
upregulated on T cells isolated from patients with MM (Rosenblatt et al. 2011).  These 
results indicate the importance of the PD-L1/PD-1 pathway in the biology of plasma cell 
dyscrasias including MM.
PD-L1 is one of two ligands (PD-L1 and PD-L2) that bind PD-1.  The PD-1 receptor is an 
inhibitory receptor expressed on T cells following T-cell activation in states of chronic 
activation, such as chronic infection or cancer (Blank et al. 2005; Keir et al. 2008).  
Binding of PD-L1 to PD-1 inhibits T-cell proliferation, cytokine production, and cytolytic 
activity thus leads to functional inactivation of T cells.  Aberrant expression of PD-L1 on 
tumor cells has been reported to impede anti-tumor immunity, which results in immune 
evasion (Blank and Mackensen 2007).  Therefore, interruption of the PD-L1/PD-1 
pathway represents an attractive strategy to enhance tumor-specific T-cell immunity.
Therapeutic targeting of PD-L1 or PD-1 results in strong and often rapid anti-tumor 
effects in several mouse tumor models (Iwai et al. 2002; Strome et al. 2003) and also 
demonstrates clinical activity with drugs such as atezolizumab (Besse et al. 2015; 
Rosenberg et al. 2015; Vansteenkiste et al. 2015).
Atezolizumab is a humanized IgG1 monoclonal antibody (mAb) that targets PD-L1 by 
altering interaction with its receptors, PD-1 and B7-1 (also known as CD80).  Both of 
these interactions provide inhibitory signals to T cells.  Atezolizumab was engineered 
with a modified Fc domain to eliminate the antibodydependent cellular cytotoxicity 
at clinically relevant doses, which prevents the depletion of activated T cells 
(Herbst et al. 2014).


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1.5
BACKGROUND ON COBIMETINIB
Cobimetinib is a potent and selective inhibitor of MEK1 and MEK2.  Cobimetinib 
(Cotellic®) is approved for use with vemurafenib for the treatment of advanced 
BRAF V600 mutated melanoma in the European Union, United States, and Switzerland,
as well as other countries.
1.5.1
Summary of Nonclinical Studies with Cobimetinib
Cobimetinib inhibits proliferation of a variety of human tumor cell lines through inhibition 
of MEK1 and MEK2.  In addition, cobimetinib inhibits ERK1 and ERK2 phosphorylation 
and induces apoptosis in xenograft tumor models.  Cobimetinib accumulates in tumor 
xenografts and remains at high concentrations in the tumor after plasma concentrations 
have declined.  The activity of cobimetinib to inhibit ERK1 phosphorylation is more 
closely correlated with its concentration in tumor tissue than in plasma; in general, there 
is a good correlation between reduced ERK1 phosphorylation and efficacy in tumor 
xenograft models.  Tumor regression has been observed in several human tumor 
xenograft models.  This regression was dose dependent with up to 100% regression at 
the highest doses tested.  The models studied included colorectal cancer (CRC), 
malignant melanoma, breast carcinoma, and lung carcinoma.
A characterization of the pharmacologic and pharmacokinetic (PK) properties of 
cobimetinib was performed in a series of nonclinical studies.  The nonclinical toxicity of 
cobimetinib was characterized in single- and repeat-dose toxicology studies in rats and 
dogs, in vitro genotoxicity studies, embryolethality/teratogenicity studies in rats, and 
nonclinical cardiovascular, neuro-behavioral, and respiratory safety pharmacology 
studies.  Additional information on nonclinical studies is summarized in the Cobimetinib 
Investigator’s Brochure.
1.5.2
Summary of Clinical Study with Cobimetinib Monotherapy
As of August 2016, cobimetinib had been administered alone or in combination with 
other agents to more than 1000 adult patients with cancer and approximately 
120 healthy volunteers in 24 clinical trials; the vast majority of patients had been treated 
with cobimetinib plus other agents, such as vemurafenib.  These included 2 trials of 
cobimetinib as a single agent, 7 clinical pharmacology studies, and 15 trials of 
cobimetinib in combination with other agents.
Cobimetinib monotherapy was assessed in Study MEK4592g, a Phase I,
non-randomized, open-label, safety and PK dose-escalation study.  The study was 
conducted in patients with metastatic or unresectable solid tumors for which standard 
curative or palliative measures did not exist or were no longer effective.  A total of 
115 patients were treated, and the study has been completed.


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The study consisted of five treatment stages:

Stage I:  Dose-escalation cohorts; patients were treated on a 21-days-on, 7-days-off 
(21/7) schedule to determine the maximum-tolerated dose (MTD). 

Stage IA:  Dose-escalation cohorts; patients were treated on a 14-days-on, 
14-days-off (14/14) schedule to determine the MTD on an alternate dosing regimen.

Stage II:  Expansion cohort with the MTD determined in Stage I (60 mg once a day
[QD] 21/7) in patients who harbored a BRAF, NRAS, or KRAS mutation.

Stage IIA:  Expansion cohort with the MTD determined in Stage IA (100 mg QD 
14/14) in patients harboring a BRAF, NRAS, or KRAS mutation.

Stage III:  A dedicated drug-drug interaction study at the MTD determined in Stage I 
(60 mg QD 21/7) in approximately 20 patients with solid tumors.
Adverse Events
All patients in Study MEK4592g experienced an adverse event.  The most frequent 
adverse events were diarrhea (67.0%), fatigue (50.4%), rash (49.6%), nausea and 
vomiting (33.9% each), and peripheral edema (28.7%).  Other events that occurred in
10% of patients included anemia, abdominal pain, constipation, hypokalemia, 
decreased appetite, headache, dizziness, back pain, increased AST, dermatitis 
acneiform, pruritus, and dry skin.  Among the patients who received cobimetinib 60 mg 
QD 21/7, the most frequent treatment-emergent adverse events were diarrhea (64.4%), 
rash (53.3%), fatigue (48.9%), nausea and peripheral edema (31.1% each), and 
vomiting (28.9%).
Grade 3 Adverse Events
Among all cobimetinib-treated patients, 5 patients (4.3%) experienced a Grade 4 
adverse event, and 53 patients (46.1%) experienced a Grade 3 adverse event.  
The most frequent Grade 3 and Grade 4 adverse events were hyponatremia (9.6%), 
fatigue (8.7%), anemia (7.8%), and diarrhea (6.1%) and hypokalemia (6.1%).
Serious Adverse Events 
A total of 49 patients (42.6%) experienced a serious adverse event.  The most common 
types of serious adverse events were gastrointestinal disorders (n17), but there were 
no trends in specific preferred terms.  The gastrointestinal serious adverse events, such 
as intestinal obstructions and gastrointestinal hemorrhages, occurred in patients with 
gastrointestinal malignancies.  Serious adverse events reported for more than 2 patients 
among all patients in the study were anemia, bile duct obstruction, dehydration, 
syncope, and respiratory arrest (3 patients each [2.6%]).
Efficacy 
Best overall response (BOR) was assessed for 74 of 97 patients in Stages I, IA, II, and 
IIA.  Overall 6 patients (all of whom had melanoma; 6.2%) had a confirmed partial 
response (PR), 28 patients (28.9%) had stable disease (SD), and 40 patients (41.2%) 
had progressive disease (PD). Out of the 14 CRC patients, all patients experienced PD. 


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In Stage III of Study MEK4592g, 18 patients were enrolled and BOR was assessed for 
14 of 18 patients.  Four patients (22.2%) had SD as their BOR, and 2 patients (11.1%) 
had unconfirmed tumor responses. 
A recent case report refers to a young patient with a highly resistant MM harboring the 
BRAF V600E mutation in Exon 15 (c.1799TA) who was treated with the combination of 
vemurafenib and cobimetinib. The patient achieved at least a very good partial 
response (VGPR) but declined bone marrow biopsy to confirm complete response (CR)
and remained in remission at the time of the publication (Mey et al. 2016).
For additional data, including the complete safety profile of cobimetinib and data from 
clinical studies with cobimetinib administered as a single agent or in combination with 
other anti-cancer agents, refer to the Cobimetinib Investigator’s Brochure.
1.5.2.1
Clinical Pharmacokinetics of Cobimetinib
The pharmacokinetics of cobimetinib administered as a single agent have been 
characterized in patients with cancer following oral (PO) administration after single and 
multiple dosing in the Phase Ia dose-escalation Study MEK4592g. Additionally, clinical 
pharmacology studies have been conducted in healthy volunteers to determine the 
absolute bioavailability, effect of food, and effect of proton-pump inhibitor on cobimetinib 
pharmacokinetics.
Cobimetinib has a mean terminal elimination half-life of 43.6 hours. Cobimetinib 
exposure (area under the concentrationtime curve [AUC] at steady state and maximum 
observed concentration at steady state [Cmax]) was dose-proportional across the dose 
range of 0.05 mg/kg (3.5 mg for a 70-kg adult) to 100 mg (clinically relevant dose range) 
following PO administration. Cobimetinib binds to plasma proteins (95%) in a 
concentration-independent manner. 
Cobimetinib is extensively metabolized by CYP3A, and to a lesser extent by UGT2B7,
and eliminated in feces with minimal renal elimination. In vitro data showed that 
cobimetinib is a CYP3A and CYP2D6 inhibitor; however, clinical studies showed no PK 
interaction with probe substrates of CYP3A or CYP2D6.  Cobimetinib can be 
administered without regard to food, proton-pump inhibitors, or other acid-reducing 
agents. Concomitant administration of strong CYP3A inhibitors with cobimetinib should 
be avoided if possible and may require dose reduction for cobimetinib. Cobimetinib may 
be co-administered with weak CYP3A inhibitors without any dose adjustment, while 
caution should be exercised when administering moderate inducers and inhibitors with 
cobimetinib.
Cobimetinib is a substrate of the efflux transporter P-glycoprotein but does not appear to 
inhibit P-glycoprotein or the uptake transporters (OATP1B1, OATP1B3, or OCT1) at 
clinically relevant concentrations. 


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Cobimetinib monotherapy did not result in prolongation of the corrected QT interval.  
Cobimetinib pharmacokinetics were not affected in patients with mild (n151) and 
moderate (n48) renal impairment based on population PK analysis.
For details on the cobimetinib clinical pharmacokinetics or further clinical information on 
cobimetinib as monotherapy or with other anti-cancer agents, see the Cobimetinib 
Investigator’s Brochure.
1.6
BACKGROUND ON VENETOCLAX
1.6.1
Summary Nonclinical Studies with Venetoclax
Venetoclax is a potent and selective small-molecule inhibitor of Bcl-2 that binds with
1,000-fold higher affinity for Bcl-2 (inhibitor constant [Ki] 0.010 nM) than for Bcl-XL 
(Ki48 nM) or Mcl-1 (Ki 444 nM) (Souers et al. 2013). In vitro, venetoclax has 
demonstrated activity against patient-derived chronic lymphocytic leukemia (CLL) cells 
and a variety of lymphoma and leukemia cell lines (Souers et al. 2013). 
A characterization of the pharmacologic and PK properties of venetoclax was performed 
in a series of nonclinical studies.  The nonclinical toxicity of venetoclax was 
characterized in single- and repeat-dose toxicology studies in rat and dog, in vitro 
genotoxicity studies, and nonclinical cardiovascular, neuro-behavioral, and respiratory 
safety pharmacology studies.  
Venetoclax demonstrated high protein binding to human, rat, dog, and monkey plasma 
proteins (99.9%). Blood to plasma ratios showed that venetoclax does not partition
preferentially into the RBCs. Following PO administration of venetoclax to nonclinical 
species and humans, parent compound and metabolites were cleared mainly via biliary 
excretion and fecal elimination, with minimal renal clearance.  In humans, M27 was 
identified to be a major human disproportionate metabolite.
In vitro, venetoclax is metabolized by CYP3A.  It is a weak inhibitor of UGT1A1, 
CYP2C9, and CYP2C8 in vitro, but it is not predicted to cause clinically relevant 
inhibition due to high plasma protein binding.  Venetoclax is not an inhibitor or inducer of 
CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4 at clinically relevant concentrations. 
Venetoclax is a substrate of the efflux transporters P-glycoprotein 1 (Pgp) and breast 
cancer resistance protein (BCRP).  Venetoclax is a Pgp, BCRP, and weak OATP1B1 
inhibitor in vitro.  Venetoclax does not appear to be an in vitro substrate for the human 
OATP isoforms, 1B1 or 1B3, or OCT1.  Venetoclax is not an inhibitor of UGT1A4, 
UGT1A6, UGT1A9, or UGT2B7.
Additional information on nonclinical studies for venetoclax is summarized in the 
Venetoclax Investigator’s Brochure.


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1.6.2
Summary of Clinical Data for Venetoclax
As of 28 November 2016, on the basis of data available in the AbbVie and 
Genentech/Roche clinical databases, a total of 2759 patients have been exposed to at 
least one dose of venetoclax in the oncology and immunology development programs.
A total of 2534 oncology patients had data available in AbbVie and Genentech/Roche 
studies as of 28 November 2016. Of the 2534 patients, 1435 patients had CLL/small 
lymphocytic leukemia (SLL), 626 patients had non-Hodgkin lymphoma (NHL), 
178 patients had MM, and 295 patients had acute myeloid leukemia (AML). An 
additional 127 participants were healthy volunteers. A total of 663 oncology patients 
received the drug as monotherapy, 1871 patients received the drug in combination with 
other therapies, and 1 patient received venetoclax as a single dose in a drug-drug 
interaction study and did not re-enroll in a subsequent monotherapy study. Additionally, 
98 patients had been exposed to at least one dose of venetoclax in the AbbVie 
immunology study, M13-093, as of 28 November 2016.
Two clinical studies for venetoclax have been conducted in the MM indication, one with 
venetoclax as single agent and the other study with venetoclax in combination with 
bortezomib and dexamethasone.  Two additional venetoclax studies are currently 
ongoing: a Phase II study in combination with carfilzomib and dexamethasone, and a 
Phase III in combination with bortezomib and dexamethasone.  
Study M14-031 (BELLINI) is an ongoing Phase III, multicenter, randomized, double-blind 
study of bortezomib and dexamethasone in combination with either venetoclax or 
placebo in patients with relapsed and refractory (R/R) MM who are sensitive or naive to 
PIs. The study has been unblinded, as per protocol, for the final analysis of the primary 
efficacy endpoint. As of the data cut-off date of 26 November 2018, 194 patients
were randomly assigned to the venetoclax arm and 97 patients to the placebo arm 
(2:1 randomization). The study met its primary endpoint of progression-free survival 
(PFS) (median 22.4 versus 11.5 months, HR 0.63, 95% CI: 0.44 to 0.90) and showed 
statistically significant improvements in overall response rate (ORR) (82% versus 66%) 
and very good partial response or better (59% versus 36%) in the venetoclax arm 
compared with the control arm. However, there were 51 deaths in the safety analysis 
set, 40 (20.7%) in the venetoclax arm and 11 (11.5%) in the placebo arm (median OS 
overall survival [OS] has not been reached in either arm). The imbalance was 
predominantly seen in the treatment-emergent deaths, i.e., those occurring on therapy or 
within 30 days after the last dose of therapy. Among the 14 treatment-emergent deaths 
reported, 13 (6.7%) were in the venetoclax arm and 1 (1.0%) in the placebo arm. Of the 
13 treatment-emergent deaths in the venetoclax arm, 8 were attributed by investigator to 
an event of infection, with 50% also in the setting of refractory or progressive disease. 
Although the majority of infection-related deaths occurred within 180 days of starting 
study treatment, some have occurred later, even after a year or more on treatment.


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A higher rate of Grade 3 or 4 neutropenia was observed in the venetoclax arm compared 
with the placebo arm, but an association of infection-related deaths with neutropenia has 
not been established at this point. Among the 37 nontreatment-emergent deaths 
(those occurring more than 30 days after the last dose of study treatment), 27 (14.0%) 
were in the venetoclax arm (6 deaths attributed to infection, 3.1%), and 10 (10.4%) in the 
placebo arm (2 deaths attributed to infection, 2.1%). Additional deaths were reported in 
the BELLINI study after the data cut-off of 26 November 2018. As of 1 March 2019, 
there were 65 deaths in the safety analysis set, 48 (24.7%) in the venetoclax arm and 
17 (17.5%) in the placebo arm.
Summarized data on venetoclax studies in the MM indication are shown in Table 1.  
For more detailed clinical information on venetoclax, refer to the Venetoclax 
Investigator’s Brochure.


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Table 1
Summary of Clinical Studies with Venetoclax in Patients with 
Multiple Myeloma
Study
Study Title
Dosage Regimen
No. of 
Patients
M13-367
A Phase 1 Study Evaluating the 
Safety and Pharmacokinetics of 
ABT-199 in Subjects with 
Relapsed or Refractory Multiple 
Myeloma
Escalating doses of venetoclax 
were given daily at 300, 600, 900, 
or 1200 mg. The 1200-mg dose is 
being evaluated in the in the 
safety expansion cohort.
66
(enrolled)
A combination cohort is exploring 
venetoclax and dexamethasone 
in subjects with R/R MM positive 
for t(11;14).
9
(enrolled)
M12-901
A Phase 1b Study Evaluating the 
Safety and Pharmacokinetics of
ABT-199 in Relapsed or 
Refractory Multiple Myeloma 
Subjects Who Are Receiving
Bortezomib and Dexamethasone 
as Their Standard Therapy
Escalating doses of daily 
venetoclax (50–1200 mg), 
combined with bortezomib 
(1.3 mg/m2 SC) and 
dexamethasone (20 mg PO)
66
(enrolled)
M14-031
A Phase 3, Multicenter, 
Randomized, Double-Blind Study 
of Bortezomib and 
Dexamethasone in Combination 
with Either Venetoclax or Placebo 
in Subjects with Relapsed or 
Refractory Multiple Myeloma Who 
Are Sensitive or Naïve to 
Proteasome Inhibitors
Oral daily dose of either 
venetoclax 800 mg plus 
bortezomib 1.3 mg/m2 and 
dexamethasone 20 mg or 
placebo plus bortezomib and 
dexamethasone
194 
(venetoclax 
arm), and 97 
(placebo 
arm)
M15-538
A Phase 2, Open-Label, 
Dose-Escalation Study to 
Evaluate the Safety and Efficacy 
of Venetoclax in Combination with 
Carfilzomib-Dexamethasone (Kd) 
in Participants with Relapsed or 
Refractory MM and Have 
Received 1 to 3 Prior Lines of 
Therapy.
Venetoclax tablet administered 
orally once daily during 
Cycles 118. Two dose levels of 
venetoclax 400 mg once daily or 
800 mg once daily.
NA
NAnot applicable. POorally; R/R MMrelapsed/refractory multiple myeloma.
1.6.3
Venetoclax Clinical Pharmacology and Pharmacokinetics
Venetoclax clinical pharmacology is being evaluated in several Phase I to III clinical 
trials, and preliminary data are available from three Phase I studies (M12-175, M13-367, 
M12-630), four Phase Ib studies (M13-365, M12-901, GO29440, GP28331), one 
Phase II study (M14-212), and five dedicated clinical pharmacology studies (M13-364, 
M14-497, M13-363, M14-253, M15-101).


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The venetoclax formulation being used in clinical trials is a tablet formulation in strengths 
of 10, 50, and 100 mg. After a single dose in CLL/SLL patients, after a low-fat meal, 
venetoclax plasma concentrations peaked at approximately 6 hours after dosing. 
The mean harmonic terminal-phase elimination half-life (t1/2) of venetoclax was 
approximately 17 hours, and the mean oral clearance was approximately 13 L/hr. No 
accumulation was seen after repeated QD administration of venetoclax over the 100- to 
800-mg QD dose range in CLL/SLL patients. Preliminary data from CLL/SLL patients 
suggested that venetoclax AUC was approximately dose-proportional across the 150- to 
1200-mg dose levels at steady state. Preliminary data did not suggest apparent PK 
differences among patients with CLL/SLL, NHL, MM, or AML. Low-fat and high-fat 
meals increased the venetoclax exposure compared with fasting in healthy volunteers by 
approximately 3.4- and 5.1-fold, respectively.  Venetoclax should always be given after a 
low-fat meal.
Venetoclax is eliminated almost entirely through the hepatic route via metabolism by 
CYP3A enzymes. Specific recommendations are provided for co-administration of 
venetoclax with moderate and strong inhibitors and inducers of CYP3A
(see Section 4.4.4). Venetoclax does not appear to be a clinically significant inhibitor 
of CYP2C9. 
Preliminary results from a dose- and exposure-response analysis based on 
Study M12-175 data indicate that there is no relationship between venetoclax dose or 
exposure and QT interval corrected using Fridericia’s formula for doses up to 1200 mg 
(8 g/mL plasma concentrations) of venetoclax.
For details on the clinical pharmacokinetics of venetoclax, see the Venetoclax 
Investigator’s Brochure.
1.6.4
Clinical Safety Data for Venetoclax
As of the clinical data cutoff date of 28 November 2016, data on venetoclax 
monotherapy in patients with R/R MM come from Study M13-367. This study includes a 
dose-escalation portion and an expanded safety cohort portion. Sixty-six patients have 
been enrolled in Study M13-367 in the dose-escalation and safety expansion cohorts of 
venetoclax monotherapy, and 9 patients were enrolled in the combination with 
dexamethasone cohort. 
Most patients (96.0%) in Study M13-367 experienced at least one treatment-emergent 
adverse event. The most common treatment emergent adverse events were nausea 
(41.3%), diarrhea (34.7%), fatigue (24.0%), and anemia and platelet count decreased 
(21.3% each). Over half (62.7%) of patients experienced events Grade 3 or above; the 
most common events were platelet count decreased (16.0%), and anemia and 
neutrophil count decreased (13.3% each).


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Serious adverse events were reported in 26 (34.7%) patients, including events of
pneumonia and malignant neoplasm progression (6 patients each), sepsis (3 patients), 
and anemia, pain, pyrexia, cough, and hypotension (2 patients each). All other events 
occurred in 1 patient each.
In Study M12-901 escalating doses of venetoclax are administered with bortezomib and 
dexamethasone in patients with R/R MM. Most (98.5%) patients experienced at least 
one treatment-emergent adverse event. The most common adverse events were 
diarrhea (45.5%); constipation (42.2%); thrombocytopenia (39.4%); nausea (36.4%);
neuropathy peripheral and insomnia (33.3% each); anemia; edema peripheral and 
peripheral sensory neuropathy (27.3% each); and asthenia, fatigue, and dyspnea 
(24.2% each).  
Fifty-five (83.3%) patients experienced events Grade 3 or above; the most common 
event was thrombocytopenia in 20 (30.3%) patients. 
Serious adverse events were reported in 36 (54.5%) patients, including pneumonia 
(5 patients); pyrexia (4 patients); febrile neutropenia, influenza, and sepsis (3 patients);
and thrombocytopenia, cardiac failure, disease progression, lower respiratory tract 
infection, respiratory failure, hypoxia, hypotension and pulmonary embolism (2 patients
each). All other events occurred in 1 patient each.
Tumor lysis syndrome (TLS) is an important risk identified particularly in patients with 
R/R CLL but has not been observed in patients with MM.
Refer to the Venetoclax Investigator’s Brochure for further information on the clinical 
safety of venetoclax.
1.7
BACKGROUND ON ATEZOLIZUMAB
1.7.1
Summary of Nonclinical Studies with Atezolizumab
Atezolizumab is a humanized IgG1 mAb 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 patients with 
cancer and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent as well as in combination with 
chemotherapy, targeted therapy, and cancer immunotherapy.


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Atezolizumab is approved for the treatment of urothelial carcinoma (UC), nonsmall cell 
lung cancer (NSCLC), small-cell lung cancer, triple-negative breast cancer, 
hepatocellular carcinoma, and melanoma.
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical studies.
1.7.2
Clinical Experience with Atezolizumab Monotherapy
1.7.2.1
Ongoing Clinical Studies
Atezolizumab is currently being tested in multiple Phase I, II, and III studies, both as a 
single agent and in combination with several anti-cancer therapies (see the 
Atezolizumab Investigator’s Brochure for study descriptions).  Much of the safety and 
efficacy data summarized below is from the Phase I Study PCD4989g, a multicenter, 
first-in-patient, open-label, dose-escalation study to evaluate the safety, tolerability, 
immunogenicity, pharmacokinetics, exploratory pharmacodynamics, and preliminary 
evidence for biological activity of atezolizumab administered as a single agent by IV 
infusion to patients with locally advanced or metastatic solid malignancies or 
hematologic malignancies.
1.7.2.2
Clinical Safety of Atezolizumab 
As of 17 May 2017, approximately 11,000 patients with solid tumor and hematologic 
malignancies have received atezolizumab in clinical studies as a single agent or in 
combination with cytotoxic chemotherapy and/or targeted therapy. 
Safety findings of single-agent atezolizumab across multiple tumor types in the clinical 
development program 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, no MTD has been 
determined, no dose-limiting toxicities (DLTs), and no clear dose-related trends in the 
incidence of adverse events have been observed.  Among 2160 patients treated with 
single-agent atezolizumab for whom pooled safety data are available, the most 
commonly reported adverse events (i.e., ≥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 each study treatment.
Adverse events were comparable between patients who received atezolizumab 
monotherapy and those who were treated with atezolizumab in combination with 
targeted therapy and/or chemotherapy.  For example, the percentage of patients who 
experienced an adverse event among a pooled population of 2160 patients with 
metastatic urothelial carcinoma (mUC) and NSCLC, who received single-agent 
atezolizumab, was 95.4%, compared with 98.7% in Study GP28328, in which 
atezolizumab is used in combination with chemotherapy.  Similarly, serious adverse 


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events occurred at rates of 38.5% among the mUC/NSCLC pool and 45.0% among 
patients in GP28328, and rates of adverse events leading to discontinuation of 
atezolizumab due to any adverse event were 6.6% among the UC/NSCLC, and 8.3% in 
Study GP28328.  Rates of treatment-related Grade 5 adverse events were also similar
in these populations (0.2% in the pooled UC/NSCLC population and 0.9% in 
Study GP28328).
Immune-Mediated Adverse Events
Immune-mediated 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-mediated adverse 
events are closely monitored during the atezolizumab clinical program.  Immune 
mediated adverse events associated with atezolizumab include hepatitis, pneumonitis, 
colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal 
insufficiency, Guillain-Barré syndrome, myasthenic syndrome/myasthenia gravis, and 
meningoencephalitis.  
Refer to the Atezolizumab Investigator’s Brochure for additional details on the safety 
profile of the agent.
1.7.3
Atezolizumab Clinical Pharmacology and Pharmacokinetics
The key PK findings from the above-listed atezolizumab monotherapy clinical studies are 
summarized below: 

The pharmacokinetics of atezolizumab monotherapy have been characterized in 
patients in Study PCD4989g at doses 0.01 mg/kg to 20 mg/kg every 3 weeks 
(Q3W), including the fixed dose 1200 mg (equivalent to 15 mg/kg). Exposure to 
atezolizumab increased dose proportionally over the dose range of 1 mg/kg to 
20 mg/kg. While a subset of ATA-positive patients in Study PCD4989g receiving 
0.3 to 3 mg/kg atezolizumab Q3W experienced a reduction of atezolizumab 
minimum concentration under steady-state conditions within a dosing interval 
(Cmin) to below the PK assay lower limit of quantification, patients receiving 10 to 20 
mg/ kg atezolizumab, including the fixed 1200 mg dose, maintained geometric mean 
Cmin that was in excess of both the lower limit of quantification and the target serum 
concentration of 6 g/mL (Deng et al. 2016). 

A Phase I population pharmacokinetics (popPK) analysis that included 472 patients 
from Studies PCD4989g and JO28944 described atezolizumab pharmacokinetics 
for the dose range 120 mg/kg with a linear two-compartment disposition model with 
first-order elimination. The popPK analysis indicated that central compartment 
volume of distribution (V1) was 3.28 L and the volume of distribution under 
steadystate conditions (Vss) was 6.91 L in the typical patient. Further, the 
clearance (CL) of atezolizumab was 0.20 L/day and the t1/2 was 27 days. 
Steadystate was obtained after 6 to 9 weeks (2 to 3 cycles) of repeated dosing. 
The systemic accumulation in AUC, Cmax, and Cmin was 1.91, 1.46, and 2.75-fold, 
respectively. 


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
Based on an analysis of exposure, safety, and efficacy data, the following factors 
had no clinically relevant effect: age (2189 years), body weight, gender, positive 
ADA status, albumin levels, tumor burden, region or ethnicity, renal impairment, mild 
hepatic impairment, level of PD-L1 expression, or Eastern Cooperative Oncology 
Group (ECOG) performance status. 

The effect of moderate or severe hepatic impairment (bilirubin upper limit of 
normal [ULN] and AST ULN or bilirubin 1.0 to 1.5 ULN and any AST elevation) 
on the pharmacokinetics of atezolizumab is unknown. 

No formal PK drug-drug interaction studies have been conducted with atezolizumab. 
The drug interaction potential of atezolizumab is unknown.
For more information, refer to the Atezolizumab Investigator’s Brochure.
1.7.3.1
Clinical Activity of Atezolizumab
As of 17 May 2017, efficacy data were most extensive for patients with NSCLC 
(1651 patients enrolled in Studies GO28754 [BIRCH], GO28753 [POPLAR], GO28915 
[OAK], GO28625 [FIR], and the NSCLC cohort of PCD4989g) and patients with mUC 
(524 efficacy-evaluable patients in studies PCD4989g and GO29293 [IMvigor 210]) who 
were administered atezolizumab as a single agent.  
Efficacy parameters ORR in Cohort 1 and ORR, PFS, and OS in Cohort 2 observed in 
the Phase II IMvigor 210 study as of the clinical cutoff date of 4 July 2016 after an 
additional 10 months, and 14 months of follow-up (Cohorts 1 and 2, respectively) were 
consistent with those obtained at primary analyses of each cohort.  Similar response 
rates and consistency between primary and updated analyses were seen in the mUC 
cohort of Study PCD4989g.  In both studies, higher ORR results in the immune cell 
(IC)2/3 expression group suggest that higher levels of PD-L1 expression on ICs may be 
associated with increased benefit.
The results from the five studies evaluating atezolizumab as monotherapy in patients 
with locally advanced or metastatic NSCLC (PCD4989g, FIR, OAK, POPLAR, and 
BIRCH, single-agent treatment with atezolizumab resulted in clinically meaningful OS 
improvement in the 2L/3L NSCLC ITT population, compared with standard of care, in 
both non-squamous and squamous histologies, and across all PD-L1 expression 
subgroups.  Higher PD-L1 expression on tumor cell (TC)s or ICs was associated with 
higher ORRs and longer median PFS and OS duration.  Responses were highly durable 
across all PD-L1 expression groups.  


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On 18 May 2016, atezolizumab (Tecentriq) was granted accelerated (U.S.) Food and 
Drug Administration (FDA) approval for the treatment of patients with locally advanced or 
metastatic UC who have received prior platinum-containing chemotherapy.  On 
18 October 2016, FDA approved atezolizumab for the treatment of patients with 
metastatic NSCLC whose disease progressed during or following platinum-containing 
chemotherapy.
Refer to the Atezolizumab Investigator’s Brochure for additional details on nonclinical 
and clinical studies.
1.8
CLINICAL EXPERIENCE OF COBIMETINIB PLUS 
ATEZOLIZUMAB
Study GP28363 is a Phase Ib, open-label, multicenter study designed to assess the 
safety, tolerability, and pharmacokinetics of cobimetinib plus atezolizumab in patients 
with advanced solid tumors.
The study has two stages: Stage 1 (dose escalation) and Stage 2 (expansion). Stage 1 
is designed to establish the combination MTD for cobimetinib plus atezolizumab.  
In Stage 2, the recommended Phase II dose and schedule were investigated in 
tumor-specific expansion cohorts: KRAS-mutant metastatic CRC, NSCLC, and 
metastatic melanoma.
In the Stage 1 dose-escalation phase, there were no DLTs, and the combination of 
60 mg cobimetinib 21/7 and 800 mg atezolizumab every 2 weeks (Q2W) was 
determined to be the recommended Phase II dose.
As of 17 January 2017, a total of 150 patients were accrued and evaluable for safety.  
The most frequently observed adverse events (30%) were diarrhea (70.7%), fatigue 
(56%), rash (48%), vomiting (42%), nausea (36%), pruritus (35.3%), decreased appetite 
(34.7%), and constipation (29.3%).  Adverse events assessed as related to 
atezolizumab were reported in 117 patients (78%).  The most common such adverse 
events (i.e., 10%) were fatigue (30.7%), diarrhea (28%), pruritus (14%), rash (13.3%), 
nausea (12.7%), and pyrexia (10%).
These findings are consistent with the known adverse event profiles for atezolizumab 
and cobimetinib and did not represent additive toxicity.  
Grade 3-4 adverse events were observed in 96 (64%) of the patients, and the most 
common (2.7% or 4 patients) included fatigue (10%), anemia (9.3%), diarrhea (8%), 
abdominal pain (5.3%), rash and blood creatinine phosphokinase increased (4.7% 
each), dyspnea and aspartate aminotransferase increased (4% each), amylase 
increased and hypertension (3.3% each), and ascites, vomiting, peripheral edema, 
asthenia, pleural effusion, pulmonary embolism, blood bilirubin increased, neutrophil 
count decreased, and hypophosphatemia (2.7% each).  Most of the Grade 3-4 adverse 


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events considered related to atezolizumab were single reports except for rash and 
fatigue (2.7% each), asthenia, diarrhea, amylase increased, and lipase increased 
(2% each), and nausea, vomiting, dermatitis acneiform, aspartate aminotransferase 
increased, neutrophil count decreased, and dyspnea (1.3% each).
Seven patients (4%) were reported to have had Grade 5 adverse events. The following 
events led to death in 7 patients (4.7%):  pneumonia, large intestine perforation, small 
intestinal perforation, sepsis, road traffic accident, and respiratory failure.  The event of 
sepsis was the only Grade 5 event considered related to atezolizumab.  In this case, the 
patient had a medical history of infectious disease (right temporal lobe abscess).
Refer to the Cobimetinib and Atezolizumab Investigator’s Brochures for details on safety 
data from Study GP28363.
1.9
CLINICAL DATA OF COBIMETINIB PLUS VENETOCLAX
Study GH29914 is an ongoing, Phase Ib/II multi-arm study in which venetoclax is 
combined with either cobimetinib or idasanutlin as first-line therapy for patients with R/R
AML who are 65 years of age and not eligible for standard induction therapy.  
As of 21 June 2019, the Phase Ib dose-escalation stage for the venetoclax plus 
cobimetinib arm is fully accrued, and 30 patients have safety data available across the 
four venetoclax plus cobimetinib treatment cohorts.
Of the 30 patients treated with venetoclax plus cobimetinib, all patients (100%) reported 
at least one treatment emergent adverse event.  The most frequent treatment emergent 
adverse events (reported in 30% of patients overall) included diarrhea (76.7%), nausea 
(60.0%), febrile neutropenia (40.0%), vomiting (36.7%), fatigue (36.7%), constipation 
(33.3%), and edema peripheral (30.0%).  All, except 1 patient experienced treatment 
emergent adverse events considered related to study treatment (venetoclax, 
cobimetinib, or both).
Grade 3 or 4 treatment emergent adverse events reported in 10% of patients treated 
with venetoclax plus cobimetinib included febrile neutropenia (40.0%); diarrhea (36.7%);
anemia and pneumonia (16.7% each); lung infection, sepsis, hypokalemia, 
and thrombocytopenia (13.3% each); and ejection fraction decreased and decreased 
appetite (10.0% each).  Of these, diarrhea was considered related to treatment in all 
patients (36.7%).
Serious adverse events were reported in 24 patients (80.0%) treated with venetoclax
plus cobimetinib, of which 9 patients (30.0%) experienced serious adverse events 
considered related to study treatment (venetoclax, cobimetinib, or both).  The most 
frequently reported serious adverse events (reported in 15% of patients overall) 
included febrile neutropenia (30.0%), and lung infection and sepsis (20.0% each).


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Overall, 26 deaths (86.7%) have been reported as of the cutoff date of 21 June 2019. 
Of these, deaths due to adverse events were reported in 6 patients and included events 
of sepsis and lung infection (24 events, 6.7% each), and respiratory failure and lung 
disorder (1 event, 3.3% each).  The event of lung disorder was considered by the 
investigator to be related to both venetoclax and cobimetinib.  Twenty patients died due 
to disease progression.  
The combination of venetoclax and cobimetinib will not proceed to the Phase II 
expansion stage due to unfavorable benefitrisk profile in this population of patients with 
AML who are not eligible for cytotoxic therapy.  This was driven by Grade 3 events of 
diarrhea, which were noted to be higher than that reported for either study drug as a 
single agent, and higher overall mortality rate due to adverse events.
Caution should be given to the interpretation of the safety data generated in study 
GH29914, which should be analyzed in the context of the study population. Patients 
with R/R AML who are not eligible for cytotoxic therapy constitute a very fragile 
population. A high proportion of patients with acute leukemia invariably present with 
severe myelosuppression and cytopenias associated with infections that affect organ 
function and require hospitalization. The high frequency of clinical complications related 
to AML is an essential problem in clinical studies evaluating the toxicities of new agents 
in acute leukemias (Atallah et al. 2007; Avvisati et al. 2007).
Refer to the Cobimetinib and Venetoclax Investigator’s Brochures for details on 
nonclinical and clinical studies.
1.10
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
Despite recent advances, MM remains an incurable disease.  Most patients eventually 
relapse and have shorter remissions with each additional line of therapy until refractory 
disease develops and the patient succumbs to the consequences of bone marrow failure 
or end-organ damage. 
The estimated median survival is 67 years for patients with standard risk myeloma and 
23 years for patients with high-risk disease (Kumar et al. 2014). The outcome for
patients with MM after becoming refractory to PI or IMiD is quite poor with survival 
1 year (Kumar et al. 2012; Usmani et al. 2016). 
Therefore, there is a significant unmet medical need for patients with R/R MM, and new 
regimens with innovative mechanisms of action are highly needed.
1.10.1
Rationale for Evaluating Cobimetinib in Relapsed and 
Refractory Multiple Myeloma
The RAS/MAPK pathway is a key signaling pathway that regulates cell proliferation, 
cell-cycle regulation, cell survival, angiogenesis, and cell migration (Friday and Adjei 
2008). The MEK1/2 proteins are central components of the MAPK pathway and MEK 


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inhibition is particularly efficacious in tumors harboring oncogenic mutations in the
BRAF, KRAS, and NRAS genes.
The RAS/MAPK pathway is frequently dysregulated in MM, with NRAS, KRAS, or BRAF 
mutations being present in up to 50% of newly diagnosed MM cases (Heuck et al. 2016).  
Notably, there is no difference in the frequency of altered RAS/MAPK pathway genes 
between newly diagnosed and relapsed patients, in whom there is an increased average 
mutant allele frequency, indicating clonal selection (Heuck et al. 2015). 
Recent reports have demonstrated that MM cases with BRAF V600E mutations can 
respond to the BRAF inhibitor vemurafenib, even in the autologous stem cell transplant 
double-refractory setting, suggesting that blocking the MAPK pathway can be effective, 
even in end-stage, genetically complex cases (Andrulis et al. 2013).
Heuck et al. (2016) reported a retrospective analysis of 58 patients with MM who were 
treated on a compassionate basis with the MEK inhibitor trametinib, as a single agent or 
in combination with other drugs.  Patients were selected based on MAPK hyperactivation 
identified by comprehensive genomic profiling using the FoundationOne Heme assay. 
The median number of prior treatments was five.
In most cases, trametinib was started as a single agent and other agents were added 
during the course of the treatment. Of the 40 patients with measurable disease at time 
of trametinib initiation, 16 patients (40%) experienced a reduction of the measurable 
M-protein by at least 50%.  This number (16 patients) was reduced to 4 patients when 
only considering the time on single-agent trametinib.  The most significant adverse 
events were rash, diarrhea and cardiac toxicities (Heuck et al. 2016).
Selumetinib, a MEK1/2 inhibitor, was administered to patients with MM with a median 
number of prior therapies of 5 (range: 211). The most common toxicities included 
anemia, neutropenia, thrombocytopenia, diarrhea, and fatigue.  The response rate 
(CRPR) was 5.6% and the median PFS of 3.52 months.  One patient with a multiple 
myeloma SET domain translocation had a VGPR, 1 patient had a PR, 17 patients had 
SD, 13 patients had PD, and 4 patients could not be assessed for response 
(Holkova et al. 2016).
Despite limited activity of previous MEK inhibitors administered as single agents in 
heavily pretreated patients, the anti-MM activity seems to be improved with the 
combination strategy even in the refractory setting.  In this study, cobimetinib will be 
investigated for patients with MM, both as a single agent and in combination with either
venetoclax or venetoclax plus atezolizumab.


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1.10.2
Rationale for Evaluating Cobimetinib and Venetoclax, and 
Cobimetinib with Venetoclax and Atezolizumab in 
Relapsed/Refractory Multiple Myeloma
The Bcl-2 family protein members interact to prevent or induce apoptosis. "Activator"
BH3-only proteins (Bid, Bad, Bim, Bik, Bmf, Noxa, Puma, and Hrk) directly interact with 
"effector" Bax and/or Bak, inducing the assembly of Bak/Bax multimeric pores in the 
mitochondrial membrane and triggering cellular apoptosis.  Anti-apoptotic Bcl-2 family 
members (Bcl-2, Bcl-xL, Mcl-1, Bcl-w, BFL-1/A1) inhibit apoptosis by sequestering the 
activators and preventing engagement of Bax and Bak (Certo et al. 2006).  
In the clinical setting, venetoclax administered as monotherapy has an acceptable 
safety profile in R/R MM.  Preliminary efficacy shows significant anti-myeloma activity of 
venetoclax, particularly for MM harboring chromosomal translocation t(11;14) 
(Kumar et al. 2015; Punnoose et al. 2016).  Bcl-2 inhibition is overcome by the 
overexpression of other pro-survival proteins such as Mcl-1 (Cragg et al. 2008; 
Punnoose et al. 2016).  Antagonism of the action of pro-survival Bcl-2 proteins with a 
Bcl-2 inhibitor and enrichment of pro-apoptotic BH3-only proteins like Bim may be an 
effective strategy for overcoming the high levels of Bcl-2 and Mcl-1 to promote apoptosis 
and overcome resistance of tumor cells (Cragg et al. 2008). MEK inhibition prevents the 
phosphorylation of Bim by ERK, facilitating increased Bim expression.  Thus, MEK 
inhibition offsets the prosurvival effect of Bcl-2 (VanBrocklin et al. 2009) and the 
combination of a MEK inhibitor and a Bcl-2 inhibitor potentially shifts the apoptotic and 
pro-survival signaling equilibrium in favor of apoptosis.  Furthermore, this synergism is 
relevant in MM because hematologic malignancies are highly dependent on Bcl-2 
overexpression and its anti-apoptotic effects.  
Hence, the combination of cobimetinib plus venetoclax represents a strategy for 
inducing MM cell apoptosis by increasing Bim expression via MEK inhibition and by 
venetoclax-induced inhibition of Bcl-2.  In preclinical models of acute leukemia, MEK 
inhibition synergizes with Bcl-2/Bcl-xL family inhibitors to suppress proliferation and 
induce apoptosis in leukemic cells.  That synergism is mediated by the pro-apoptotic 
factor Bim, which is dephosphorylated as a result of MEK inhibition, allowing it to bind 
and neutralize MCL-1, thereby enhancing Bcl-2 inhibitor-induced cell death 
(Korfi et al. 2016).  Cobimetinib plus venetoclax is being explored in a R/R AML clinical
trial (Study GH29914) (see Section 1.9).
Historically, ERK signaling downstream MEK was synonymous with cell proliferation but 
it is now clear that deregulation of this pathway is linked to many other aspects of the 
tumor phenotype.  MEK inhibition potentially enhances the anti-tumor activity of 
atezolizumab since the MAPK pathway plays an important role in immune evasion.  
Clinical and nonclinical data show a negative association between MEK activity and both 
active antigen presentation (MHC antigen expression) and PD-L1 expression 
(Ebert et al. 2016; Loi et al. 2016). Consistently, MEK inhibition results in an increased 
number of tumor-infiltrating CD8T lymphocytes and both enhanced PD-L1 and MHC 


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antigen expression (Ebert et al. 2016; Loi et al. 2016).  These effects are responsible for 
the enhanced anti-tumor immune response observed with the combination of MEK 
inhibitors with agents targeting PD-L1/PD-1 (Loi et al. 2016).  Additionally, induction of 
CD4CD25FoxP3Treg cells (which are implicated in tumor immune escape) 
depend on MAPK activity.  Pharmacological inhibitors of MEK/ERK signaling inhibit the 
production of TGFβ, which induces the differentiation of CD4T-cells into Treg 
(Hossain et al. 2015).  Consequently, the hyperactivated MAPK pathway has been 
identified as a potential target for increasing the CD8+ lymphocyte tumor infiltration, 
enhancing PD-L1 and MHC antigen expression, and reversing the Treg cell 
augmentation in patients with malignant diseases. 
In the context of a pro-apoptotic state and a primed tumor microenvironment, the 
addition of atezolizumab to cobimetinib plus venetoclax may further enhance anti-tumor 
activity.  Myeloma cells have preserved adaptive mechanisms of regulating PD-L1 
expression in response to inflammatory cytokines (Liu et al. 2007).  Moreover, direct 
interaction with stromal cells also upregulates PD-L1 expression in myeloma cells 
(Tamura et al. 2013).  Notably, PD-L1 expression appears to be higher not only 
after relapse but also in more advanced disease (Stages 23 vs. Stage 1) 
(Tamura et al. 2013).
The triple combination of cobimetinib, venetoclax, and atezolizumab targets key features 
of cancer cell biology including proliferation, resistance to programmed cell death, and 
immune evasion (Hanahan and Weinberg 2011).  The combination of a MEK inhibitor 
and a Bcl-2 inhibitor is supported by emerging insights into the molecular pathogenesis 
of MM, and the addition of atezolizumab may potentially further enhance the anti-
myeloma immune response.  Based on the significant unmet medical need for patients 
with R/R MM and the safety/efficacy profile of each agent, the Sponsor considers this 
study to have a favorable benefit-to-risk assessment for patients.


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2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, tolerability, and pharmacokinetics of 
cobimetinib administered as a single agent, cobimetinib plus venetoclax, and cobimetinib 
plus venetoclax plus atezolizumab in patients with R/R MM.  Specific objectives and 
corresponding endpoints are outlined below.
Table 2
Objectives and Corresponding Endpoints
Primary Objective
Corresponding Endpoints
To evaluate the preliminary safety and 
tolerability and the preliminary efficacy of 
cobimetinib administered as single agent 
(Arm A), cobimetinibvenetoclax
(Arm B), and cobimetinibvenetoclax 
atezolizumab (Arm C)
Incidence, nature, and severity of adverse events, 
graded according to NCI CTCAE, v4.0; laboratory data
ORR (sCR, CR, VGPR, PR) as determined by the 
investigator using the IMWG response criteria 
(Kumar et al. 2016) in the safety population and 
biomarker-selected population
Secondary Efficacy Objective
Corresponding Endpoints
To further evaluate the efficacy of 
cobimetinib administered as single agent 
(Arm A), cobimetinibvenetoclax
(Arm B), and cobimetinibvenetoclax 
atezolizumab (Arm C)
CBR defined as MR or better
PFS defined as the time from randomization to the first 
occurrence of disease progression or relapse as 
determined by the investigator using the IMWG criteria 
or death from any cause during the study, whichever 
occurs first
DOR applies to patients achieving at least a PR, and is 
measured from the first observation of PR to the time 
of disease progression; deaths not due to progression
will be censored
OS defined as the time from randomization until death 
from any cause


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Table 2
Objectives and Corresponding Endpoints (cont.)
Exploratory Efficacy Objective
Corresponding Endpoint
To evaluate the time elapsed before 
requiring the start of further anti-myeloma 
treatment 
Time to next treatment defined as the time between the 
start date of the current treatment line and the start 
date of the next treatment line, death or last follow-up
Pharmacokinetic Objective
Corresponding Endpoints
To characterize the pharmacokinetics 
of cobimetinib (Arm A), to characterize 
the pharmacokinetics of cobimetinib
and venetoclax when administered 
together (Arm B), and to characterize 
the pharmacokinetics of cobimetinib, 
venetoclax, and atezolizumab when 
administered together (Arm C)
Plasma concentration of cobimetinib and venetoclax 
at specified timepoints
Serum concentration of atezolizumab at specified 
timepoints
Immunogenicity Objective
Corresponding Endpoint
To evaluate the immune response to 
atezolizumab administered in Arm C
Incidence of ADAs during the study relative to the 
prevalence of ADAs at baseline
Exploratory Immunogenicity Objective
Corresponding Endpoint
To evaluate the potential effects 
of ADAs
Correlation between ADA status and efficacy, safety, 
or PK endpoints
Exploratory Biomarker Objectives
Corresponding Endpoints
To identify biomarkers that are 
predictive of response to cobimetinib, 
venetoclax, and atezolizumab, such as 
RAS mutation, t(11;14) translocation, 
Bcl-2 family proteins, and pretreatment 
immune contexture
Identification and profiling of 
biomarkers associated with disease 
biology; the mechanisms of action of 
cobimetinib alone (Arm A), 
cobimetinib venetoclax (Arm B), or 
cobimetinib venetoclax 
atezolizumab (Arm C); mechanism of 
resistance to drugs in all the arms; 
pharmacodynamics; prognosis and 
improvement of diagnostic assays 
Determine impact of MRD
measurements with patient response 
and survival
The effect of treatment with cobimetinib, venetoclax, 
and atezolizumab on markers of MAPK pathway 
activity, apoptosis, immune infiltration and activation 
Determine impact of MRD measurements with patient 
responses and survival
Relationship between biomarkers in blood and bone 
marrow (may include somatic mutations, listed in 
Section 4.5.6) and efficacy, safety, pharmacokinetics, 
immunogenicity, or other biomarker endpoints.
ADAanti-drug antibody; CBRclinical benefit rate; CRcomplete response; DORduration of 
response; IMWGInternational Myeloma Working Group; MAPKmitogen-activated protein 
kinase; MRminimal response; MRDminimal residual disease; NCI CTCAE v4.0 National
Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0; ORRoverall
response rate; OSoverall survival; PFSprogression-free survival; PKpharmacokinetic;
PRpartial response; sCR stringent complete response; VGPRvery good partial response.




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3.1.1.1
Safety Run-In Phase
Cobimetinib plus Venetoclax Safety Run-In Cohort
The cobimetinib plus venetoclax safety run-in cohort will enroll 6 patients with a starting 
dose of cobimetinib 40 mg PO daily on Days 121, plus venetoclax 800 mg PO daily on
Days 128 of each 28-day cycle.  This combination is currently being evaluated in an 
ongoing Phase Ib/II study (Study GH29914, a multi-arm study with venetoclax in 
combination with cobimetinib and venetoclax in combination with idasanutlin in patients 
aged 60 years with R/R AML who are not eligible for cytotoxic therapy). In that study, 
cobimetinib 40 mg plus escalating doses of venetoclax (400, 600, and 800 mg) have 
been explored as part of the dose-escalation phase.
The study team will evaluate the safety and tolerability data from the first cycle of 
treatment for patients in the cobimetinib plus venetoclax safety run-in cohort in 
accordance with the following rules:

If 2 of 6 (33%) evaluable patients experience a DLT (as defined in
Section 3.1.1.2), cobimetinib 40 mg plus venetoclax 800 mg will be considered to 
have acceptable safety.

If 2 of 6 (33%) evaluable patients experience a DLT, then one or more 
sequential cohorts of 6 additional evaluable patients will be enrolled and treated with 
cobimetinib 40 mg plus lower doses of venetoclax (600 mg 400 mg 200 mg) 
until 2 of 6 evaluable patients experience a DLT.
This same approach with respect to the management of patients treated with cobimetinib 
40 mg plus venetoclax 800 mg will be used for the evaluation of cohorts of patients 
treated with cobimetinib at 40 mg and lower doses of venetoclax at (600 mg 400 mg 
200 mg). If the dose of venetoclax reaches 200 mg, then if necessary, the dose of 
cobimetinib may be reduced to a final dose of 20 mg. After the last patient has been 
enrolled and completed the DLT period in the safety run-in cohort of the cobimetinib plus 
venetoclax combination, patient enrolment in the cobimetinib plus venetoclax plus 
atezolizumab safety run-in cohort can start provided that the treatment is considered to 
have acceptable safety.
Cobimetinib plus Venetoclax plus Atezolizumab Safety Run-In Cohort
Once the dose level of cobimetinib plus venetoclax is considered safe in the safety 
run-in cohort, a cohort of 6 evaluable patients will then be treated with cobimetinib plus 
venetoclax plus atezolizumab.  Cobimetinib PO and venetoclax PO will be administered 
at the selected dose for the randomization phase of the study with atezolizumab IV 
at the fixed dose of 840 mg on Day 1 and Day 15 (3 days) of each 28-day cycle
(note: Cycle 1 of the safety run-in phase does not include the 3-day window). For this 
cohort, a staggered design will be adopted for the first 3 patients.  One patient will be 
enrolled and dosed in the initial dose cohort.  Afterwards, patients will be enrolled 
sequentially once the prior patient has completed the first cycle with an acceptable 
safety.  If no DLTs are observed in the first 3 patients, 3 more patients will be enrolled 


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simultaneously.  If a DLT is observed in 1 of the first 3 patients, the following 3 patients 
will be enrolled consecutively after the completion of the first cycle of the prior patient.
Once the last patient has completed the first cycle of therapy, patient enrollment will be 
put on hold until the study team has completed the evaluation of the safety and 
tolerability data of the cobimetinib plus venetoclax plus atezolizumab safety run-in phase
of the study in accordance with the following rules:

Cobimetinib plus venetoclax plus atezolizumab will be considered safe if 
2 evaluable patients experience a DLT during the first cycle of treatment.

If 2 of 6 (33%) evaluable patients experience a DLT, then one or more 
sequential cohorts of 6 additional evaluable patients will be enrolled and treated with 
cobimetinib 40 mg plus lower doses of venetoclax (600 mg 400 mg 200 mg) 
until 2 of 6 evaluable patients experience a DLT.

If 2 of 6 (33%) evaluable patients experience a DLT with the new lower dose 
level, this would be the selected dose for the randomization phase of the study.

If 2 of 6 (33%) evaluable patients experience a DLT, 6 additional patients will be 
enrolled and assessed for DLTs at lower dose levels.
For initial dose reductions at the starting dose, cobimetinib and atezolizumab will remain 
fixed with dose reductions for venetoclax if needed in sequential decrements of 
200 mg. If the dose of venetoclax reaches 200 mg, then if needed, the dose of 
cobimetinib may be reduced from the starting dose of 40 mg to a final dose of 20 mg.
Definition of Evaluable Patients in the Safety Run-In Cohorts 
During the safety run-in phase of the study, patients will be evaluable if they have 
completed at least 70% of the protocol-planned dose for each individual drug. If a 
significant decrease (70%) in the intended relative dose intensity is due to safety 
reasons, the toxicity will be considered a DLT. If the significant decrease (70%) in the 
intended relative dose intensity is due to unrelated adverse events or to PD, then the 
patient will be replaced.
An interim analysis for safety will be performed prior to the randomization phase to 
assess data from all safety run-in cohorts. The analysis will assess the DLTs during the 
DLT period and the tolerability of the study treatments for patients who have received 
more than one cycle of study therapy.  The interim analysis will be completed after the 
last evaluable patient in Arm C (triplet regimen) has concluded the first cycle. 
3.1.1.2
Randomization Phase 
After the safety run-in phase and prior to patient randomization (1:2:2 for Arms A:B:C), a 
biomarker assessment for the translocation t(11;14) will be performed to allow 
randomization of a representative MM population and to ensure that approximately 
20% of patients in each arm have MM with a t(11;14) (Avet-Loiseau et al. 2007).  
See Section 3.3 for patient assignment to study arms. 


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Approximately 12 patients will be randomized to the cobimetinib single-agent arm 
(Arm A) and will receive the standard single-agent cobimetinib dose of 60 mg PO daily 
on Days 121 of each 28-day cycle.  Upon progression, patients will be allowed to 
receive treatment with cobimetinib and atezolizumab at the recommended Phase II dose 
of cobimetinib 60 mg PO from Day 1 to Day 21 plus atezolizumab IV at a fixed dose of 
840 mg on Day 1 and Day 15 (3 days) of each 28-day cycle. This combination at the 
above-indicated doses is currently being explored in multiple clinical studies including a 
Phase III clinical trial in patients with metastatic CRC (Study GO30182).
Arm B (cobimetinib plus venetoclax) will randomize approximately 24 patients to receive 
cobimetinib plus venetoclax at the dose level identified in the safety run-in phase.
Arm C will randomize approximately 24 patients to receive cobimetinib plus venetoclax 
at the dose level identified in the safety run-in phase plus atezolizumab IV at a fixed 
dose of 840 mg on Day 1 and Day 15 (3 days) of each 28-day cycle.
The study drugs will be administered on 28-day cycles as follows: 
Arm A:  Cobimetinib

Cobimetinib 60 mg PO daily on Days 121

Upon progression, patients in Arm A are allowed to receive treatment with:
–
Cobimetinib 60 mg PO daily on Days 121
–
Atezolizumab 840 mg IV infusion on Day 1 and Day 15 (3 days)
Arm B:  Cobimetinib Venetoclax 

Cobimetinib 40 mg PO daily on Days 121

Venetoclax 800 mg PO daily on Days 128
Arm C:  Cobimetinib Venetoclax Atezolizumab

Cobimetinib (dose to be determined in Arm B) PO daily on Days 121

Venetoclax (dose to be determined in Arm B) PO daily on Days 128

Atezolizumab 840 mg IV on Day 1 and Day 15 (3 days)
Treatment will continue until the patient has disease progression as defined by the 
International Myeloma Working Group (IMWG) consensus criteria (Kumar et al. 2016), 
unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy,
whichever occurs first.


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All patients will be closely monitored for safety and tolerability during all cycles of 
therapy, at the treatment discontinuation visit, and during the follow-up period.  A 
treatment discontinuation visit will take place within 30 (7) days after the last dose of 
study drug. After PD and study treatment discontinuation, the required follow-up 
information will be collected via telephone calls and/or clinic visits every 3 months until 
death, withdrawal of consent, the patient is lost to follow-up, or study termination by the 
Sponsor, whichever occurs first.
Any toxicity associated with, or possibly associated with cobimetinib and/or venetoclax 
administration should be managed with supportive care and/or dose interruptions 
(maximum allowable length of treatment interruption is 28 days) and/or dose reductions. 
If the investigator considers that the patient could derive clinical benefit from the study 
treatment after an interruption longer than 28 days, study treatment may continue after 
discussion with the Medical Monitor.  Toxicity due to atezolizumab administration will be 
managed by supportive care and/or dose interruptions.  No dose modification of 
atezolizumab is allowed in this study.
A DLT will be defined as any of the following adverse events related to study treatment 
occurring during the DLT period which corresponds to the first cycle of study treatment
(from Cycle 1 Day 1 to Cycle 1 Day 28):

Any treatment-related death

Grade 4 hematologic toxicity lasting 7 days or higher (except leukopenia or 
lymphopenia)

Treatment-related non-hematologic toxicity Grade 3 (according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 
[NCI CTCAE v4.0]) except for the following:
–
Grade 3 fatigue, asthenia, fever, anorexia, or constipation
–
Grade 3 nausea, vomiting, or diarrhea that responds to maximal supportive care
within 72 hours 
–
Grade 3 rash that resolves to Grade 1 within 7 days with maximal supportive care
–
Grade 3 laboratory abnormality that is asymptomatic and deemed to be not clinically 
significant by the investigator

A patient who receives less than 70% (Postel-Vinay 2015) of the protocol-planned 
dose for each individual drug due to drug-related toxicity
If any of the DLT toxicities occur and are assessed as related to study treatment by the 
investigator, the study treatment will be halted immediately for the individual patient, and 
a thorough investigation and safety analysis will be conducted.
NCI CTCAE v4.0 will be used to characterize the toxicity profile of the study treatments 
on all patients.


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Anti-myeloma response will be evaluated according to IMWG criteria (Kumar et al. 2016; 
Appendix 5). Disease evaluations will include biochemical disease assessments, 
skeletal survey, bone marrow aspirate, and biopsy (see Section 4.5 for details and 
Appendix 1 for the schedule of activities). Investigators will assess anti-myeloma 
response every cycle, regardless of any dose delays.  Patients who discontinue 
treatment for reasons other than disease progression (e.g., for toxicity) will continue to 
have tumor assessments as scheduled until confirmed disease progression per IMWG 
criteria, withdrawal of consent, initiation of a new anti-cancer therapy, study termination 
by the Sponsor, or death, whichever occurs first.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as when all patients randomized have been followed 
until death, withdrawal of consent, lost to follow-up, or the Sponsor decides to end the 
trial, whichever occurs first.
The total length of the study, from first patient in until end of follow-up, as described 
above, is expected to be approximately 24 months.
3.3
PATIENT NUMBERS AND ASSIGNMENT TO 
TREATMENT GROUPS
Approximately 72 patients with R/R MM (across the three arms) will be recruited into this 
study, from approximately 25 centers worldwide. A Web-based randomization system 
will be used to collect patient screening information and randomize eligible patients.
The safety run-in phase of the study will consist of two sequentially enrolled cohorts:   
cobimetinib plus venetoclax safety run-in cohort (n6), and the cobimetinib plus 
venetoclax plus atezolizumab safety run-in cohort (n6); see Section 3.1.1.1. These 
patients will not be randomized. Once the dose levels are considered safe, the 
randomization phase of the study will begin. Patients will be randomized at an initial 
1:2:2 ratio to one of three treatment arms (Arm A: n12, Arm B: n24, and Arm C:  
n24). A stratified block randomization list will be used, stratified by t(11;14) 
translocation. A population cap will be used for recruitment to ensure that approximately 
20% of patients in each arm of the randomized phase have t(11;14) translocation prior to 
patient randomization; that is, Arm A will randomize approximately 3 patients with 
t(11;14), and Arms B and C each will randomize approximately 5 patients with t(11;14).
3.4
RATIONALE FOR STUDY DESIGN
3.4.1
Rationale for the Triple-Arm Design
The combinations of cobimetinib with venetoclax and cobimetinib with venetoclax and 
atezolizumab are expected to have a highly synergistic anti-tumor activity.  This study is 
designed to show the incremental additive benefit with the addition of each individual 
drug.  Arm A will assess the activity of cobimetinib as a single agent because the 
single-agent activity of cobimetinib in MM has not been explored before.  Ideally, the 


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single-agent activity of one agent should be defined to allow demonstrating the 
incremental benefit with the addition of each drug.  Upon progression patients can be 
treated with the combination of cobimetinib and atezolizumab to maximize the 
opportunity for disease control.
From the three potential doublets that could result from combining the three study 
agents, the combination of cobimetinib with venetoclax together with that of cobimetinib 
and atezolizumab, were selected because they are the doublets with the highest 
expected synergism based on the mechanism of action. This expected high synergism 
is due to the increase of the proapoptotic protein Bim resulting from the MEK inhibition 
by cobimetinib, whereas venetoclax inhibits the anti-apoptotic protein Bcl-2.  Thus, the 
combination of cobimetinib with venetoclax is the doublet that will be explored in Arm B.
The third arm (Arm C) is designed to enhance anti-tumor activity by addition of 
atezolizumab to the combination of cobimetinib and venetoclax. 
3.4.2
Rationale for the Safety Run-In Phase 
The safety run-in phase is designed to confirm safety of the doublet regimen 
(cobimetinib plus venetoclax) and further evaluate safety of the triplet regimen 
(cobimetinib plus venetoclax plus atezolizumab).  Cobimetinib has been approved for the 
treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or 
V600K mutation, in combination with vemurafenib. Cobimetinib monotherapy dose is 
well established and therefore will be directly used during the randomization phase of 
the study in patients randomized to Arm A.
As previously indicated, the selected starting dose of cobimetinib plus venetoclax is 
currently being explored in patients with R/R AML not suitable for cytotoxic therapy in 
study GH29914. Previous dose levels (venetoclax 400 mg and 600 mg in combination 
with cobimetinib 40 mg) have been considered safe in that fragile population. The safety 
run-in cohort for cobimetinib plus venetoclax aims to evaluate in 6 patients, as performed 
in dose-escalation studies with a 33 study design, if the starting dose can be expanded 
in the randomization phase of the study.
Atezolizumab will be added to cobimetinib plus venetoclax in the third safety run-in 
cohort.
The Phase Ib study (GP28363) has shown that cobimetinib administered at 60 mg PO 
21/7 with atezolizumab 840 mg IV every 2 weeks in 28-day cycles is safe and tolerable.
The starting dose of venetoclax plus cobimetinib for the triplet regimen will be the same 
as the dose level for the doublet regimen identified in the safety run-in cohort, once it 
has been shown to be safe.  Furthermore, additional safety information for the 
combination of cobimetinib and venetoclax should be available from Study GH29914 at 
the time of the start of the study.  


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Although venetoclax has some overlapping toxicities with cobimetinib and atezolizumab, 
the risk mitigation measures incorporated into this protocol are expected to manage this 
risk, including the initial enrollment of a limited number of patients until the safety and 
tolerability has been evaluated. The safety run-in cohort aims to evaluate in 6 patients if
the observed toxicity for the triplet regimen allows the starting dose to be expanded in 
the randomization phase of the study. 
3.4.3
Rationale for Cobimetinib Dose and Schedule
The planned starting dose for cobimetinib is 60 mg PO daily (the current approved dose)
on Days121 of each 28-day cycle.  This dose is the standard cobimetinib dose that 
demonstrated acceptable safety and efficacy when administered with vemurafenib in 
Study GO28141 in patients with advanced BRAF-mutated malignant melanoma 
(Larkin et al. 2014).
The selected starting dose for cobimetinib and venetoclax in the safety run-in phase 
(cobimetinib 40 mg PO daily on Days 121; venetoclax 800 mg PO daily on Days 128)
is the same as the dose currently being evaluated in Study GH29914 (patients with R/R
AML who are not eligible for cytotoxic therapy).
For the triplet regimen, cobimetinib will be administered at a dose considered to have 
acceptable toxicity in the safety run-in phase.
3.4.4
Rationale for Venetoclax Dose and Schedule
As previously mentioned, the selected starting dose of venetoclax for the safety run-in 
phase is the same as the dose currently being evaluated in Study GH29914 (venetoclax 
in combination with cobimetinib 40 mg). In that study, venetoclax dose selection was 
based on the experience from the Phase II study M14-212 with single-agent venetoclax 
in patients with RR or frontline AML. In Study M14-212, doses of up to 1200 mg daily 
were well tolerated.
The dose of venetoclax in combination with cobimetinib will be evaluated in the safety 
run-in phase. Lower dose levels of venetoclax will also be evaluated in case the 800-mg 
dose in combination with cobimetinib at 40 mg does not demonstrate acceptable safety.  
3.4.5
Rationale for Atezolizumab Dose and Schedule
Patients in Arm C (as well as patients in Arm A with disease progression), will be 
administered atezolizumab at a flat dose consisting of 840 mg IV on Day 1 and
Day 15 (3 days) of each 28-day cycle.  This dosage is equivalent to an average body 
weight-based dose of 15 mg/kg Q3W. The dosage of 15 mg/kg Q3W was selected as 
the recommended Phase II dose for atezolizumab based on both nonclinical studies and 
available clinical data from a Phase I study (PCD4989g), as described below.
The target exposure for atezolizumab was projected on the basis of clinical and 
nonclinical parameters, including nonclinical tissue distribution data in tumor-bearing 


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mice, target-receptor occupancy in the tumor, and observed atezolizumab interim 
pharmacokinetics in humans.  The target trough concentration (Ctrough) was projected to 
be 6 g/mL based on several assumptions, including the following: 1) 95% tumor 
receptor saturation is needed for efficacy and 2) the tumor interstitial concentration-to-
plasma ratio is 0.30 based on tissue distribution data in tumor-bearing mice.
In Study PCD4989g, the first-in-human study in patients with advanced solid tumors and 
hematologic malignancies, 30 patients were treated with atezolizumab at doses ranging 
from 0.01 to 20 mg/kg Q3W during the dose-escalation stage and 247 patients were 
treated with atezolizumab at doses of 10, 15, or 20 mg/kg Q3W during the 
dose-expansion stage.  Anti-tumor activity has been observed across doses ranging 
from 1 mg/kg to 20 mg/kg.  There was no evidence of dose-dependent toxicity in 
Study PCD4989g.  The MTD of atezolizumab was not reached, and no DLTs were 
observed at any dose.  Anti-drug antibodies (ADAs) to atezolizumab were associated 
with changes in pharmacokinetics for some patients in the lower-dose cohorts (0.3, 1, 
and 3 mg/kg), but patients treated at 10, 15, and 20 mg/kg maintained the expected 
target trough levels of drug despite the detection of ADAs.  To date, no relationship has 
been observed between the development of measurable ADAs and safety or efficacy.  
After review of available PK and ADA data for a range of doses, 15 mg/kg Q3W was 
identified as the lowest atezolizumab dosing regimen that would maintain Ctrough at
6 g/mL, while further safeguarding against interpatient variability and the potential for 
ADAs to lead to subtherapeutic levels of atezolizumab.
Simulations (Bai et al. 2012) do not suggest any clinically meaningful differences in 
exposure following a fixed dose compared with a body weightadjusted dose. 
Therefore, patients in this study will be treated Q2W at a fixed dose of 840 mg 
(equivalent to an average body weightbased dose of 15 mg/kg Q3W).
3.4.6
Rationale for Patient Population
This study will recruit patients with R/R MM who have received three to five prior lines of 
therapy (including a PI and an IMiD), who are refractory or intolerant to their last prior 
therapy, and who have responded to at least one line of therapy.  In particular, the 
double refractory population has a dismal prognosis with a median OS of approximately 
9 months (Kumar et al. 2012). Patients are required to have had at least a minimal 
response (MR) or better to one prior line of therapy.
Despite the recent approval of daratumumab for patients with MM who have received at 
least three prior lines of therapy, the response rate for daratumumab monotherapy is 
31% and the median duration of response (DOR) is 7.6 months (Usmani et al. 2016). 
Therefore, a significant proportion of patients do not derive benefit from daratumumab 
monotherapy, and new combinations with novel mechanisms of action are highly 
desirable in this patient population.


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3.4.7
Rationale for Blood and Bone Marrow Sampling for Biomarker 
Assessments
An exploratory objective of this study is to evaluate biomarkers (including but not limited 
to MAPK pathway, Bcl-2 pathway, and immune-related biomarkers) that will help to 
predict response in patients treated with cobimetinib alone (Arm A), cobimetinib plus 
venetoclax (Arm B), or cobimetinib plus venetoclax plus atezolizumab (Arm C).  An 
exploratory objective of this study is to make a preliminary assessment of potential 
pharmacodynamic markers to provide evidence for the biologic activity of cobimetinib 
alone (Arm A), cobimetinib plus venetoclax (Arm B), or cobimetinib plus venetoclax plus 
atezolizumab (Arm C) in patients with R/R MM and may allow for the early prediction of 
clinical benefit or mechanism of resistance with the use of this treatment regimen.
In addition, minimal residual disease (MRD) will be assessed in this study as it is most 
likely one of the most important features that may contribute to the link between the 
depth of response and long-term outcomes (Kumar et al. 2016).
In addition, potential correlations of these biomarkers with the safety and activity of 
cobimetinib with venetoclax and atezolizumab will be explored.
3.4.8
Rationale for Pharmacokinetic Collection
The proposed PK sampling scheme for assessment of venetoclax, cobimetinib, and 
atezolizumab concentrations, together with available data from other clinical studies, will 
be used to investigate the impact of concomitant administration on PK parameters of 
each compound. 
On the basis of the clearance mechanisms of each compound, it is not expected that 
concomitant administration of venetoclax, cobimetinib, and atezolizumab will 
substantially alter the pharmacokinetics of any of the administered compounds.
Atezolizumab is primarily eliminated by catabolism to inactive metabolites, and therefore 
has a low potential for CYP-related drug interactions. Cobimetinib and venetoclax are 
metabolized primarily by CYP3A, based on in vitro data, which is unlikely to be affected 
by atezolizumab. 
The pharmacokinetics of cobimetinib in combination with venetoclax (Arm B) and with 
venetoclax and atezolizumab (Arm C) will be compared to single-agent cobimetinib 
pharmacokinetics (Arm A). In addition, the pharmacokinetics of each compound will be 
compared with available PK data for each molecule from previous studies. Serum and 
plasma samples will be collected as outlined in Appendix 2.


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4.
MATERIALS AND METHODS
4.1
PATIENTS
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years

Able to comply with the study protocol, in the investigator’s judgment

ECOG Performance Status of 0, 1, or 2 (see Appendix 4)

Life expectancy of at least 12 weeks

Documented MM as defined by the below criteria:
–
Monoclonal plasma cells in the bone marrow 10% or presence of a biopsy-proven 
plasmacytoma
–
Measurable disease as defined by any of the following: 
Serum M-protein level 1.0 g/dL or urine M-protein level 
200 mg/24 hours; or 
Light chain MM: Serum Ig free light chain (FLC) 10 mg/dL and abnormal 
serum Ig kappa/lambda FLC ratio

Received 3 to 5 prior lines of therapy for MM, including a PI and an IMiD
–
A line of therapy consists of 1 complete cycle of a single agent, a regimen 
consisting of a combination of several drugs, or a planned sequential therapy of 
various drugs (e.g., induction therapy followed by stem cell transplantation [SCT] is 
considered 1 line of therapy) (Rajkumar et al. 2015) 

Achieved a response (MR or better) to at least one prior regimen

Documented evidence of PD (as defined by the IMWG criteria) on or after their last 
prior therapy, or patients who were intolerant to their last prior therapy
Note: There is no required time period between last prior therapy and evidence 
of PD.

Toxicities resulting from previous therapy (including peripheral neuropathy) that
must be resolved or stabilized to Grade 1

Laboratory values as follows:
–
Hemoglobin level 7.5 g/dL (5 mmol/L) (without growth factor support)
–
Platelet count 50,000/mm3 or 30,000 if bone marrow plasma cell 50% (without 
transfusion support)
–
Absolute neutrophil count 1000/mm3 (without growth factor support)
–
AST and ALT 2.5the ULN
–
Total bilirubin1.5ULN


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–
Adequate renal function as demonstrated by a calculated creatinine clearance of
40 mL/min; determined via urine collection for 24-hour creatinine clearance or by
the Cockcroft-Gault formula 

For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two contraceptive measures, and agreement to 
refrain from donating eggs, as defined below:
–
A woman is considered to be of childbearing potential if she is post-menarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with 
no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus).
–
Women must remain abstinent or use two contraceptive methods with a failure rate 
of 1% per year during the treatment period and for at least 3 months after the final 
dose of cobimetinib, 1 month after the final dose of venetoclax, and 5 months after 
the final dose of atezolizumab.  Women must refrain from donating eggs 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, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception.
–
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

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 female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at least 
3 months after the last dose of cobimetinib 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, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Anti-myeloma treatment within 14 days or 5 PK half-lives of the treatment, 
whichever is longer, before the date of randomization

Completion of autologous stem cell transplant within 100 days prior to the date of 
randomization

Prior allogeneic stem cell transplant as well as prior solid organ transplant

Spinal cord compression not definitively treated with surgery and/or radiation


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
Prior treatment with MEK inhibitors, Bcl-2 inhibitors, or immune checkpoint inhibitor 
therapies including antiCTLA-4, antiPD-1 or antiPD-L1

Treatment with systemic immunostimulatory agents (including, but not limited to, 
CD137 agonists or interferon and interleukin 2 [IL-2]) within 28 days or 5 half-lives of 
the drug (whichever is longer) prior to initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antiTNF-agents) within 14 days prior to initiation of study treatment, or 
anticipation of need for systemic immunosuppressive medication during the course 
of the study, with the following exceptions:
–
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 approval has been obtained.

Surgical procedure (including open biopsy, surgical resection, or any other major 
surgery) or significant traumatic injury within 28 days prior to enrollment, or 
anticipation of need for major surgical procedure during the course of the study

Prior radiation therapy within 14 days prior to study enrollment and/or persistence of 
radiation-related adverse effects

Minor surgical procedure within 7 days (including placement of a vascular access 
device)

History or evidence of retinal pathology on ophthalmic examination that is 
considered a risk factor for neurosensory retinal detachment/central serous 
chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular 
degeneration:

History of serous retinopathy

History of RVO

Evidence of ongoing serous retinopathy or RVO at baseline

Left ventricular ejection fraction (LVEF) below institutional lower limit of normal

History of clinically significant cardiovascular dysfunction including the following:
–
Inadequately controlled hypertension (defined as systolic blood pressure 
150 mmHg and/or diastolic blood pressure 100 mmHg that is treated or 
untreated)
–
Prior history of hypertensive crisis or hypertensive encephalopathy
–
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
arterial thrombosis) within 6 months of study enrollment 
–
History of stroke or transient ischemic attack within 6 months prior to enrollment
–
History of myocardial infarction within 6 months prior to first dose of study drug in 
Cycle 1
–
New York Heart Association Class III or IV cardiac disease


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–
Unstable arrhythmias, or unstable angina 
–
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Any previous venous thromboembolism Grade3 within 12 months of study 
enrollment

INR 1.5 and aPTT 1.5ULN within 7 days prior to study enrollment

History or evidence of inherited bleeding diathesis or significant coagulopathy at risk 
of bleeding

History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins (for patients in Arm C only)

History of other malignancy that could affect compliance with the protocol or 
interpretation of results
–
Patients with a history of curatively treated basal or squamous cell carcinoma of the 
skin or in situ carcinoma of the cervix are allowed.

Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid 
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix 7 for a more comprehensive list of 
autoimmune diseases and immune deficiencies), with the following exceptions:
–
Patients with a history of autoimmune-related hypothyroidism who are on thyroid 
replacement hormone are eligible for the study.
–
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for the study.
–
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) 
are eligible for the study provided all of following conditions are met:
Rash must cover 10% of body surface area.
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids
There is no occurrence of acute exacerbations of the underlying condition 
requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, or high potency or oral 
corticosteroids within the previous 12 months

Uncontrolled serious medical or psychiatric illness

History of malabsorption or other condition that would interfere with absorption of 
study drugs

Active tuberculosis


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
Severe infection within 28 days prior to initiation of study treatment, including, but 
not limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia

Treatment with therapeutic oral or IV antibiotics within 14 days prior to initiation of 
study treatment
–
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study.

Positive test results for hepatitis B (hepatitis B surface antigen [HBsAg] and/or total 
hepatitis B core antibody [HBcAb]) or hepatitis C virus (HCV) antibody
–
Patients positive for HBcAb are eligible only if polymerase chain reaction (PCR) is 
negative for hepatitis B virus (HBV) DNA.
–
Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.

Known history of HIV seropositivity

Treatment with a live, attenuated influenza vaccine (e.g., FluMist) within 28 days 
prior to Cycle 1 Day 1, at any time during the study, and for at least 5 months after 
the last dose of study drug (for patients in Arm C only)

Received strong CYP3A inhibitors (such as ketoconazole and clarithromycin), 
moderate CYP3A inhibitors (such as fluconazole, ciprofloxacin, and verapamil) 
strong CYP3A inducers (such as carbamazepine and phenytoin), and moderate 
CYP3A inducers (such as efavirenz, modafinil) within 7 days prior to the initiation of 
study treatment

The following foods/supplements are prohibited at least 7 days prior to initiation of 
and during study treatment:
–
St John’s wort or hyperforin (potent CYP3A enzyme inducer)
–
Grapefruit juice (potent CYP3A enzyme inhibitor)

Pregnant or lactating, or intending to become pregnant during the study
–
Women of childbearing potential must have a negative serum pregnancy test within 
7 days prior to initiation of study drug
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study.  Patients will initially be enrolled into the safety run-in phase; 
these patients are not randomized.  Once the dose levels are considered safe during the 
safety run-in phase of the study, randomization using an IxRS will begin for all three 
treatment arms (Arm A, Arm B, and Arm C; see Section 3.3).
4.3
STUDY TREATMENT 
The investigational medicinal products (IMPs) for this study are cobimetinib, venetoclax, 
and atezolizumab.  Cobimetinib, venetoclax, and atezolizumab packaging will be 
overseen by Roche clinical trial supplies department and will bear a label with the 
identification required by local law as well as the protocol number.  The packaging and 


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labeling of the study drugs will be in accordance with the Sponsor’s standards and local 
regulations.  Local packing and labeling requirements may differ in some countries.
Upon delivery of the IMPs to the site, site personnel should check for damage and verify 
proper identity, quality, integrity of seals and temperature conditions.  Site personnel 
should report any deviations or product complaints to the study monitor upon discovery.
Cobimetinib, venetoclax, and atezolizumab will be stored at the clinical site under the 
required storage conditions as indicated on the study drug labels.  Patients will be asked 
to store cobimetinib and venetoclax at the required storage conditions noted on the 
label, out of the reach of children or other co-inhabitants.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Cobimetinib
Cobimetinib will be supplied by the Sponsor as tablets.  The 20-mg cobimetinib drug 
product is a film-coated, white, round, immediate-release tablet.  Cobimetinib will be 
packaged in blister packs.  Cobimetinib should not be stored above 25°C (77°F).  If the 
study drug is stored outside of the permitted temperature ranges, quarantine the affected 
supply and contact the study monitor.
For further details, see the pharmacy manual and the Cobimetinib Investigator’s 
Brochure.
4.3.1.2
Venetoclax
Venetoclax (GDC-0199/ABT-0199) is manufactured by AbbVie, Inc. and will be supplied 
by the Sponsor as oral film-coated tablets of 100-mg strength.  Venetoclax tablets will be 
packaged in high-density polyethylene plastic bottles to accommodate the study design.  
Venetoclax tablets must be stored at 15°C25°C (59°F77°F). 
For information on the formulation and handling of venetoclax, see the pharmacy manual 
and the Venetoclax Investigator’s Brochure.
4.3.1.3
Atezolizumab
Atezolizumab will be supplied by the Sponsor as sterile liquid in 20-mL glass vials.  The 
vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution, but may contain 
more than the stated volume to enable delivery of the entire 20 mL volume.  Extraction 
of 14 mL of atezolizumab solution from a 1200 mg per vial contains 840-mg dose.
For information on the formulation and handling of atezolizumab, refer to the pharmacy 
manual and the Atezolizumab Investigator's Brochure.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Cobimetinib
Patients in Arm A will receive 60 mg cobimetinib (three tablets of 20 mg each) PO once 
daily on Days 121 of each 28-day cycle.


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Patients in Arm B will receive cobimetinib PO on Days 121 of each 28-day cycle. 
The final dose will be confirmed after the safety run-in phase.
Patients in Arm C will start receiving cobimetinib at the established dose in the safety 
run-in phase. The final dose of cobimetinib will be confirmed after the safety run-in 
phase. 
For patients in Arms B or C, cobimetinib and venetoclax should be taken at the same 
time, with venetoclax taken after cobimetinib. If the patient cannot take all the pills at the 
same time, venetoclax should be taken within 15 minutes after cobimetinib 
administration.
Cobimetinib should be taken at approximately the same time each day.  It can be taken 
with or without food.  If a dose of cobimetinib is missed or if vomiting occurs when the 
dose is taken, resume dosing with the next scheduled dose. On days that PK sampling 
is required, the study treatment dose should occur in the clinic to ensure accurate timing 
of the PK sampling.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.5.
Any overdose or incorrect administration of study drug should be noted on the Study 
Drug Administration electronic Case Report Form (eCRF).  Adverse events associated 
with an overdose or incorrect administration of study drug should be recorded on the 
Adverse Event eCRF.
4.3.2.2
Venetoclax
Patients in Arm B will receive venetoclax PO daily on Days 128 of each 28-day cycle.
The final dose will be confirmed after the safety run-in phase of the study.
Patients in Arm C will start receiving venetoclax at the established dose during the safety 
run-in phase.
For patients in Arms B or C, venetoclax and cobimetinib should be taken at the same 
time, with venetoclax taken after cobimetinib. If the patient cannot take all the pills at the 
same time, venetoclax should be taken within 15 minutes after cobimetinib 
administration.
Each dose of venetoclax will be taken PO daily with approximately 240 mL of water 
within approximately 30 minutes after the completion of breakfast or the 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.  A meal containing approximately 30% of the total caloric content from 
fat is recommended to ensure adequate absorption of venetoclax.  The following is an 


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example of a breakfast that contains approximately 520 Kcal that has 30% of its total 
caloric content from fat (approximately 17 grams of fat): 1 box cereal (3040 g), skim 
milk (240 mL), 1 boiled egg, 1 slice of toast (15 g), and 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 
his or her venetoclax dosing in the clinic on PK sampling days, the patient may have a 
low-fat snack in the morning.  The patient must be instructed not to take the 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, resume dosing with the next scheduled dose.  In cases where a dose 
of venetoclax is missed or forgotten, the patient should take the dose as soon as 
possible, ensuring that the dose is taken with food within 8 hours after the missed dose.  
Otherwise, the dose should not be taken. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.5.
Any overdose or incorrect administration of study drug should be noted on the Study 
Drug Administration eCRF.  Adverse events associated with an overdose or incorrect 
administration of study drug should be recorded on the Adverse Event eCRF.
4.3.2.3
Atezolizumab
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 6. 
Atezolizumab infusions will be administered per the instructions outlined in Table 3.
Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Day 1 and
Day 15 (3 days) of each 28-day cycle until loss of clinical benefit, unacceptable toxicity, 
or symptomatic deterioration attributed to disease progression.  Atezolizumab will be 
delivered in 250 mL 0.9% NaCl IV infusion bags.


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Table 3
Administration of First and Subsequent Atezolizumab Infusions
First Infusion
Subsequent Infusions

No premedication is permitted.

Vital signs (heart rate, respiratory rate, 
blood pressure, and temperature) should 
be recorded within 60 minutes prior to the 
infusion.

Atezolizumab should be infused over 
60 (15) minutes.

Vital signs should be recorded during the 
infusion at 15, 30, 45, and 60 minutes 
(5 minutes for all timepoints) 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 infusion-
related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator.

Vital signs should be recorded within 
60 minutes prior to the infusion and every 
15 minutes (5 minutes) during the 
infusion and at 30 (10) minutes after the 
infusion.

Atezolizumab should be infused over 
30 (10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (15) minutes if the 
patient experienced an infusion-related 
reaction with the previous infusion.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Guidelines for medical management of infusion-related reactions (IRRs) are provided 
in Appendix 8.
No dose modification for atezolizumab is allowed.  Guidelines for treatment interruption 
or discontinuation are provided in Section 5.1.5 and Appendix 8.
Any overdose or incorrect administration of study drug should be noted on the Study 
Drug Administration section of the eCRF.  Adverse events associated with an overdose 
or incorrect administration of study drug should be recorded on the Adverse Event 
section of the eCRF.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (cobimetinib, venetoclax, and 
atezolizumab) will be provided by the Sponsor where required by local health authority 
regulations.  The study site (i.e., investigator or other authorized personnel [e.g., 
pharmacist]) is responsible for maintaining records of IMP delivery to the site, IMP 
inventory at the site, IMP use by each patient, and disposition or return of unused 
IMP, thus enabling reconciliation of all IMP received, and for ensuring that patients 
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The study site should follow all instructions included with each shipment of IMP.  The 
study site will acknowledge receipt of IMPs to confirm the shipment condition and 
content.  Any damaged shipments will be replaced.  The investigator or designee must 
confirm that appropriate temperature conditions have been maintained during transit, 
either by time monitoring (shipment arrival date and time) or temperature monitoring, 
for all IMPs received and that any discrepancies have been reported and resolved before 
use of the IMPs.  All IMPs must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions, with access limited to the investigator and authorized staff.
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs.
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
Refer to the pharmacy manual and/or the Cobimetinib, Venetoclax, and Atezolizumab 
Investigator's Brochures for information on IMP handling, including preparation and 
storage, and accountability. 
4.3.4
Post-Trial Access to Cobimetinib, Venetoclax, and 
Atezolizumab
The Sponsor will offer post-trial access to the study drugs (cobimetinib, 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 Sponsor study drug(s) after completing the study if all
of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
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A patient will not be eligible to receive Sponsor study drug(s) after completing the study 
if any of the following conditions are met:

The Sponsor study drug is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
wouldn't otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for R/R MM

The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for R/R MM

Provision of study drug is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY, 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 study treatment from
14 days prior to initiation of study drug to the 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:

Anti-emetics and anti-diarrheal prophylaxis
–
The use of anti-emetics and anti-diarrheal prophylaxis is strongly recommended. 
For patients who experience Grade 3 diarrhea, anti-diarrheal prophylaxis is 
mandatory (see Section 5.1.1.3). The use of drugs for anti-emetic or anti-diarrheal
prophylaxis must be documented in the eCRF.

Oral contraceptives

Hormone-replacement therapy

Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin)

G-CSF and anti-infective prophylaxis as per institutional guidelines (provided the 
anti-infective medication is not prohibited in this study, see Section 4.4.5).

Inactivated influenza vaccinations during study treatment and at the initiation of 
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
Pneumococcal vaccination may be considered during the initiation of screening 
procedures for all patients who have not previously received the vaccine. 

Megestrol administered as an appetite stimulant 

Mineralocorticoids (e.g., fludrocortisone)

Corticosteroids administered for chronic obstructive pulmonary disease or asthma

Low-dose corticosteroids (equivalent to 7.5 mg of prednisolone per day) 
administered for orthostatic hypotension or adrenocortical insufficiency
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 patient care with supportive therapies 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 6 for anaphylaxis precautions).
4.4.2
Cautionary Therapy for Atezolizumab-Treated Patients
Systemic corticosteroids, immunosuppressive medications, and TNF-inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab.  
Therefore, in situations in which systemic corticosteroids, immunosuppressive 
medications, or TNF-inhibitors would be routinely administered, alternatives, including 
antihistamines, should be considered.  If the alternatives are not feasible, systemic 
corticosteroids, immunosuppressive medications, and TNF-inhibitors may be 
administered at the discretion of the investigator.
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy (refer to Section 5.1.5 and Appendix 8 for details).
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(see Section 4.4.5) may be used during the study at the discretion of the investigator.
4.4.3
Cautionary Therapy for Cobimetinib-Treated Patients
Hemorrhage, including major hemorrhages defined as symptomatic bleeding in a critical 
area or organ, can occur with cobimetinib. Caution should be used in patients with 


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additional risk factors for bleeding, such as CNS tumor involvement and/or in patients 
that use concomitant medications that increase the risk of bleeding (including antiplatelet 
or anticoagulant therapy).
Cobimetinib is metabolized by CYP3A.  Cobimetinib exposures were increased 6.6-fold 
in presence of itraconazole in healthy subjects. Cobimetinib exposures may be 
increased in presence of these agents, though to a lesser extent in patients with 
malignant diseases compared to that observed in healthy subjects.  
Concomitant use of strong inhibitors of CYP3A (e.g., clarithromycin, grapefruit juice, 
itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole) should be 
avoided if possible. Caution should be exercised when co-administering with moderate 
inhibitors of CYP3A (e.g., erythromycin, fluconazole, diltiazem, verapamil). 
In clinical situations that necessarily require the concomitant administration of strong or 
moderate CYP3A inhibitors the cobimetinib dose should be reduced to 20 mg upon 
discussion with the Medical Monitor.
After discontinuation of the moderate or strong CYP3A inhibitor, wait for 7 days before 
increasing the cobimetinib dose back to the initial dose level.
The above lists of medications are not necessarily comprehensive. Thus, the 
investigator should consult the prescribing information for any concomitant medication. 
In addition, the investigator should contact the Medical Monitor if questions arise 
regarding medications not listed above.
4.4.4
Cautionary Therapy for Venetoclax-Treated Patients
Concomitant use of strong (e.g., clarithromycin, grapefruit juice, itraconazole, 
ketoconazole, posaconazole, telithromycin, and voriconazole) and moderate 
(e.g., erythromycin, fluconazole, diltiazem, verapamil) inhibitors of CYP3A should be 
avoided if possible, unless the concurrent use of CYP3A inhibitors is considered 
necessary to treat or prevent a serious medical condition; consider using alternative 
medications.
In case the concurrent use of strong CYP3A inhibitors cannot be avoided, reduce the 
venetoclax dose by 75%. As well for in case of concomitant administration of moderate 
CYP3A inhibitors, reduce the venetoclax dose by 50%. 
After discontinuation of the moderate or strong CYP3A inhibitor wait for 7 days before 
increasing the venetoclax dose back to the initial dose level.
The above lists of medications are not necessarily comprehensive. Thus, the 
investigator should consult the prescribing information for any concomitant medication. 


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In addition, the investigator should contact the Medical Monitor if questions arise 
regarding medications not listed above.
4.4.5
Prohibited Therapy
Any 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 anti-cancer agent (see Section 4.1.2), 
and during study treatment until disease progression is documented and patient has 
discontinued study treatment.  This includes but is not limited to chemotherapy, 
hormonal therapy (except for contraceptives, hormone-replacement therapy, or 
megestrol acetate), immunotherapy, radiotherapy, investigational agents, or herbal 
therapy.
The following medications are prohibited while receiving study treatment, unless 
otherwise noted:

Traditional herbal medicines, as their use may result in unanticipated drug-drug 
interactions that may cause or confound assessment of toxicity.

Denosumab (a RANKL inhibitor) because it could potentially alter the efficacy and 
safety of atezolizumab. Patients who are receiving denosumab prior to enrollment 
must be willing and eligible to receive a bisphosphonate instead while in the study.

Any live, attenuated vaccine (e.g., FluMist) within 28 days prior to Cycle 1 Day 1 or 
at any time during the study and for at least 5 months after the last dose of study 
drug (for patients in Arm C only).

For cobimetinib:
–
CYP3A inducers will result in significantly lower exposures of cobimetinib.  
Therefore, the medications listed below should be avoided.  If use of one of these 
medications is necessary, the risks and benefits should be discussed with the 
Medical Monitor prior to concomitant administration with cobimetinib. 
Avoid strong and moderate CYP3A inducers (e.g., rifampin, phenytoin, 
carbamazepine, phenobarbital, and St. John’s wort) as they increase the 
metabolism of cobimetinib.  Strong inducers of CYP3A should be avoided, 
or selection of an alternate concomitant medicinal product, with no or 
minimal potential to induce CYP3A should be considered.
–
Concomitant use of strong (e.g., clarithromycin, grapefruit juice, itraconazole, 
ketoconazole, posaconazole, telithromycin, and voriconazole) and moderate 
(e.g., erythromycin, fluconazole, diltiazem, verapamil) inhibitors of CYP3A should be 
avoided if possible.

For venetoclax:
–
Avoid strong and moderate CYP3A4 inducers (e.g., rifampin, phenytoin, 
carbamazepine, phenobarbital, and St. John’s wort) as they increase the 
metabolism of venetoclax. If patient requires use of strong or moderate CYP3A4 


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inducers during the expansion phase, once the cohort designated venetoclax dose 
has been reached, use with caution and contact the Medical Monitor for guidance.
–
Concomitant use of strong (e.g., clarithromycin, grapefruit juice, itraconazole, 
ketoconazole, posaconazole, telithromycin, and voriconazole) and moderate 
(e.g., erythromycin, fluconazole, diltiazem, verapamil) inhibitors of CYP3A should be 
avoided if possible.
–
Avoid concomitant use of venetoclax with P-gp inhibitors (e.g., amiodarone, 
azithromycin, captopril, carvedilol, cyclosporine, felodipine, quercetin, quinidine, 
ranolazine, ticagrelor) 

For atezolizumab:
–
Use of steroids to premedicate patients for whom CT scans with contrast are 
contraindicated (i.e., patients with contrast allergy or impaired renal clearance); in 
such patients, magnetic resonance imaging (MRI) or a non-contrast CT scan of the 
anatomical region of interest must be performed. 
–
Immunomodulatory agents, including but not limited to interferons or IL-2, during the 
entire study; these agents could potentially increase the risk for autoimmune 
conditions when administered with atezolizumab
The above lists of medications are not necessarily comprehensive. Thus, the 
investigator should consult the prescribing information for any concomitant medication.  
In addition, the investigator should contact the Medical Monitor if questions arise 
regarding medications not listed above.
4.5
STUDY ASSESSMENTS
Please see Appendix 1 for the schedule of activities to be performed during the study.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-specific procedures.  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 by the Sponsor 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 and Demographic Data
Medical history includes clinically significant diseases, prior surgeries, and reproductive 
status.  In addition, all medications (e.g., prescription drugs, over-the-counter drugs, 
vaccines, herbal or homeopathic remedies, nutritional supplements) used by the patient 
within 14 days prior to Cycle 1 Day 1 drug will be recorded.


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Demographic data will include age, sex, and self-reported race/ethnicity.  Baseline 
disease characteristics data will include the international staging system, ECOG 
Performance Status, date of diagnosis, prior systemic therapy, and prior radiation 
therapy. 
4.5.3
Physical Examinations
A complete physical examination should be performed at screening and should include 
an evaluation of the head, eyes, ears, nose, throat, neck, and lymph node regions, and 
the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems. Any abnormality identified at baseline should 
be recorded on the General Medical History and Baseline Conditions eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF.
Height will be recorded on Cycle 1 Day 1 only.  Weight will be recorded at screening and
on Day 1 of each cycle.
Patients will be asked specifically about vision changes as part of each physical 
examination in addition to interval medical history.  
4.5.4
Vital Signs
Vital signs include respiratory rate, heart rate, temperature (°C), and systolic and 
diastolic blood pressure while the patient is in a seated position.  
For patients receiving cobimetinib as a single agent or in combination with venetoclax,
vital signs will be collected as outlined in the schedule of activities (see Appendix 1).  
For patients receiving atezolizumab, either with the triplet regimen (Arm C) or in those 
patients in which atezolizumab is added on to cobimetinib monotherapy upon PD
(Arm A), vital signs will be collected at screening and thereafter as follows during each 
atezolizumab administration.

Cycle 1 
Vital signs will be measured and recorded at the following timepoints:
–
Within 60 minutes prior to infusion
–
During infusion, every 15 (5) minutes
–
30 (10) minutes after infusion

Subsequent Cycles


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Vital signs will be measured and recorded at the following timepoints:
–
Within 60 minutes prior to infusion
–
During infusion, every 15 (5) minutes
–
30 (10) minutes after infusion
4.5.5
Tumor and Response Evaluations
Patients will undergo tumor assessments as specified in Appendix 1, regardless of dose 
delays, until disease progression per IMWG 2016 criteria (see Appendix 5).  Thus, tumor 
assessments are to continue per schedule in patients who discontinue treatment for 
reasons other than disease progression, even if they start new anti-cancer therapy.  
At the investigator’s discretion, tumor assessments may be repeated at any time if PD
is suspected. All response categories require two consecutive assessments made at 
any time.
Screening assessments must include:

Serum protein electrophoresis (SPEP) serum immunofixation electrophoresis 
(SIFE)

Urine protein electrophoresis (UPEP; requires 24-hour urine collection) urine
immunofixation electrophoresis (UIFE)

Serum free light chains (sFLCs)

2-microglobulin

Quantitative immunoglobulins (including IgA, IgG, IgM)

Bone marrow aspiration and biopsy tissue sample (for local disease assessment 
including cytogenetics; however, parts of this sample will be sent to the central 
laboratory)

Skeletal survey
–
Historical skeletal survey will be accepted if performed within 35 days of 
randomization and there is no clinical indication for repeating the skeletal survey in 
the interim between last imaging and randomization

CT scan/positron emission tomography (PET)-CT or MRI with bidimensional 
measurements for the assessment of extramedullary disease in patients with a 
history of plasmacytomas or if clinically indicated at screening
The following samples will be collected at the beginning of each cycle, starting at 
Cycle 1:

SPEP

UPEP (requires 24-hour urine collection, only if baseline UPEP is 200 mg/24 hr)

sFLCs

Quantitative Ig levels


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The following confirmatory assessments are required for all response categories 
(stringent complete response [sCR], CR, VGPR, PR, and MR):

Two consecutive assessments should be obtained 

If extramedullary disease was previously present, CT scan/PET-CT or MRI with 
bidimensional measurements to confirm reduction in size per IMWG criteria

No known evidence of progressive or new bone lesions (radiographic imaging is not 
required)

To confirm a VGPR, the additional following assessment is required:
–
UPEP in patients being followed by serum M-protein, even if a UPEP was not 
performed at screening
The following assessments, in addition to all of the above, are required to confirm sCR 
or CR:

SIFE and UIFE 

sFLCs 

Bone marrow aspiration and biopsy sample (repeat sample is not required for 
confirmation)

If extramedullary disease was previously present, CT/PET CT scan or MRI to 
confirm complete resolution
Patients with a confirmed sCR, CR, VGPR, or PR will be considered to have achieved a 
response.  In addition, patients who achieve a MR or better will be considered to have 
received clinical benefit (Stewart et al. 2015). 
To confirm PD, the following assessments are required:

If PD is suspected by rising M-protein, SPEP and UPEP with SIFE and UIFE should 
be obtained on two consecutive assessments from local laboratory readings, and 
ideally a bone marrow biopsy sample (does not need to be repeated for 
confirmation) should be obtained to determine if rising M protein is associated with 
an increase in malignant plasma cells.  If PD is suspected on development of new 
bone lesions or soft tissue plasmacytomas or an increase in size of existing bone 
lesions or soft tissue plasmacytomas, skeletal survey/CT scan/PET-CT/MRI should 
be obtained and compared with baseline imaging.

If PD is suspected on hypercalcemia attributed solely to MM, local laboratory test 
results of serum calcium levels should be 11.0 mg/dL and confirmed on a second 
assessment.
The following assessments are not sufficient to determine PD:

Rising sFLC (except for light chain myeloma) or quantitative Igs
–
In this situation, SPEP and UPEP should be performed and PD determination 
should be made based on laboratory test results.


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
Clinical relapse and relapse from CR categories 

General worsening of patient’s condition
–
Due to the possible delay in manifestation of clinical efficacy, investigators are 
requested not to discontinue patients from treatment for presumed lack of response 
after only one cycle of study treatment.
Bone marrow aspirate and biopsy tissue sample will be collected during the study for the 
assessment of percent plasma cells, morphology, and biomarker studies 
(see Section 4.5.6 for bone marrow collection requirements for exploratory biomarker 
studies); at screening, the local bone marrow assessments will also include cytogenetics 
by fluorescence in situ hybridization (FISH). Gene expression signatures associated 
with RAS/MAPK activation using genomic profiling will be conducted locally or a through 
a central lab and will be analyzed retrospectively.  In the study, bone marrow aspiration 
and biopsy sample collection will be performed as described in the laboratory manual at 
the timepoints specified in Appendix 1 and as needed to confirm CR or PD.
Response will be assessed by the investigator with use of IMWG criteria (see
Appendix 5).
4.5.5.1
Extramedullary Disease
All patients with clinically suspected extramedullary disease or known extramedullary 
disease at the time of screening must undergo imaging during screening (a historical 
imaging assessment is acceptable if performed no more than 35 days prior to 
randomization and there is no clinical indication for repeating the imaging survey in the 
interim between last imaging and randomization) to evaluate for the presence or extent 
of extramedullary disease.  This can be performed by CT scan of the chest, abdomen, 
and pelvis (preferably with IV contrast if renal function is adequate), PET/CT, or whole 
body MRI.  Patients who are found to have extramedullary disease will undergo repeat 
imaging (preferably the same modality as performed at screening) every 12 weeks.  
Imaging should also be performed upon clinical suspicion of PD or confirmation of CR.  
Chest X-ray or ultrasound of the abdomen, liver, or spleen may be substituted for CT, 
PET/CT, or MRI if, per the investigator’s assessment, patients are not able to safely 
tolerate these imaging modalities, and the anatomic location of the extramedullary 
disease is compatible with these alternative imaging methods.
4.5.5.2
Skeletal Survey
A skeletal survey (including skull, all long bones, chest, and pelvis) assessed by X-ray, 
whole-body low-dose CT, MRI, or PET scan is required for all patients during screening 
(a historical study is acceptable if performed no more than 35 days prior to 
randomization). If necessary, a skeletal survey may be required to confirm a response 
(see Section 4.5.5) or may be done at any time during the study if clinically indicated. 
If plasmacytomas are seen on skeletal survey, bidimensional tumor measurements 
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4.5.6
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: WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and 
other cells)

Chemistry panel (serum or plasma):  sodium, potassium, magnesium, chloride, 
bicarbonate (or total CO2), glucose, BUN or urea, creatinine, total protein, albumin, 
phosphorus, calcium, total bilirubin, alkaline phosphatase (ALP), ALT, AST, LDH, 
CPK, lipase, and amylase
–
Serum chemistry includes serum cholesterol and triglycerides at baseline. 

Coagulation: PT, aPTT, INR

Quantitative Igs

Thyroid function testing:  thyroid-stimulating hormone (TSH), free triiodothyronine 
(T3) (or total T3 for sites where free T3 is not performed), free thyroxine (T4)

HIV serology
–
For patients with unknown HIV status, HIV testing must be performed at screening if 
not in contradiction with local regulations.

HBV serology: HBsAg, hepatitis B surface antibody, total HBcAb
–
If a patient has a negative HBsAg test result and a positive total HBcAb test result at 
screening, an HBV DNA test must be performed to rule out active HBV infection 
based on HBV viral load per local guidelines.

HCV serology:  HCV antibody
–
If a patient has a positive HCV antibody test result at screening, an HCV RNA test 
should be performed to rule out active HCV infection prior to initiation of study 
treatment.

Pregnancy test
–
All women of childbearing potential will have a serum pregnancy test performed at 
screening (within 7 days prior to initiation of study drug), and then monthly and as 
clinically indicated.
–
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with 
no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus).
–
After study treatment discontinuation, a monthly pregnancy test should be 
performed (in women of childbearing potential) for at least 3 months after the last 
dose of cobimetinib, 1 month after the last dose of venetoclax, and 5 months after 
the last dose of atezolizumab.


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
Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood) 
and microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial 
cells, bacteria)

Fresh bone marrow aspirate for local assessment of percent plasma cells, karyotype 
and myeloma FISH panel

Serum samples for serum M-protein (SPEP SIFE) and sFLCs

24-hour urine sample for urine M-protein (UPEP UIFE)
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis:

Serum samples for immunogenicity (ADA) assessment
Serum samples will be assayed for the presence of ADAs to atezolizumab with 
use of validated immunoassays.

Serum samples for PK analysis
Serum samples will be assayed for atezolizumab concentration with use of a 
validated immunoassay.

Plasma samples for PK analysis
Plasma samples will be assayed for cobimetinib concentration with use of a 
validated assay.
Plasma samples will be assayed for venetoclax concentration with use of a 
validated assay.

Blood (whole blood, EDTA-plasma, and serum) samples will be obtained according 
to the schedule in Appendix 1 and will be evaluated from all eligible patients for 
immune related, tumor type related, and other exploratory research on biomarkers 
(including but not limited to T-cell profiling, T-cell receptor repertoire, immune cell 
subsets, minimal residual disease, and enumeration of T, B, and NK cells).
–
Whole blood samples may be processed to obtain plasma, serum peripheral blood 
mononuclear cells (PBMCs) and their derivatives (e.g., RNA and DNA).
–
MRD assessment will be performed using bone marrow aspirates and exploratory 
MRD assessment will be performed using peripheral blood.

Serum samples for analysis of autoantibodies:  anti-nuclear antibody, anti-double 
stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear 
anti-neutrophil cytoplasmic antibody

Fresh bone marrow aspirate and biopsy tissue samples will be collected at 
screening, during the study, and at the time of confirmation of response or disease 
progression and will be submitted with the associated pathology report for 
exploratory research on biomarkers (see Appendix 1 for collection timepoints)
–
For bone marrow aspirate samples, 10 mL of aspirate should be collected.  
Preferably, the same aspirate site used for collection of local bone marrow
laboratory analyses (e.g., flow cytometry, cytogenetics, FISH) should not be used 
for collection of bone marrow samples for exploratory analyses.  For every 10 mL of 


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bone marrow collected, a separate aspirate site should be selected if possible (all 
aspirate sites can be on the ipsilateral iliac crest).  Trephine or core biopsy tissue 
samples should preferably be 1.5 cm in length (2 cm is optimal).  If fresh tissue is 
unavailable, an archival block or 1520 unstained slides should be sent to the 
Sponsor (see the laboratory manual for further details).
–
Samples collected at the time of progression (mandatory), if deemed clinically 
feasible by the investigator, should be obtained within 30 days after progression or 
prior to the initiation of subsequent anti-cancer therapy, whichever is sooner.
–
In patients with extramedullary disease, in the rare instance that a bone marrow
biopsy is not feasible, tissue obtained from an extramedullary plasmacytoma is 
acceptable, but should meet the following criteria:
If an excisional biopsy is performed, then a formalin-fixed, paraffin 
embedded block (preferred) or a minimum of 15 serially sectioned, 
unstained slides is required.  If 10 serially sectioned slides are available, 
consult with the Medical Monitor.  For core-needle biopsy tissue 
specimens, at least 3 core tissue samples should be submitted for 
evaluation.
Tumor tissue should be of good quality based on total and viable tumor 
content.  
Acceptable samples include core-needle biopsy tissue samples for deep 
tumor tissue or lymph nodes or excisional, incisional, punch, or forceps 
tissue-sample biopsies for cutaneous, subcutaneous, or mucosal lesions.

MRD assessment will be performed using bone marrow aspirates and peripheral 
blood.
Exploratory biomarker research may include, but will not be limited to, the biomarkers 
listed in Table 4.
Blood samples will be obtained for biomarker evaluation (including but not limited to 
biomarkers that are related to MM or tumor immune biology) from all patients.  Samples 
will be processed to obtain plasma for the determination of changes in blood-based 
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Table 4
Proposed Non-Inherited Biomarkers for Exploratory Research
Sample Type
Timing
Proposed Non-Inherited Biomarkers
Plasma
At multiple timepoints as
indicated in Appendix 1

Cytokine levels
Serum

Immunofixation, including 
assessment of atezolizumab 
interference (“reflex assay”)
RNA extracted from 
blood

Gene expression profiling: 
markers of MAPK pathway, 
apoptosis pathway, immune cell 
signatures
DNA extracted from 
blood

T-cell receptor clonality, MRD
PBMCs isolated from 
blood

Frequency of immune cells, 
myeloma cells; T-cell profiling
Bone marrow aspirate
Baseline (fresh) and 
subsequent timepoints
during and after treatment 

Frequency of immune cells, 
myeloma cells; T-cell profiling, 
MRD
DNA extracted from 
bone marrow 
aspirate/biopsy

Oncogenic mutation panel: 
genomic alterations 
RNA extracted from 
bone marrow 
aspirate/biopsy

Gene expression profiling: 
markers of MAPK pathway, 
apoptosis pathway, immune cell 
signatures
Bone marrow biopsy
Prior to study (archival) or 
baseline (fresh)
and Cycle 4, Day 1

Immunohistochemistry: Bcl-2
family proteins, MHC I, T cells, 
tumor cells
MAPKmitogen-activated protein kinase; MHCmajor histocompatibility complex; 
MRDminimal residual disease; PBMCperipheral blood mononuclear cell.
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 4.5.10), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Plasma/serum samples collected for PK and immunogenicity (ADA) analysis may be 
needed for additional PK and ADA assay development and validation and for 
additional immunogenicity characterization; therefore, these samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed.

Blood, serum, plasma, bone marrow aspirate, bone marrow tissue samples, and any 
derivatives thereof (e.g., DNA, RNA, proteins), collected for biomarker research will 


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be destroyed no later than 5 years after the final Clinical Study Report has been 
completed.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
Given the complexity and 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 in the study data 
publication.
4.5.7
Left Ventricular Ejection Fraction
All patients will require regular evaluation of LVEF at screening and during study 
conduct.
Evaluation of LVEF by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) 
scan using the same method for each patient must be performed according to the
timepoints specified in Appendix 1. 
Evaluation of LVEF does not need to be performed at the treatment discontinuation visit 
if an evaluation has been performed within the last 12 weeks and there are no clinically 
significant findings and/or changes from baseline.
Any patient who develops clinical signs or symptoms suspicious of cardiac failure should 
undergo an LVEF assessment.  Evaluation of LVEF must be performed by the same 
method (ECHO or MUGA scan) for each patient.  It is strongly encouraged that the same 
laboratory and operator perform ECHO/MUGA scans for each individual patient.  
Investigators must be aware of local institution regulations regarding repeat MUGA 
scans.  The repeat administration of radioisotopes is limited in some nuclear medicine 
laboratories, and some patients in this study could require monitoring on four or more 
occasions.
4.5.8
Electrocardiograms
An ECG is required at screening and on Cycle 1 Day 1.  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.


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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
Ophthalmic Examination
All patients will require regular ophthalmic examinations at screening and during study 
conduct.
Ophthalmic examination must be performed according to the timepoints specified in 
Appendix 1.
The objective of baseline ophthalmic examination is to evaluate for evidence of retinal 
pathology that may be a risk factor for central serous retinopathy or RVO.  Ophthalmic 
examination must be performed by an ophthalmologist.  
Baseline and serial surveillance ophthalmic examination will include visual acuity testing, 
intraocular pressure measurements by tonometry, slit-lamp ophthalmoscopy, indirect 
ophthalmoscopy, and optical coherence tomography (spectral- or time-domain).  
Spectral-domain optical coherence tomography, if not available, may be substituted with 
time-domain optical coherence tomography.
4.5.10
Optional Samples for Research Biosample Repository
4.5.10.1
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 biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
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4.5.10.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RBR sampling, this section of the protocol (Section 4.5.10) will not be 
applicable at that site.
4.5.10.3
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 the study treatment used
or diseases:

Leftover blood, serum, plasma, bone marrow aspirate, and bone marrow tissue 
samples and any derivatives thereof (e.g., DNA, RNA, proteins, peptides), including 
leftover 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 mutations via whole genome sequencing (WGS), whole exome sequencing 
(WES), next-generation sequencing (NGS), 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.  Data will be analyzed in the 
context of this study but will also be explored in aggregate with data from other studies.  
The availability of a larger dataset will assist in identification of important pathways, 
guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens 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).


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4.5.10.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR specimens, 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 specimens 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.
4.5.10.5
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 specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens. 
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate 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 
specimens and data will continue to be used as part of the RBR research.
4.5.10.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR 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.  If a patient 
wishes to withdraw consent to the testing of his or her specimens, the investigator must 
inform the Medical Monitor in writing of the patient's wishes through use of the 
appropriate RBR Subject Withdrawal Form and, if the trial is ongoing, must enter the 


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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 specimens 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 Study BO39813 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from Study BO39813.
4.5.10.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  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:

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 adverse event that requires study treatment discontinuation per the guidelines 
in Section 5.1 and the Atezolizumab Investigator’s Brochure

Any medical condition that may jeopardize the patient’s safety if he or she continues 
study treatment

Investigator or Sponsor determines it is in the best interest of the patient

Use of another non-protocol anti-cancer therapy

Pregnancy

Symptomatic deterioration attributed to disease progression

Disease progression per IMWG criteria (see Appendix 5), as assessed by the 
investigator (except for patients in Arm A who may crossover to Arm B or Arm C 
upon discussion with the Medical Monitor).


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Patients will return to the clinic for a treatment discontinuation visit within 30 (7) days 
after the last dose of study treatment.  The visit at which response assessment shows 
PD may be used as the treatment discontinuation visit.  Patients who discontinue study 
treatment for any reason other than PD will continue to undergo tumor response
assessments as outlined in the schedule of activities (see Appendix 1).
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 (unless the patient withdraws consent or the Sponsor 
terminates the study).  If a 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 study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status only.
The primary reason for study drug discontinuation should be documented on the 
appropriate eCRF.
4.6.2
Patient Discontinuation from 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 withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time

Study termination or site closure

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

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 information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.
4.6.3
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.  


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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)
5.
ASSESSMENT OF SAFETY
Cobimetinib is approved in combination with vemurafenib for the treatment of advanced 
BRAF V600-mutated melanoma in the United States and the European Union as well as 
other countries.  The safety plan for patients in this study is based on clinical experience 
with cobimetinib in completed and ongoing studies.  The anticipated important safety 
risks for cobimetinib are outlined below.  Please refer to the Cobimetinib Investigator's 
Brochure for a complete summary of safety information. 
Venetoclax is approved for the treatment of patients with CLL in the United States and 
the European Union.  Please refer to the Venetoclax Investigator’s Brochure for a 
complete summary of safety information.
Atezolizumab is approved for the treatment of patients with urothelial bladder cancer and 
NSCLC in the United States and is currently in clinical development for other indications.  
The following information is based on results from nonclinical and clinical studies and 
published data on similar molecules.  Please refer to the Atezolizumab Investigator’s 
Brochure for a complete summary of safety information.
Several measures will be taken to ensure the safety of patients who participate in this 
study including periodic teleconferences; for the safety run-in cohorts, weekly 
teleconferences are planned between the Sponsor’s medical personnel and the medical 
site staff taking care of study patients.  Eligibility criteria have been designed to exclude 
patients at higher risk for toxicities.  Patients will undergo close safety monitoring during 
the study, including assessment of the nature, frequency, and severity of adverse 
events.  In addition, guidelines for managing adverse events, including criteria for 
dosage modification, and treatment interruption or discontinuation, are provided below.


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5.1
SAFETY PLAN
The risks associated with cobimetinib, venetoclax, and atezolizumab are detailed in
Section 5.1.1, Section 5.1.2, and Section 5.1.3, respectively.  In addition, the guidelines 
for managing adverse events, including criteria for dosage modification and treatment 
interruption or discontinuation, are provided below.
5.1.1
Risks Associated with Cobimetinib
Information related to risks attributed to cobimetinib is based on safety data from the 
Phase III study GO28141 (cobimetinib plus vemurafenib), the Phase Ib study NO25395 
(cobimetinib plus vemurafenib), and the Phase I study MEK4592g (cobimetinib 
monotherapy).  For further information regarding clinical safety, please refer to the 
current Cobimetinib Investigator’s Brochure.
5.1.1.1
Important Identified Risks Associated with Cobimetinib
Hemorrhage
Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical 
area or organ, can occur with cobimetinib.  In clinical studies with cobimetinib, events of 
cerebral hemorrhage, gastrointestinal tract hemorrhage, reproductive tract hemorrhage, 
and hematuria have been reported.
In the Phase III study GO28141, Grade 14 hemorrhagic events were reported in 13.0% 
of patients treated with cobimetinib plus vemurafenib and in 7.3% of patients treated with 
placebo plus vemurafenib.  The majority of hemorrhagic events were Grade 1 or 2 and 
non-serious.  Grade 34 hemorrhage events were reported in 1.2% of patients receiving 
cobimetinib plus vemurafenib and in 0.8% of patients receiving placebo plus 
vemurafenib.
Caution should be used in patients with additional risk factors for bleeding, such as in 
patients who use concomitant medications that increase the risk of bleeding (including 
anti-platelet or anticoagulant therapy).
Instructions for dose modifications for hemorrhage events are included in Section 5.1.5. 
Serous Retinopathy
Serous retinopathy (fluid accumulation within the layers of the retina) has been observed 
in patients treated with MEK-inhibitors, including cobimetinib (Flaherty et al. 2012).  
Manifestations of serous retinopathy include visual disturbances, findings of retinal 
detachment, and retinopathy.  Serous retinopathy events may also be asymptomatic.
Serous retinopathy has been characterized in the Phase III study GO28141.  The study 
incorporated prospective serial ophthalmic examinations for all enrolled patients.  Serous 
retinopathy was reported more frequently in patients treated with cobimetinib plus 
vemurafenib than with placebo plus vemurafenib (25.5% vs. 2.8%, respectively), and 
approximately half the events were asymptomatic Grade 1 events.  Few patients treated 


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with cobimetinib plus vemurafenib experienced Grade 3 ocular events (2.8%); the 
majority of these events were managed with dose modification of both cobimetinib and 
vemurafenib. 
To address serous retinopathy with cobimetinib treatment, all patients are required to 
undergo a baseline ophthalmic examination to assess for history or evidence of retinal 
pathology that is considered a risk factor for or indicative of neurosensory retinal 
detachment, central serous chorioretinopathy, neovascular retinopathy, or retinopathy of 
prematurity.  Patients will also undergo ophthalmic examinations at specified time points 
throughout the study (see Appendix 1). Details regarding baseline and subsequent 
ophthalmic examinations are provided in Section 4.5.9.
Guidelines for management of patients who develop Grade 2 visual disorders or 
retinopathy are provided in Section 5.1.5.7.
Left Ventricular Dysfunction
Decrease in LVEF from baseline has been reported in patients receiving cobimetinib.  
Left ventricular dysfunction may occur with signs and symptoms of cardiac failure, or 
reduction in LVEF events may be asymptomatic.
Left ventricular dysfunction has been characterized in the Phase III study GO28141.  
The study incorporated prospective serial LVEF evaluation in all patients.  With active 
surveillance, measured reductions in left ventricular ejection fraction were observed 
more frequently in patients treated with cobimetinib plus vemurafenib than placebo plus 
vemurafenib (8.5% vs. 3.7%, respectively, of Grade 2 or 3 severity).  Of the patients 
treated with cobimetinib plus vemurafenib, 2 patients (0.8%) had symptomatic reduction 
in LVEF, and the remaining patients were asymptomatic.  Most LVEF reduction events in 
patients on cobimetinib plus vemurafenib (62%) improved or resolved with management 
according to the dose-modification guidelines (see Section 5.1.5.10). 
Rhabdomyolysis and CPK Elevations
Elevations in CPK have been observed in patients who received cobimetinib 
monotherapy as well as when administered with other agents.  The majority of CPK 
elevations reported were asymptomatic, non-serious, and resolved with or without study 
drug interruption.  One event of rhabdomyolysis was reported in the Phase III Study 
GO28141 (cobimetinib plus vemurafenib), and rhabdomyolysis has been reported in 
postmarketing experience.
In Study GO28141, elevated CPK was reported as an adverse event more frequently in 
patients treated with cobimetinib plus vemurafenib (32.4% all grades, 11.3% Grade 3 
events) than placebo plus vemurafenib (8.1% all grades, 0% Grade 3 events).  CPK 
will be monitored at baseline and monthly during treatment or as clinically indicated. 
Instructions for dose modification for elevated CPK and rhabdomyolysis are included in
Section 5.1.5.6.


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Photosensitivity (when administered with vemurafenib)
No evidence of phototoxicity has been observed with cobimetinib as a single agent.  
However, photosensitivity was observed on the Study GO28141 with a higher 
frequency in the cobimetinibvemurafenib arm vs. placebovemurafenib arm (46.3% vs. 
35.4%, respectively).  The majority of events were Grades 1 or 2, with Grade 3 events 
occurring in 3.6% of patients in the cobimetinibvemurafenib arm versus 0% in the 
placebovemurafenib arm.  Grade 3 photosensitivity events in the 
cobimetinibvemurafenib arm were primarily treated with topical medication in 
conjunction with interruption of study agents. 
Pneumonitis
Events of pneumonitis have been reported in cobimetinib clinical studies. Most 
reported events were considered non-serious and low-severity grade.  In the 
Phase III Study GO28141, pneumonitis events were reported more frequently in 
patients treated with cobimetinibvemurafenib than placebovemurafenib (1.6% vs. 
0.4%, all grades).  There were no reported Grade 3 events in either study arm.  
Serious events were reported in 2 patients (0.8%) treated with 
cobimetinibvemurafenib. Guidelines for managing drug-induced pneumonitis are 
provided in Section 5.1.5.13.  
Diarrhea
In clinical studies GO28141 and NO25395, diarrhea was the AE most commonly 
reported in patients who received cobimetinibvemurafenib treatment.  In the 
Phase III Study GO28141, 61.3% of patients in cobimetinibvemurafenib arm 
experienced diarrhea. Of these, 6.9% of patients experienced Grade 3 diarrhea events. 
Three patients (1.2%) in the cobimetinibvemurafenib arm had diarrhea reported as an 
SAE.
The diarrhea events were generally manageable, and few events of diarrhea occurred 
with concurrent dehydration, or other clinical sequelae.  Overall, the diarrhea events 
were managed by antidiarrheal agents, and no patient in the cobimetinibvemurafenib 
arm of Study GO28141 discontinued either study treatment due to diarrhea.
Guidelines for managing gastrointestinal toxicity are provided in Section 5.1.5.8.
5.1.1.2
Potential Risks Associated with Cobimetinib
Liver Laboratory Abnormalities 
Liver laboratory test abnormalities, including increases in ALT, AST, and alkaline 
phosphatase, have been reported as adverse events and serious adverse events in 
patients treated with cobimetinib plus vemurafenib.
In the Phase III study GO28141, liver laboratory test abnormalities reported as Grade 3
adverse events occurred more frequently in patients treated with cobimetinib plus 
vemurafenib than placebo plus vemurafenib (20.5% vs. 15.1%, respectively).


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Generally, elevations in liver laboratory tests were managed effectively with dose 
modification guidelines.  In both study arms, the majority of Grade 3 liver laboratory 
test abnormalities resolved.
Impaired Female Fertility
There is a potential for effects on fertility and embryo-fetal toxicity based on results from 
nonclinical studies. 
While no dedicated fertility studies have been conducted with cobimetinib in animals, 
degenerative changes observed in reproductive tissues included increased 
apoptosis/necrosis of corpora lutea and seminal vesicle, epididymal and vaginal 
epithelial cells in rats, and epididymal epithelial cells in dogs.  These changes were
reversible upon discontinuation of cobimetinib administration.
Teratogenicity and Development Toxicity
In a dedicated embryo-fetal toxicity study, cobimetinib produced fetal toxicity (resorptions 
and reductions in fetal weight), and teratogenicity (malformations of the great vessels 
and skull) at similar systemic exposures to those observed in patients administered the 
60 mg dose.
5.1.1.3
Other Risks with Cobimetinib
Rash
In the Phase III study GO28141, combined rash events of all types and grades were 
reported more frequently in patients treated with cobimetinib plus vemurafenib than 
placebo plus vemurafenib (69% vs. 62%, respectively), although Grade 3 events 
(approximately 14% and 12% of patients treated with cobimetinib plus vemurafenib and 
placebo plus vemurafenib, respectively) and types of rash reported were similar between 
study arms.  Specific events in patients treated with cobimetinib plus vemurafenib 
included rash (40% all grades, 5% Grade 3), rash maculo-papular (15% all grades, 
7% Grade 3) and acneiform rash (14% all grades, 2% Grade 3).
Generally, Grade 3 rash events were effectively managed with dose modification 
guidelines.  In GO28141, approximately 90% of Grade 3 rash events resolved in 
both arms.
Gastrointestinal Toxicity
A range of gastrointestinal adverse events, including nausea, vomiting, and diarrhea,
(see Section 5.1.1.1 for details), have been reported in all cobimetinib studies in adult 
cancer patients.
Nausea and vomiting have been reported in association with cobimetinib.  Most nausea 
and vomiting events were considered non-serious and low-severity grade.  In the 
Phase III study GO28141, nausea and vomiting events were reported more frequently in 
the active cobimetinib arm than the control arm (nausea 41.3% vs. 25.3%; vomiting 


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24.3% vs. 12.6%). However, of patients treated with cobimetinib plus vemurafenib, few 
experienced Grade 3 events (nausea 0.81%, vomiting 1.2%).
The combination of diarrhea, nausea, and vomiting has the potential to contribute to 
clinically significant volume depletion/dehydration from the combination of fluid losses 
with decreased oral intake. In the majority of cases, diarrhea has been effectively 
managed with antidiarrheal agents and supportive care. Routine primary antiemetic 
prophylaxis is not recommended. Routine primary anti-diarrheal prophylaxis is highly 
recommended in patients receiving cobimetinib plus venetoclax.  In patients who 
experienced Grade 3 diarrhea secondary anti-diarrheal prophylaxis is mandatory
(see Table 5).
Table 5
Gastrointestinal Prophylaxis Guidelines
Anti-Emetic Prophylaxis Guidelines

3060 minutes before administration of study medication, the patient should receive a 
5-HT3-receptor antagonist (e.g., ondansetron, granisetron or palonosetron) on Days 17.  
Longer-acting formulations of 5-HT3-receptor antagonists, such as granisetron 
transdermal system (Sancusopatch) or extended-release (Sustol), can also be used.

Rescue medications:

Combination of Ativan 0.5 mg, Benadryl12.5 mg and Haldol 2.5 mg can be given for 
breakthrough nausea

Dexamethasone can also be administered as a rescue medication

Caution:

Aprepitant (EmendOral) is a moderate CYP3A inhibitor and is a prohibited therapy 
on this study

Avoid agents such as metoclopramide, which may stimulate GI motility
Anti-Diarrheal Prophylaxis Guidelines

30 minutes before the first dose of study medication, administer loperamide 
prophylactically (loading dose 4 mg) followed by 2 mg/4mg QID not exceeding 16 mg in 
any 24-hour period. 

If the patient has diarrhea, please follow the guidelines for managing gastrointestinal 
toxicity provided in Table 14. 

For patients who do not experience diarrhea, the recommendation is to administer the 
treatment prophylaxis for the first 35 days of study treatment and if there are no signs of 
increased transit of bowel movements, abdominal cramps or pain, the patient may 
discontinue loperamide.

Caution:  Use loperamide (P-gp substrate) with caution when co-administered with 
venetoclax (P-gp inhibitor).  There is a potential for enhanced central effects when 
loperamide is administered with P-gp inhibitors.
GIgastrointestinal; QID4 times a day.
Guidelines for managing gastrointestinal toxicity are provided in Section 5.1.5.8. 


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Hypersensitivity 
There have been few reports of hypersensitivity and/or anaphylaxis in clinical trials with 
patients who have been exposed to cobimetinib as a single agent or in combination with 
other agents.  These have appeared to be isolated reports, and in some cases, occurred 
in patients with histories of drug allergies.  Thus, the relationship of cobimetinib to these 
events is unclear.
In the Phase III study GO28141, Grade 3 hypersensitivity events were reported in 
3 patients in the cobimetinib and vemurafenib arm compared with no such events in the 
placebo plus vemurafenib arm.  All events required hospitalization and treatment with 
steroids. 
Investigators should promptly evaluate and treat patients who are suspected of 
experiencing a hypersensitivity reaction.
5.1.2
Risks Associated with Venetoclax
Information related to venetoclax-associated risks is based mainly on review of data 
from Phase IIII experience (see the Venetoclax Investigator’s Brochure) in CLL and 
Phase III data in AML (Studies M14-212, M14-358, and M14-387; see Table 1).  
Venetoclax has demonstrated that it is generally well tolerated, and toxicities appear to 
be mostly manageable and/or reversible.  Refer to the current Venetoclax Investigator’s 
Brochure for details on the safety data from these studies and for additional information 
on venetoclax warnings and precautions.  Risks include infectious complications, 
cytopenias, effects on fertility, treatment-emergent malignancies (second primary 
malignancies), and food effect.
See Section 5.1.5 for the monitoring and management of specific toxicities.
Tumor Lysis Syndrome
To date, the principal adverse reaction associated with venetoclax in the single-agent 
Phase I dose-escalation CLL study M12-175 has been TLS (primarily but not exclusive 
related to the first dose).  These include cases of TLS that have led to clinical sequelae 
including death in 2 patients.  Among the non-CLL studies, 6 patients with NHL 
experienced Grade 34 adverse events of laboratory TLS.  Although several events of 
hyperphosphatemia and two events of rising potassium have been observed in the R/R
AML study (Study M14-212), no patients experienced TLS during administration of 
venetoclax.
Although no cases of TLS have been reported in patients with MM, patients will be 
actively monitored and managed to prevent potential.
Neutropenia
Neutropenia is an important identified risk for venetoclax, specifically in CLL. Clinical 
data from the oncology studies suggest that the neutropenia adverse events are 


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observed among patients who receive venetoclax as a single agent or in combination 
with other therapeutic agents, with slightly higher frequency observed in some 
combination studies. Serious adverse events of neutropenia leading to discontinuations 
are few across the entire venetoclax oncology program.  Cytopenia management 
guidelines are provided in Section 5.1.5.1.
Granulocyte colony-stimulating factors can be used for supportive measures, however 
the guidance for their use in non-CLL indications is per routine local oncology practice.
Cytopenias 
Anemia has been reported with slightly higher frequency in some oncology studies in 
which venetoclax is combined with other chemotherapeutic agents; 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, with slightly
higher frequency in studies in which venetoclax is combined with other agents.  
However, most of the events were non-serious and assessment of these events is 
confounded by the patients' underlying disease state, prior therapies, and preexisting 
thrombocytopenia, including autoimmune thrombocytopenia in several patients. The 
dataset in non-CLL indications is small.
Lymphopenia has been observed in nonclinical studies.  Although opportunistic 
infections have been reported in the clinical program, data are confounded by patients’ 
underlying disease and prior therapies.  In oncology studies, anti-infective prophylaxis 
should be implemented as clinically indicated, including appropriate prophylaxis for viral, 
fungal, bacterial, or pneumocystis carinii pneumonia infections. 
See Section 5.1.5.1 for the management of cytopenias.
Effects on Fertility and Reproductive Toxicity
There were no effects of venetoclax on female or male mouse fertility; however, a risk to 
human male fertility exists based on the testicular toxicity (germ cell depletion) observed 
at all dose levels in the repeat-dose dog studies.  Reversibility of this finding has not 
been demonstrated. It is not known whether the dog testicular findings translate to 
humans.  Male patients should be instructed to consider sperm banking before treatment 
with venetoclax if they are considering preservation of fertility.
In embryo-fetal development studies, venetoclax was administered to pregnant mice and 
rabbits during the respective periods of organogenesis.  In pregnant mice, venetoclax 
was associated with increased post-implantation loss and decreased fetal body weight at 
150 mg/kg/day (approximately 1.2 times the human AUC exposure at the 400-mg 
human dose).  No fetal toxicity was observed in rabbits up to the highest dose tested 
(approximately 0.2 times the human AUC exposure at the 400-mg human dose).


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Treatment-Emergent Malignancies (Second Primary Malignancies)
Events of second primary malignancies have been reported across the oncology 
program.  No pattern has been observed.  Because venetoclax is being evaluated in 
patients with R/R disease who had previously been treated with various cytotoxic 
agents, second primary malignancies are closely monitored.
Infections
Serious infection, including sepsis, is an important identified risk for venetoclax. 
Infections have been reported in the clinical studies of venetoclax for malignant 
diseases. However, these events are confounded by the common complications of the 
underlying malignancies, comorbidities, and concomitant immunosuppressive 
medications. To date, a clear relationship has not been established 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 patients with hematologic malignancies and are similar across all indications. 
Infections are closely monitored in venetoclax program across all indications. 
See Section 5.1.5.2 for the management of infection.
Food Effect
Administration with a low-fat meal increased venetoclax exposure by approximately 
3.4-fold, and administration with a high-fat meal increased venetoclax exposure by 5.1-
to 5.3-fold compared with fasting conditions.  Venetoclax should be administered with a 
meal (see Section 4.3.2.2). 
5.1.3
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, Guillain-Barré syndrome, 
myasthenic syndrome or myasthenia gravis, hypophysitis, meningoencephalitis, 
myocarditis, nephritis, myositis, and severe cutaneous adverse reactions.  Immune-
mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), which are 
considered to be potential risks for atezolizumab.  Refer to Appendix 8 of the protocol 
and Section 6 of the Atezolizumab Investigator's Brochure for a detailed description of 
anticipated safety risks for atezolizumab.
5.1.4
Anticipated Overlapping Adverse Events for Cobimetinib, 
Venetoclax, and Atezolizumab
Special consideration is given to areas of potential overlapping toxicity based on 
nonclinical and previous human experience data with each compound individually or with 
other molecules.  Safety findings common to two and/or all molecules assessed as 
single agents individually and/or in combination with other molecules include the topics 
below.  Patients in the three study arms should be closely monitored for evidence of 


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toxicity and, in the case of the Arms B and C, for overlapping and/or potentiation of these 
and any other acute toxicities.  If any evidence of overlapping and/or potentiation of the 
below toxicities is observed, patients should receive maximal supportive care as 
clinically indicated.  Any modification of study treatment should follow the guidelines in
Section 5.1.5.
Hypersensitivity Reactions and/or Infusion Reactions
Hypersensitivity reactions or infusion reactions are described in the warning and 
precautions of the Atezolizumab Investigator’s Brochure. There have been few reports 
of hypersensitivity and/or anaphylaxis in clinical trials with patients who have been 
treated with cobimetinib as single agent therapy or in combination with other agents. 
These have appeared to be isolated reports, and in some cases, occurred in patients 
with histories of drug allergies.  Thus, the relationship of cobimetinib to these events is 
unclear. Investigators should promptly evaluate and treat patients who are suspected of 
experiencing a hypersensitivity reaction.
Please refer to the respective Investigator’s Brochures for more details.  Patients in this 
study should be closely monitored for any evidence of overlapping and/or potentiation of 
hypersensitivity and/or infusion reactions.
Dermatologic Reactions
Dermatologic reactions (i.e., rash, pruritus, maculopapular) are described in the 
warnings and precautions of the Atezolizumab Investigator’s Brochure and are defined 
as adverse drug reaction in the Cobimetinib Investigator’s Brochure. 
Skin toxicities of rash have been reported in patients treated with cobimetinib as a single 
agent or with other therapies.  In the pivotal study, serious events of rash, rash 
maculopapular and acneiform dermatitis were more frequent in the active cobimetinib 
arm than in the control arm.  Dermatologic reactions have been reported in 42% of 
patients receiving single-agent atezolizumab.  Reactions have been mild to moderate 
(1% reported as severe).
Ocular Toxicity 
Ocular toxicities have been observed with both cobimetinib and atezolizumab. 
Serous retinopathy (fluid accumulation within the layers of the retina) and retinal 
detachment are class-effects of MEK inhibitors, including cobimetinib, and are described 
as both warnings and precautions as well as identified risks in the Cobimetinib 
Investigator’s Brochure.  The majority of events in cobimetinib-treated patients were 
reported as chorioretinopathy or retinal detachment. Uveitis has been observed in 
association with atezolizumab.  Initial symptoms reported by patients may not distinguish 
between either serous retinopathy or uveitis and will require additional ophthalmic 
examination for a definitive diagnosis.  


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Baseline and serial surveillance ophthalmic examinations will be performed for patients 
in this study as detailed in Section 4.5.9. Please refer to Section 5.1.5.7 for further 
details regarding management and dose modifications related to ocular events.
Patients should be advised to use caution when driving or using machines if their vision 
is impaired. 
Hepatic Toxicity and/or Liver Laboratory Abnormalities
Liver laboratory test abnormalities, including elevated AST, elevated ALT, elevated 
-glutamyltransferase, elevated ALP, and elevated bilirubin, are warnings and 
precautions for cobimetinib as described in the Cobimetinib Investigator’s Brochure.  
The risk of immune-mediated hepatitis has been associated with the administration of 
atezolizumab, and it is described in the summary of important identified risks section of 
the Atezolizumab Investigator’s Brochure. 
Please refer to the respective Investigator’s Brochures for more details.  Patients in this 
study should be closely monitored for any evidence of overlapping and/or potentiation of 
hepatic toxicity.
Pneumonitis
Pneumonitis has been reported in 1.4% of patients receiving single-agent atezolizumab.  
These events have been primarily observed in patients with lung cancer.  Pneumonitis is 
an identified risk for cobimetinib observed in patients treated with cobimetinib, as 
described in the Cobimetinib Investigator’s Brochure. 
Please refer to the Cobimetinib and Atezolizumab Investigator’s Brochures for more 
details.  Patients in this study should be closely monitored for any evidence of 
overlapping and/or potentiation of pneumonitis or other respiratory events.
Diarrhea, Nausea, and Vomiting
Diarrhea, nausea, and vomiting are identified risks and/or adverse drug reactions for 
cobimetinib, venetoclax, and atezolizumab as described in each respective Investigator’s 
Brochure. Immune-mediated colitis has also been associated with the administration of 
atezolizumab. The combination of diarrhea, nausea, and vomiting has the potential to 
contribute to clinically significant volume depletion, dehydration, and/or electrolyte 
abnormalities from the combination of fluid losses with decreased oral intake.
Prompt supportive treatment should be instituted in case of gastrointestinal toxicity. 
Fatigue
Fatigue is a common adverse event associated with anti-neoplastic agents, but it is also 
a symptom of the underlying disease, or other drug-related toxicities (e.g., anemia, 
electrolyte imbalance, hypothyroidism, dehydration) or a combination of all these 
causing factors.  Fatigue has been reported in association with cobimetinib, venetoclax, 


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and atezolizumab.  Attempts to identify and correct all potential causes of fatigue should 
be made in patients complaining of fatigue. 
Please refer to the respective individual Cobimetinib, Venetoclax, and Atezolizumab 
Investigator’s Brochures for more details.
Other Toxicities
In addition to the areas of potential overlapping toxicity described earlier in this section, a 
variety of other identified risks and/or adverse drug reactions (e.g., diarrhea, anemia)
have been described in patients treated with cobimetinib, venetoclax, and/or 
atezolizumab. For details, please refer to the respective package inserts (if applicable) 
and Investigator’s Brochures for this information. 
Patients in this study should be closely monitored for any evidence of overlapping and/or 
potentiation of toxicities, including other general adverse events and/or any evidence of 
impaired ability to drive or use machines.
5.1.5
Management of Patients Who Experience Specific Adverse 
Events
Any toxicity associated with or possibly associated with study drug treatment should be 
managed with symptomatic treatment, dose interruptions, and/or dose reductions.  
If cobimetinib and/or venetoclax are interrupted due to toxicity, the maximum allowable 
length of treatment interruption is 28 days before cobimetinib and/or venetoclax is 
considered permanently discontinued.
Criteria for treatment modifications and guidelines for the management of toxicities 
attributable to cobimetinib, venetoclax, and/or atezolizumab are summarized in
Section 5.1.5.1Section 5.1.5.18.
For cobimetinib and venetoclax, dose modifications may include dose reduction, dose 
interruption, and/or dose discontinuation.  The dose levels for cobimetinib and 
venetoclax dose reduction are provided in Table 6 and Table 7.  
Table 6
Recommended Doses of Cobimetinib in Arm A, Arm B, and 
Arm C
Dose Level
Cobimetinib Dose (mg) 
Arm A
Cobimetinib Dose (mg)
Arm B and Arm C
DL-0
60
40
DL-1
40
20
DL-2
20



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Table 7
Recommended Doses of Venetoclax in Arm B and Arm C
Dose Level
Venetoclax Dose (mg)
Reduced Dose (mg)
DL-0
800
600
DL-1
600
400
DL-2
400
200
For atezolizumab, dose modification may include holding study treatment or permanent 
discontinuation.  There will be no dose reduction for atezolizumab in this study.  
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over 1 month to 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.  If atezolizumab is withheld for 
12 weeks after event onset, the patient will be discontinued from atezolizumab.  
However, atezolizumab may be withheld for 12 weeks to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being 
withheld for 12 weeks if the Medical Monitor agrees that the patient is likely to derive 
clinical benefit.  Atezolizumab treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures) with Medical Monitor approval.  The investigator and 
the Medical Monitor will determine the acceptable length of treatment interruption.
Recognizing that new knowledge will be acquired and unforeseen safety issues may 
arise in the course of the study, the guidelines are not exhaustive and do not represent 
the full spectrum of care or treatment options described.  The dose modification 
guidelines are not intended to replace clinical judgment or dictate care of individuals. 
If these modifications are unclear or if a patient experiences an unexpected adverse 
event, please contact the Medical Monitor (see Section 5.4.1). 
5.1.5.1
Cytopenias
Based on the safety profile of cobimetinib, a mild increase in the venetoclax hematologic 
toxicity is anticipated. In this study, blood counts will be monitored closely throughout 
treatment (see Appendix 1).  Growth factors will be permitted for febrile neutropenia or 
neutropenic sepsis according to local practice, and patients will be monitored and 
treated promptly in case of infections. Dose interruptions or reductions will be allowed 
based on toxicity.
Recommended dose modifications for hematological toxicities are presented in Table 8. 


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Table 8
Recommended Dose Modifications for Hematological Toxicities
Grade 3 or 4 
neutropenia with 
infection or fever; 
or Grade 4 
hematologic 
toxicities (except 
lymphopenia)
1st occurrence

Interrupt venetoclax.

To reduce the infection risks associated with 
neutropenia, anti-infective prophylaxis and 
G-CSF for management should be considered 
per institutional guidelines.

Once the toxicity has resolved to Grade 1 or 
baseline level, venetoclax therapy may be 
resumed at the same dose.
2nd and 
subsequent 
occurrences

Interrupt venetoclax.

Consider using anti-infective prophylaxis and 
G-CSF for management per institutional 
guidelines. 

For Grade 4 (as well as for Grade 3
thrombocytopenia associated with 
hemorrhage) follow local institution guidelines 
for platelet transfusion

Follow dose reduction guidelines in Table 7
when resuming treatment with venetoclax 
after resolution. A larger dose reduction may 
occur at the discretion of the physician.
G-CSFgranulocyte colony-stimulating factor
Venetoclax may be re-initiated at a lower dose per Table 7. If a patient continues to 
derive clinical benefit but has persistent neutropenia, the dose of venetoclax may be 
further reduced per the dose reduction guidelines.
5.1.5.2
Infections
Patients with MM are at increased risk for infections.  As noted in the exclusion criteria 
(see Section 4.1.2), patients receiving antimicrobial agents for therapeutic intent are not 
permitted to start treatment. Patients should be carefully screened for evidence of active 
or uncontrolled infections or disorders prior to enrollment.  Patients receiving study 
medication must be closely monitored for infections and prompt therapy will be instituted, 
as necessary. 
If indicated, anti-infective prophylaxis should be administered per institutional guidelines.  
Prophylactic antimicrobial therapy per institutional guidelines is permitted. Potential for 
drug-drug interactions should be considered.  See Section 4.4.5 for details on prohibited 
and cautionary medications.
Patients should be advised to report fever and should be assessed for further 
management as per standard medical practice. 


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In the event of Grade 3 or serious infection, treatment with venetoclax should be 
interrupted. Upon resolution, treatment can either be resumed at a reduced dose as 
outlined in Table 7 or discontinued at the discretion of the investigator.
5.1.5.3
Tumor Lysis Syndrome
TLS has not been described with the use of venetoclax in patients with MM. However,
TLS cannot be excluded as a potential complication of the combination treatments. If 
the patient experiences TLS, study treatment should be put on hold and prompt 
supportive measures should be instituted as per institutional guidelines. 
No prophylaxis measures for TLS are mandated in this protocol. However, it is strongly 
recommended to start oral hydration (approximately 1 to 2 liters as tolerated per day)
starting from 72 hours prior to the first dose of venetoclax. An early chemistry laboratory 
analysis is requested at 46 hours after the administration of the first dose of venetoclax
on Cycle 1 Day 1. Prophylaxis with uric acid reducing agents should be considered for 
patients with high uric acid levels. Clinical and laboratory evidence of TLS during 
treatment should be monitored and managed promptly. 
For patients at higher risk (e.g., high tumor burden, plasmablastic morphology, 
unfavorable karyotype, or compromised renal function), more intensive measures 
(e.g., intravenous hydration, frequent monitoring of labs, hospitalization) should be 
considered at the investigator’s discretion. If the patient experiences TLS, study 
treatment drugs should be put on hold. Continued monitoring may be necessary.  If the 
event resolves within 2448 hours, the patient can resume study treatment at the same 
dose level. For events requiring more than 48 hours to resolve, the study treatment 
should be resumed with a dose reduction of venetoclax to the next lower dose level. 
5.1.5.4
Hepatotoxicity
Hepatotoxicity has been associated with the administration of either atezolizumab or
cobimetinib.  Eligible patients must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminase, and liver function will be 
monitored throughout study treatment. 
While in this study, patients presenting 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.
If LFTs increase, neoplastic, concurrent medications, viral hepatitis, and toxic etiologies 
should be considered and addressed, as appropriate. Imaging of the liver, gall bladder, 
and biliary tree should be performed to rule out neoplastic or other causes for the 
increased LFTs.  Anti-nuclear antibody, perinuclear anti-neutrophil cytoplasmic antibody, 
anti-liver kidney microsomal antibodies, and anti-smooth muscle antibody tests should 
be considered.


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Patients with LFT abnormalities should be managed according to the guidelines in
Table 9.
Table 9
Guidelines for the Management of Hepatotoxicity
Event
Action to Be Taken
AST/ALT ULN to 3 ULN with 
total bilirubin 2 ULN 

Continue all study treatment.

Continue with the standard monitoring plan (i.e., LFTs 
Q4W before dosing).
AST/ALT 3 ULN to 5 ULN 
with total bilirubin 2 ULN 

Continue all study treatment.

Monitor LFTs at least weekly.

Consider referral to a hepatologist.
Patients in Arm C:

For suspected immune-mediated events of
5 days duration:

Consider withholding atezolizumab. a

Consider administering 12 mg/kg/day oral 
prednisone or equivalent followed by 1 month taper.

Restart atezolizumab if event resolves to Grade 1 or 
better within 12 weeks. b, c

Permanently discontinue cobimetinib, venetoclax, and 
atezolizumab if event does not resolve to Grade 1 or 
better within 12 weeks. a, b, c
AST/ALT 5 ULN to 10 ULN 
with total bilirubin 2 ULN  

Continue all study treatment.

Monitor LFTs at least weekly.  

Consider dose reduction/interruption according to 
evolution

Consider referral to a hepatologist.
Patients in Arm C:

For suspected immune-mediated events:

Withhold atezolizumab.

Consider administering 12 mg/kg/day oral 
prednisone or equivalent followed by 1 month taper.

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.

Permanently discontinue cobimetinib, venetoclax and 
atezolizumab if event does not resolve to Grade 1 or 
better within 12 weeks. a, b, c


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Table 9
Guidelines for the Management of Hepatotoxicity (cont.)
AST/ALT 3 ULN with bilirubin 
2 ULN
Patients in All Arms:

Consult hepatologist and consider liver biopsy.

Permanently discontinue all study drugs for 
life-threatening hepatic events, and contact the Medical 
Monitor.
Patients in Arm C:

Consider administering 12 mg/kg/day oral prednisone or 
equivalent followed by 1 month taper (for possible 
autoimmune hepatitis).

If LFTs do not decrease within 48 hours after initiation of 
systemic steroids, consider adding an 
immunosuppressive agent (e.g., mycophenolate or TNF-
antagonist).

Monitor LFTs every 4872 hours until decreasing and 
then follow weekly.

Restart atezolizumab at fixed dose and cobimetinib at 
1 dose reduction after discussion with Medical Monitor if 
AST/ALT 3 ULN with bilirubin 2 ULN and steroid 
dose 10 mg oral prednisone equivalent per day. a, b ,c
AST/ALT 10ULN

Permanently discontinue all study drugs. a

Consult hepatologist and consider liver biopsy.
Patients in Arm C:

Consider administering 12 mg/kg/day oral prednisone or 
equivalent (for possible autoimmune hepatitis).  If event 
resolves to Grade 1 or better, taper corticosteroids over 
1 month.

If LFTs do not decrease within 48 hours after initiation of 
systemic steroids, addition of an alternative 
immunosuppressive agent (e.g., mycophenolate or TNF-
antagonist) or dose escalation of corticosteroids may be 
considered.

Monitor LFTs every 4872 hours until decreasing and 
then follow weekly.
LFTliver function test; Q4W every 4 weeks; TNF-tumor necrosis factor-alpha; ULNupper 
limit of normal.
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.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Atezolizumab may be withheld for a period of time beyond 12 weeks to allow corticosteroids to 
be reduced to 10 mg/day oral prednisone or equivalent.  The acceptable length of the 
extended period of time must be agreed upon by the investigator and the Medical Monitor.


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5.1.5.5
Dermatologic Toxicity
Treatment-emergent rash has been associated with atezolizumab and cobimetinib.  The 
majority of the cases of rash were mild in severity and self-limited, with or without 
pruritus.  Although uncommon, cases of severe cutaneous adverse reactions such as 
Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with 
atezolizumab.  
A dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy 
should be considered unless contraindicated.
Dermatologic toxicity and rash should be managed according to the guidelines in 
Table 10.
Table 10 Guidelines for the Management of Dermatologic Events
Event
Action to Be Taken
General guidance

A dermatologist should evaluate persistent and/or severe rash 
or pruritus.  A biopsy should be considered unless 
contraindicated.
Dermatologic event,
Grade 1 or 2

Continue study drugs.

Initiate supportive care (e.g., antihistamines, topical 
corticosteroids).  If event does not improve, consider 
treatment with higher-potency topical corticosteroids.

For Grade 2 rash, consider referral to dermatologist.
Acneiform rash:

Consider topical corticosteroids (e.g., hydrocortisone 2.5%, 
alclometasone) and oral antibiotics (minocycline, doxycycline, 
or antibiotics covering skin flora) as clinically indicated.
Dermatologic event, Grade 3

Withhold study drugs.

Refer patient to dermatologist.  A biopsy should be performed 
if appropriate.

Consider initiating treatment with 10 mg/day oral prednisone 
or equivalent, increasing dose to 12 mg/kg/day if event does 
not improve within 4872 hours.

If event resolves to Grade 2 or better within 28 days, resume 
cobimetinib with dose reduced by one level.  If not, 
permanently discontinue cobimetinib.
Patients in Arm C:

If event resolves to Grade 2 or better within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue 
atezolizumab. a, b

Monitor if event does not resolve to Grade 1 or better within 
12 weeks. a, b, c


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Table 10 Guidelines for the Management of Dermatologic Events (cont.)
Event
Action to Be Taken
Acneiform rash:

Consider continuation of topical corticosteroids (e.g., 2.5% 
alclometasone) and oral antibiotics (e.g., minocycline, 
doxycycline or antibiotics covering skin flora) when restarting 
cobimetinib.
Dermatologic event, Grade 4

Permanently discontinue study drugs and contact Medical 
Monitor. c
Stevens-Johnson syndrome or 
toxic epidermal necrolysis 
(any grade)
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis:

Withhold atezolizumab for suspected Stevens-Johnson 
syndrome or toxic epidermal necrolysis.

Confirm diagnosis by referring patient to a specialist 
(dermatologist, ophthalmologist or urologist as relevant) for 
evaluation and, if indicated, biopsy.

Follow the applicable treatment and management guidelines 
above.

If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab.
Note:  Venetoclax dose may continue at the same level as per the investigator’s judgment.
a If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow corticosteroids (if 
initiated) to be reduced to 10 mg/day oral prednisone or equivalent.  The acceptable length 
of the extended period of time must be agreed upon by the investigator and the Medical 
Monitor.
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.
5.1.5.6
CPK Elevations and Rhabdomyolysis
Rhabdomyolysis and CPK elevation have been seen with cobimetinib (see the
Cobimetinib Investigator’s Brochure).  Permanent discontinuation of cobimetinib 
treatment should be considered if rhabdomyolysis or symptomatic CPK elevations are 
attributed to cobimetinib and do not improve after temporary interruption.  Guidelines for 
the management of CPK elevations and rhabdomyolysis are provided in Table 11.


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Table 11 Guidelines for the Management of Grade 3 or Higher Elevations 
in CPK and Rhabdomyolysis
Event
Action to Be Taken
General guidance

Rule out cardiac cause (check ECG, serum cardiac troponin, 
and CPK-isoforms M and B fraction) and rule out 
rhabdomyolysis (clinical examination; serum creatinine, 
potassium, calcium, phosphorus, uric acid, and albumin; and 
urine myoglobin). 

Assess patient for any history of strenuous physical activity, 
blunt trauma, or recent IM injections.
For Grade 3 CPK elevations 
that are asymptomatic and 
deemed not clinically 
significant

Study drug dosing does not need to be modified or 
interrupted to manage asymptomatic Grade 3 CPK 
elevations.

Recheck CPK at least once a week.
For Grade 4 CPK elevations 
that are asymptomatic and 
deemed not clinically 
significant 

Interrupt study drugs. 

If improved to Grade 3 within 4 weeks, restart cobimetinib 
at a dose reduced by 20 mg, if clinically indicated.

If CPK elevations do not improve to Grade 3 within 4 weeks 
following dose interruption, permanently discontinue 
cobimetinib treatment.

Resumption of venetoclax and atezolizumab may be 
considered in patients who are deriving benefit.
Rhabdomyolysis or 
symptomatic CPK elevations

Interrupt study drugs.

If severity is improved by at least one grade and symptoms 
resolve within 4 weeks, restart cobimetinib at a dose reduced 
by 20 mg, if clinically indicated.  

If rhabdomyolysis or symptomatic CPK elevations do not 
improve within 4 weeks, permanently discontinue cobimetinib 
treatment.

Resumption of venetoclax and atezolizumab may be 
considered in patients who are deriving benefit after 
discussion with the Medical Monitor.
CPKcreatine phosphokinase; IMintramuscular.
5.1.5.7
Visual Disorders
Serous retinopathy events have been associated with cobimetinib.  Visual complaints 
have been associated with atezolizumab or cobimetinib, and should be evaluated by an 
ophthalmologist. 
Uveitis or episcleritis and other immune-mediated ocular disease may be associated 
with atezolizumab. For further information, see the Atezolizumab Investigator’s 
Brochure. 
A severity guide for eye disorders classified as “other” per NCI CTCAE is provided in
Table 12. 


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Table 12 National Cancer Institute Common Terminology Criteria for 
Adverse Events v4.0 Eye DisordersOther, Specify
Grade
Description
1
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
2
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age appropriate instrumental ADL
3
Severe or medically significant but not immediately sight threatening; 
hospitalization or prolongation of existing hospitalization indicated; 
disabling; limiting self-care ADL
4
Sight-threatening consequences; urgent intervention indicated; blindness 
(20/200 or worse) in the affected eye
ADLactivities of daily living.
Atezolizumab- and cobimetinib-associated ocular toxicity should be managed according 
to the guidelines in Table 13.


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Table 13 Guidelines for Managing Ocular Toxicity 
Event
Action to Be Taken
General guidance

An ophthalmologist should evaluate visual complaints. 

Uveitis or episcleritis and other immune-mediated ocular 
disease may be associated with atezolizumab and may be 
treated with topical corticosteroid eye drops.  Atezolizumab 
should be permanently discontinued for immune-mediated
ocular event that is unresponsive to local immunosuppressive 
therapy.

Serous retinopathy is associated with cobimetinib. In clinical 
trials, most events were Grade 1 (asymptomatic) or 2 
(symptomatic).  Most events in clinical trials resolved or 
improved to asymptomatic Grade 1 following dose interruption 
or reduction.  If serous retinopathy is diagnosed, cobimetinib 
should be withheld until visual symptoms improve to Grade 1.  
Serous retinopathy can be managed with treatment 
interruption, dose reduction or with treatment discontinuation. 

RVO has been reported in patients treated with MEK inhibitors 
other than cobimetinib.
Serous retinopathy
Serous retinopathy, Grade 1 a or 2 b (tolerable): 

Continue cobimetinib and atezolizumab without dose change.

Continue ophthalmology follow-up as clinically indicated.
Serous retinopathy, Grade 2 b (intolerable) or Grade 3 or 4 c, d:

Interrupt cobimetinib until Grade 1. 

For ocular adverse events of suspected immune-mediated 
etiology, follow guidelines for atezolizumab provided in 
Appendix 8.

Consult ophthalmology and undergo complete ophthalmic 
examination, which includes visual acuity testing, intra-ocular 
pressure measurements, slit lamp ophthalmoscopy, indirect 
ophthalmoscopy, visual field, and OCT.  Consider a fluorescein 
angiogram and/or indocyanine green angiogram, if clinically 
indicated.

Cobimetinib should be dose reduced by 1 dose level when 
restarting. 

Consider permanent discontinuation of cobimetinib if serous 
retinopathy recurs despite 2 dose level reductions for patients 
receiving cobimetinib monotherapy or cobimetinib plus 
atezolizumab or one dose level reduction for patients in Arm B 
and Arm C.
Severity grade assessment 
based on NCI CTCAE v4.0
“Eye DisordersOther”
scale a, b, c, d
Retinal vein occlusion (any 
grade)

If RVO (any grade) is diagnosed, cobimetinib dosing should be 
permanently discontinued and RVO treated per institutional 
guidelines.

Continue atezolizumab.


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Table 13 Guidelines for Managing Ocular Toxicity (cont.)
Event
Action to Be Taken
Potential immune-mediated
ocular inflammatory toxicity 
(e.g., uveitis, iritis, 
episcleritis, or retinitis)

For ocular adverse events of suspected immune-mediated 
etiology, follow guidelines for atezolizumab provided in 
Appendix 8.

Continue cobimetinib as clinically indicated.
ADLactivities of daily living; NCI CTCAENational Cancer Institute Common Terminology 
Criteria for Adverse Events; OCToptical coherence tomography; RVOretinal vein occlusion.
a Grade 1: Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated.
b Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental ADL.
c Grade 3: Severe or medically significant but not immediately sight threatening; hospitalization 
or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL.
d Grade 4: Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or 
worse) in the affected eye.


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5.1.5.8
Gastrointestinal Events
Table 14 Guidelines for Managing Gastrointestinal Toxicity
Event
Action to Be Taken
General guidance

All events of diarrhea or colitis should be thoroughly 
evaluated for more common etiologies other than drug 
induced effects.

For events of significant duration or severity or associated 
with signs of systemic inflammation or acute phase 
reactants, check for immune-mediated colitis (see
Section 5.1.5.9). 

Anti-diarrheal prophylaxis (e.g., loperamide) is strongly 
recommended for patients treated with venetoclax in 
combination with cobimetinib. In patients receiving 
venetoclax plus cobimetinib who have experienced Grade 3 
diarrhea anti-diarrheal medication is mandatory (see Table 5) 

Administer anti-diarrheal agents and other maximal 
supportive care per institutional guidelines such as:  at the 
first report of watery diarrhea or loose stool, initiate maximal 
anti-diarrheal supportive care (Lomotiland loperamide).
Suggested regimen: 

Loperamide:  Initiate dose with 4 mg, then 4 mg every 
6 hours around the clock, alternating with Lomotil. 

Lomotil (diphenoxylate and atropine):  Dispense 2 tablets 
(diphenoxylate 5 mg, atropine 0.05 mg) every 6 hours around 
the clock. 

Continue Lomotil and loperamide until no loose stools for 
24 hours. 

If Grade 2 diarrhea persists after 48 hours total treatment 
with Lomotil and loperamide, consider second-line agents 
(e.g., octreotide, budesonide, tincture of opium). 
Oral supplementation: 

Initiate oral supplementation of potassium and/or magnesium 
if serum levels are LLN. 

Consider oral rehydration therapy (e.g., Pedialyte) for 
Grade 1 diarrhea or vomiting. 
Dietary modifications: 

Stop all lactose-containing products and eat small meals. 

The BRAT (banana, rice, apples, toast) diet, without fiber 
(other vegetables and fruits), may be helpful. 

Encourage adequate hydration with salt-containing liquids, 
such as broth or Gatorade.
Diarrhea, Grade 1 or Grade 2 
(tolerable)

Continue cobimetinib, venetoclax, and atezolizumab.

Initiate supportive care and monitor patient closely.

Investigate etiology, referring patient to GI specialist for 
evaluation of possible colitis if appropriate.


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Table 14 Guidelines for Managing Gastrointestinal Toxicity (cont.)
Event
Action to Be Taken
Diarrhea, Grade 2 (intolerable) 
or Grade 3

Withhold cobimetinib, venetoclax, and atezolizumab.

Initiate supportive care and monitor patient closely.

Discontinue medications that may exacerbate colitis in 
patients receiving atezolizumab (e.g., NSAIDs) while 
investigating etiology.

Investigate etiology, referring patient to GI specialist for 
evaluation of possible colitis, including biopsy if appropriate
in patients receiving atezolizumab.

If event resolves to Grade 1 or better within 28 days, resume 
cobimetinib and venetoclax with dose reduced by one level
with continued supportive care or anti-diarrheal prophylaxis. 
If not, permanently discontinue cobimetinib and venetoclax.
Patients in Arm C:

If event resolves to Grade 1 or better within 12 weeks, 
resume atezolizumab at fixed dose.  If not, permanently 
discontinue atezolizumab. a, b, c  
Diarrhea, Grade 4

Permanently discontinue study drugs and contact Medical 
Monitor.

Initiate supportive care and monitor patient closely.

Discontinue medications that may exacerbate colitis 
(e.g., NSAIDs) while investigating etiology.

Rule out bowel perforation.

Investigate etiology, referring patient to GI specialist for 
evaluation of possible colitis, including biopsy if appropriate.
GIgastrointestinal; NSAID non-steroidal anti-inflammatory drug.
a If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids 
(if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.  The acceptable 
length of the extended period of time must be agreed upon by the investigator and the Medical 
Monitor.
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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5.1.5.9
Colitis
Immune-mediated colitis has been associated with the administration of atezolizumab.
If the presence of diarrhea is of significant duration or magnitude or in case it is 
associated with signs of systemic inflammation or acute phase reactants (e.g., increased 
C-reactive protein, platelet count, or bandemia), it is recommended to do the following:

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 for confirmation of the diagnosis of colitis. If possible, one or 
two biopsy specimens should be snap-frozen and stored. 

Perform laboratory tests to rule out alternate etiology (i.e., WBCs and stool 
calprotectin).
Table 15 Guidelines for the Management of Atezolizumab-Induced Colitis
Event
Action to Be Taken
Colitis, Grade 1

Continue study drugs.

Initiate supportive care and monitor patient closely. 

Discontinue medications that may exacerbate colitis 
(e.g., NSAIDs).

Refer patient to gastrointestinal specialist for evaluation and 
confirmatory biopsy if symptoms persist for 7 days.
Colitis, Grade 2

Withhold study drugs.

Initiate supportive care and monitor patient closely.

Discontinue medications that may exacerbate colitis 
(e.g., NSAIDs).

Refer patient to gastrointestinal specialist for evaluation and 
confirmatory biopsy.

For recurrent events or events that persist 5 days, initiate 
treatment with 12 mg/kg/day oral prednisone or equivalent.

If event resolves to Grade 1 or better within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue 
atezolizumab and cobimetinib. a, b, c

If event resolves to Grade 1 or better within 28 days, resume 
cobimetinib with dose reduced by one level.  If not, permanently 
discontinue cobimetinib.


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Table 15 Guidelines for the Management of Atezolizumab-Induced Colitis
(cont.)
Event
Action to Be Taken
Colitis, Grade 3

Withhold study drugs.

Initiate supportive care and monitor patient closely.

Discontinue medications that may exacerbate colitis 
(e.g., NSAIDs).

Refer patient to gastrointestinal specialist for evaluation and 
confirmatory biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue 
atezolizumab and cobimetinib. a, b, c

If event resolves to Grade 1 or better within 28 days, resume 
cobimetinib with dose reduced by one level.  If not, permanently 
discontinue cobimetinib.
Colitis, Grade 4

Permanently discontinue atezolizumab and cobimetinib, and 
contact Medical Monitor. c

Initiate supportive care and monitor patient closely.

Discontinue medications that may exacerbate colitis 
(e.g., NSAIDs).

Refer patient to gastrointestinal specialist for evaluation and 
confirmatory biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent 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.
NSAIDnon-steroidal anti-inflammatory drug.
a If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for 
corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.  The 
acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
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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5.1.5.10
Cardiac Adverse Events
Decrease in LVEF from baseline has been reported in patients receiving cobimetinib.  
Left ventricular dysfunction may occur with signs and symptoms of cardiac failure, or 
reduction in LVEF events may be asymptomatic.
Guidelines for the management of congestive heart failure/reduction in LVEF are 
provided in Table 16.


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Table 16 Guidelines for the Management of Congestive Heart Failure/Reduction in Left Ventricular 
Ejection Fraction
Patient
LVEF Value
Recommended Action with 
Cobimetinib and Atezolizumab a
LVEF Value Following 
Treatment Break
Recommended Cobimetinib 
Daily Dose
Asymptomatic
50%
(or 40%49% and10% 
absolute decrease from BL)

Continue atezolizumab and 
cobimetinib at current dose
N/A
N/A
40% (or 40%49% 
and10% absolute 
decrease from BL)

Interrupt cobimetinib 
treatment for 2 weeks

Continue atezolizumab as 
clinically indicated
10% absolute 
decrease from BL

First occurrence:  40 mg b

Second occurrence:  20 mg b

Third occurrence:  permanent 
discontinuation b
40%
(or 10% absolute 
decrease from BL)

Permanent discontinuation
Symptomatic
N/A

Interrupt cobimetinib 
treatment for 4 weeks.

Consider withholding 
atezolizumab.

Discuss with Medical 
Monitor regarding 
resumption of atezolizumab.  

Cardiology consultation is 
strongly recommended.
Asymptomatic 
and10% absolute 
decrease from BL

First occurrence:  40 mg

Second occurrence:  20 mg

Third occurrence:  permanent 
discontinuation
Asymptomatic and 
40% (or 10% 
absolute decrease from 
BL)

Permanent discontinuation
Symptomatic 
regardless of LVEF

Permanent discontinuation
BLbaseline; LVEFleft ventricular ejection fraction; N/Anot applicable.
a Treatment with venetoclax may continue at the discretion of the investigator.
b For patients in Arm B and Arm C, first occurrence: 20 mg; second occurrence:  permanent discontinuation.


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5.1.5.11
Hemorrhage
Treatment with venetoclax may continue at the discretion of the investigator, unless the 
event is related to thrombocytopenia in which case the recommendations provided for 
cytopenias should be followed (see Table 8).
Table 17 Guidelines for the Management of Hemorrhage
Event
Action to Be Taken
Grade 3 hemorrhage

Interrupt cobimetinib treatment.  There are no data on the 
effectiveness of cobimetinib dose modification for 
hemorrhage events.  Clinical judgment should be applied 
when considering restarting cobimetinib treatment.

Continue atezolizumab treatment.
Grade 4 hemorrhage or any 
grade cerebral hemorrhage

Interrupt cobimetinib treatment.  Permanently discontinue 
cobimetinib for hemorrhage events attributed to 
cobimetinib.

Continue atezolizumab treatment.
5.1.5.12
Pancreatitis
Cobimetinib and venetoclax may continue without interruption and/or dose reduction at 
the discretion of the investigator per medical judgment.  For management guidelines
related to atezolizumab and pancreatitis, refer to Appendix 8.


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5.1.5.13
Pulmonary Events, Including Pneumonitis
Table 18 Guidelines for Managing Pulmonary Events, Including
Pneumonitis
Event
Action to Be Taken
General guidance

Mild-to-moderate events of pneumonitis have been reported 
with atezolizumab and cobimetinib.  All pulmonary events 
should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia/infection, lymphangitic 
carcinomatosis, pulmonary embolism, heart failure, chronic 
obstructive pulmonary disease, or pulmonary hypertension.

For events concerning for pneumonitis, consider comprehensive 
infectious evaluation including viral etiologies.
Pulmonary Event or 
Pneumonitis, Grade 1 
(asymptomatic)

Continue study drugs and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.
Pulmonary Event or 
Pneumonitis, Grade 2

Withhold study drugs for up to 12 weeks after event onsetb.

Refer patient to pulmonary and infectious disease specialists 
and consider bronchoscopy or BAL. 

If bronchoscopy is consistent with immune-mediated etiology, 
initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day oral prednisone.

Resume study drugs if event resolves to Grade 1 or better 
within 12 weeks. a, b

Permanently discontinue study drugs and contact Medical 
Monitor if event does not resolve to Grade 1 or better within 
12 weeks. a, b, c

For recurrent events, treat as a Grade 3 or 4 event.
Pulmonary Event or 
Pneumonitis, Grade 3 or 4

Permanently discontinue study drugs and contact Medical 
Monitor. c

Refer patient to pulmonary and infectious disease specialists 
and consider bronchoscopy or BAL. 

If bronchoscopy is consistent with immune-mediated etiology, 
initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 

If pulmonary event does not improve within 48 hours or worsens
after initiating corticosteroids, consider adding an 
immunosuppressive agent (e.g., infliximab, cyclophosphamide, 
IV Ig, or mycophenolate mofetil).

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.


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Table 18 Guidelines for Managing Pulmonary Events, Including
Pneumonitis (cont.)
BALbronchoscopic alveolar lavage.
a If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids
(if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.  The acceptable 
length of the extended period of time must be agreed upon by the investigator and the Medical 
Monitor.
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.
5.1.5.14
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.  Guidelines for the management of neurologic disorders are provided 
in Appendix 8.
5.1.5.15
Infusion-Related Reactions and Cytokine-Release Syndrome
Patients may develop IRRs or cytokine-release syndrome (CRS) during the 
administration of atezolizumab. 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an IRR or CRS with atezolizumab may receive 
premedication with antihistamines, antipyretics, and/or analgesics (e.g., acetaminophen) 
for subsequent infusions. Metamizole (dipyrone) is prohibited in treating 
atezolizumab-associated IRRs because of its potential for causing agranulocytosis.
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for the medical management of IRRs and CRS are provided in Appendix 8.
5.1.5.16
Endocrine Events
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have
been associated with the administration of atezolizumab.
Patients with unexplained symptoms, such as headache, fatigue, myalgias, impotence, 
mental status changes, or constipation, should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies, as well as for hyponatremia or 
hyperkalemia. An endocrinologist should be consulted if an endocrinopathy is 
suspected.  TSH and free T3, and T4 levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., 


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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.
Guidelines for the management of hypothyroidism and hyperthyroidism, adrenal 
insufficiency, hyperglycemia, and hypophysitis are provided in Appendix 8.
5.1.5.17
Immune-Mediated Adverse Events
Down-modulating PD-L1/PD-1 signaling may permit the emergence of auto-reactive 
T cells and clinical autoimmunity.  Adverse events associated with drug exposure and 
consistent with an autoimmune etiology are termed immune-mediated adverse events.
Patients should be informed of, and carefully monitored for, evidence of clinically 
immune-mediated adverse event (e.g., rash, colitis, uveitis, hepatitis, thyroid disease).  
Efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other 
etiologic causes prior to labeling an adverse event an immune-mediated adverse event.  
Serological, immunological, and histological (biopsy) data should be used to support the 
diagnosis of an immune-mediated toxicity.  
Although many low-grade immune-mediated adverse events respond well to 
symptomatic therapy, high-grade immune-mediated adverse events require 
corticosteroid therapy and, in rare corticosteroid-refractory cases, the use of other 
immune-suppressive therapies, such as infliximab or mycophenolate mofetil.
5.1.5.18
Immune-Mediated Myocarditis
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab.  Guidelines for the management of immune-mediated myocarditis are 
provided in Appendix 8.
5.1.5.19
Immune-Mediated Meningoencephalitis
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Guidelines for the management of immune-mediated
meningoencephalitis are provided in Appendix 8.
5.1.5.20
Immune-Mediated Nephritis
Immune-mediated nephritis is an identified risk associated with the administration of 
atezolizumab.  Guidelines for the management of immune-mediated nephritis are 
provided in Appendix 8.
5.1.5.21
Other Unspecified Adverse Events
General dose modification recommendations for cobimetinib are provided in Table 19.  
Guidelines for the management of non-laboratory related adverse events are provided in
Table 20, and guidelines for the management of unspecified Grade 3 and higher 
laboratory related adverse events are provided in Table 21.


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Table 19 Dose Modifications Recommendations for Cobimetinib
Grade a
Recommended Cobimetinib Dosage
Grade 1 or Grade 2 (tolerable)
No dose reduction
Grade 2 (intolerable) or
Grade 3 or 4
1st Appearance b
Interrupt treatment until Grade 1, restart treatment at 
40 mg once daily
2nd Appearance b
Interrupt treatment until Grade 1, restart treatment at 
20 mg once daily
3rd Appearance b
Consider permanent discontinuation
NCI CTCAE v4.0National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4.0.
a The intensity of clinical adverse events graded by the NCI CTCAE v4.0.
b For patients in Arm B and Arm C, first appearance: 20 mg; second appearance: permanent 
discontinuation.
Cobimetinib dose modification should be based on the prescriber’s assessment of 
individual patient safety or tolerability.  If doses are omitted for toxicity; missed doses 
should not be replaced.  Once the dose has been reduced, it should not be increased at 
a later time. 


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Table 20 Guidelines for the Management of Unspecified Related Adverse 
Events Grade 3 or Higher Other Than Laboratory Abnormalities
Atezolizumab dose cannot be reduced. Atezolizumab-related toxicity can be managed 
only by dose interruption or discontinuation.
Event
Action to Be Taken
Other unspecified related 
events (other than 
laboratory abnormalities), 
Grade 3

Interrupt dosing of attributable study drug at the discretion of the 
investigator. During this time, treatment may continue with 
non-attributable study drugs.

If attributable study drug has been held and the event resolves 
to Grade 1 within 28 days, then restart dosing of attributable 
study drug. 

If attributable study drug has been held and the event does not 
resolve to Grade 1 within 28 days, then discontinue 
attributable study drug. If attributable study drug is 
discontinued, treatment may continue with other study drugs at 
the discretion of the investigator.
Other unspecified related 
events (other than 
laboratory abnormalities), 
Grade 4 first occurrence

During this time, treatment may continue with non-attributable 
study drugs.

If the Grade 4 event is attributed to one study drug: 

Interrupt dosing of the attributable study drug at the 
discretion of the investigator. During this time, treatment 
may continue with non-attributable study drugs.

If the attributable study drug has been held and the event 
resolves to Grade 1 within 28 days, then restart dosing of 
the attributable study drug.

If the attributable study drug has been held and the event 
does not resolve to Grade 1 within 28 days, then 
discontinue the attributable study drug. If the attributable 
study drug is discontinued, treatment may continue with 
other study drugs at the discretion of the investigator.
Other unspecified related 
events (other than 
laboratory abnormalities), 
Grade 4 second 
occurrence

If the Grade 4 event is attributed to cobimetinib or atezolizumab: 

If the Grade 4 event recurs despite reduction of the 
attributable study drug by one dose level or interruption, 
discontinue the attributable study drug at the discretion of 
the investigator. During this time, treatment may continue 
with non-attributable study drugs.


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Table 21 Guidelines for Grade 3 and Higher Unspecified Laboratory 
Abnormality Adverse Events
Event
Action to Be Taken
Other unspecified events 
that are laboratory 
abnormalities, Grade3

For Grade 3 toxicities associated primarily with laboratory 
abnormalities only and for which guidance has not already been 
specified elsewhere in this protocol (e.g., elevation of lipase or 
amylase, or decreases in phosphorus without clinical or other 
evidence of pancreatitis or other hepatic dysfunction), all study 
drugs may continue without interruption and/or dose reduction at 
the discretion of the investigator.
5.1.5.22
Immune-Mediated Myositis
Immune-mediated myositis is an identified risk associated with the administration of 
atezolizumab.  Guidelines for the management of immune-mediated myositis are 
provided in Appendix 8.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
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
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 drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 


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Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following:

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Pneumonitis

Colitis

Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, or hypophysitis

Systemic lupus erythematosus

Neurologic:  Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, 
meningoencephalitis

Nephritis

Events suggestive of hypersensitivity, infusion-related reactions, cytokine release
syndrome, HLH, and MAS

Ocular events
–
RVO (Grade ≥1)
–
Serous retinopathy, including any events of retinal detachment, retinal 
pigment epithelium detachment, neurosensory retinal detachment, and 
central serous chorioretinopathy 
–
Ocular inflammatory toxicities (e.g., uveitis, retinitis, optic neuritis)

Significant muscular toxicities
–
Rhabdomyolysis or Grade 3 CPK elevation
–
Myopathies including myositis

Grade 3 hemorrhage or any grade cerebral hemorrhage

Grade 3 rash

Grade 2 cardiac events, including:
–
Symptomatic heart failure or Grade 2 left ventricular ejection fraction reduction 
–
Myocarditis, pericarditis, or atrial fibrillation 

Vasculitis

Grade 3 diarrhea

Significant liver toxicity
–
Hepatitis, including AST and/or ALT 10ULN


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–
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):
Treatment emergent ALT or AST 3ULN in combination with either an 
elevated total bilirubin (2ULN) or clinical jaundice, without initial findings of 
cholestasis (elevated serum ALP)
No other reason can be found to explain the combination of increased ALT/AST 
and total bilirubin, such as:  liver metastasis; viral hepatitis A, B, or C; alcoholic 
and autoimmune hepatitis; other liver diseases; or exposure to other drugs 
known to cause liver injury 

Any TLS

Grade 4 thrombocytopenia

Grade 3 infection

Hepatitis B reactivation

Myositis
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 Section 5.4Section 5.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 90 days after the 
last dose of study drug.  For patients receiving atezolizumab (in both the safety run-in 
phase and the randomization phase), this period should be extended up to 135 days 
after the last dose of atezolizumab.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.


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5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 22 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 22 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 


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adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis 
(e.g., "infusion-related reaction") on the Adverse Event eCRF.  If possible, avoid 
ambiguous terms such as "systemic reaction."  Associated signs and symptoms should 
be recorded on the dedicated Infusion-Related Reaction eCRF.  If a patient experiences 
both a local and systemic reaction to the same dose of study drug, each reaction should 
be recorded separately on the Adverse Event eCRF, with signs and symptoms also 
recorded separately on the dedicated Infusion-Related Reaction eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than IRRs (see Section 5.3.5.1), a diagnosis (if known) should 
be recorded on the Adverse Event eCRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the Adverse Event eCRF.  If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis.


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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.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 
to "serious," providing the date that the event became serious, and completing all data 
fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms


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
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., ALP 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 
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.


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If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with clinical 
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
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 MM
should be recorded on the Death Attributed to Progressive Disease eCRF.  All other 
deaths that occur during the adverse event reporting period, regardless of relationship to 
study drug, must be recorded on the Adverse Event eCRF and immediately reported to 
the Sponsor (see Section 5.4.2).
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.


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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 Multiple Myeloma
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 IMWG 2016 criteria.  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 drug administration 
or insertion of access device for study drug administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer


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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
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).
No safety data related to overdosing of cobimetinib, venetoclax, or atezolizumab are 
available.  
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event


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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:
, M.D.
Telephone No.:
Email:
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 Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The 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 Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 135 days after the last dose of study treatment for patients 
who receive atezolizumab and 90 days after the last dose of study treatment for patients 
who do not receive atezolizumab.  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 
the form using the fax number or email address provided to investigators.  Once the 


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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 last dose of study 
treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or within 3 months after the last dose of cobimetinib, 1 month after the last dose of 
venetoclax, and 5 months after the last dose of atezolizumab.  A 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 drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
3 months after the last dose of cobimetinib.  The investigator should report the 
pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit the form to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or 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 drug.  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 with additional
information on the course and outcome of the pregnancy as it 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
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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 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, 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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5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 135 days after the last 
dose of atezolizumab and 90 days for patients who do not receive atezolizumab), all 
deaths, regardless of cause, should be reported through use of the Long-Term Survival 
Follow-Up eCRF.  In addition, if the investigator becomes aware of a serious adverse 
event that is believed to be related to prior exposure to study treatment, the event should 
be reported through use of the Adverse Event eCRF.  However, if the EDC system is not 
available, the investigator should report these events directly to the Sponsor or its 
designee, either by faxing or by scanning and emailing the paper Clinical Trial Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form using the fax number 
or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Cobimetinib Investigator's Brochure 

Venetoclax Investigator’s Brochure

Atezolizumab Investigator’s Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Data from the safety run-in phase and the randomization phase will be analyzed 
separately, that is, data will not be combined across the two phases for Arms B and C 
when listing or summarizing data. For each phase, analyses to assess safety will be 
conducted using the safety-evaluable population, defined as all patients who receive any 
amount of study drug and analyzed according to the treatment arm they received. 
Analyses to assess efficacy will also be conducted in the same manner using the safety
population. Patients who fail to receive no component of their planned study medication 


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will be excluded from the safety population, and will be included in any intent-to-treat 
analyses.
There is no formal hypothesis testing planned therefore analyses will be solely 
descriptive.  The safety, tolerability, clinical activity, and pharmacokinetics of the three 
treatment arms will be described and summarized as warranted by sample size. That is, 
listings may be used in lieu of summary tables in the event of a small sample size. 
Continuous variables will be summarized using mean, standard deviation, median, and 
range; categorical variables will be summarized using counts and percentages.  
Additional details regarding specific analyses and data handling will be documented in a 
separate statistical analysis plan.
6.1
DETERMINATION OF SAMPLE SIZE
Design considerations were not made with regard to power or to control the type I error, 
but to obtain preliminary efficacy, safety, tolerability, and PK information of cobimetinib 
as a single agent (Arm A), cobimetinib plus venetoclax (Arm B), and cobimetinib plus 
venetoclax plus atezolizumab (Arm C) in patients with R/R MM.
Approximately 72 patients are anticipated to be recruited in this study: approximately
12 patients in the safety run-in cohorts, 12 patients in Arm A, 24 patients in Arm B, and 
24 patients in Arm C. 
If patients must be replaced or additional cohorts are enrolled during the safety run-in, 
the total sample size for this study may increase and the study team may enroll 
6 additional patients (in each safety run-in cohort, if necessary) at a reduced dose level 
(see Section 3.1).  Depending on the outcome of the review of the clinical data from the 
additional 6 patients, the study team will determine if the expansion stage can initiate 
with this lower combination dose. 
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for patient discontinuations from the study treatment and from 
the study will be listed and summarized.  Enrollment, study treatment administration, and 
major protocol deviations will be evaluated for their potential effects on the interpretation 
of study results.
For safety-evaluable patients, study drug administration data will be tabulated or listed 
by cohort, and any dose modifications will be flagged.  Descriptive statistics will be used 
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6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics such as age, sex race/ethnicity, weight, type 
of malignancy, and baseline ECOG Performance Status will be summarized using 
descriptive statistics for continuous variables and proportions for categorical variables, 
as appropriate. 
6.4
EFFICACY ANALYSES
For all primary, secondary, and exploratory efficacy analyses listed within this section, 
data will be analyzed and summarized separately for the safety run-in phase and the 
randomization phase; data will not be combined across phases. 
6.4.1
Primary Efficacy Endpoint
The primary efficacy objective of this study is to evaluate the anti-myeloma activity of 
cobimetinib administered as a single agent (Arm A), cobimetinib in combination with 
venetoclax (Arm B), and cobimetinib in combination with venetoclax and atezolizumab 
(Arm C) based on the overall response rate (ORR) as determined by the investigator 
using the IMWG response criteria (Kumar et al. 2016). ORR is defined as sCR, CR, 
VGPR, or PR and will be analyzed in the efficacy population and in biomarker-selected 
sub-populations (e.g., MAPK activation, t[11;14]). For Arm A, ORR will also be analyzed 
separately in the cobimetinib single-agent arm and for those patients who are treated 
with cobimetinib plus atezolizumab upon disease progression.
Descriptive statistics will be used to evaluate the incidence, nature and severity of 
adverse events, graded according to the NCI CTCAE v4.0. 
6.4.2
Secondary Efficacy Endpoints
Further analyses of anti-myeloma activity will be based on definitions of responses 
according to IMWG (see Appendix 5) as defined below:  

Clinical benefit rate defined as MR or better (PR, VGPR, CR, sCR)

PFS defined as the time from randomization to the first occurrence of disease 
progression or relapse as determined by the investigator using the IMWG criteria or 
death from any cause during the study, whichever occurs first.

DOR applies to patients achieving at least a PR, and is measured from the first 
observation of PR to the time of disease progression; deaths not due to progression 
will be censored.

Overall survival (OS) defined as the time from randomization until death from any 
cause. 
6.4.3
Exploratory Efficacy Endpoints
An exploratory efficacy endpoint will assess the time to next treatment, defined as the 
time between the start date of the current treatment line and the start date of the next 
treatment line, death, or last follow-up. 


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6.5
SAFETY ANALYSES
The safety analyses will include all patients who received at least one dose of any study 
drug, and will be analyzed and summarized separately for the safety run-in phase and 
the randomization phase; data will not be combined across phases.
Adverse events, deaths, change in laboratory test results, change in vital signs, and 
exposure to components of study treatment will be assessed to determine the safety of 
treatment regimen. 
Verbatim descriptions of adverse events will be mapped to appropriate thesaurus terms.  
All adverse events occurring on or after treatment Day 1 will be summarized by the 
mapped term, appropriate thesaurus levels, and NCI CTCAE, v4.0 toxicity grade.  
In addition, adverse events leading to treatment withdrawal or death, and serious 
adverse events will be listed with more detailed information, such as the day of onset of 
an adverse event, duration of adverse event, toxicity grade, etc. 
Relevant laboratory and vital signs (heart rate, blood pressure, and temperature) and 
ECG data will be displayed by time post-dose, with NCI CTCAE Grade 3 and 4 values 
identified where appropriate.  Additionally, changes in laboratory data will be 
summarized by grade using the NCI CTCAE toxicity grade.  Selected vital signs and 
selected laboratory data will be summarized by visit.  
The extent of study drug exposure (dose and duration) will be examined to determine 
the degree of treatment tolerability.  In addition to treatment duration and total dose 
received, any dose modification of study drugs will also be summarized.  
Concomitant medications received during the treatment period will be summarized.   
6.6
PHARMACOKINETIC ANALYSES
The PK analyses population will consist of patients from Arm A, Arm B, and Arm C who 
have received at least one dose of study medication and for whom at least one 
evaluable PK sample is collected. PK data will be analyzed and summarized separately 
for the safety run-in phase and the randomization phase; data will not be combined 
across phases. Cobimetinib and venetoclax area under the plasma concentration vs. 
time curve, maximum concentration, and time to maximum concentration (AUC, Cmax,
and Tmax) will be reported for individual patients. Atezolizumab Cmax and Cmin will be 
reported for individual patients. Summary PK data will be provided, as data permit. 
Existing population PK models for cobimetinib, venetoclax, and atezolizumab will be 
used to investigate the relationship between drug exposure and efficacy or safety 
outcomes using population approaches for each medication.
Additional PK analyses will be conducted as appropriate based on the available data.


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6.7
IMMUNOGENICITY ANALYSES 
The immunogenicity analysis population for atezolizumab will consist of all patients from 
Arm C with any ADA assessment, with patients grouped by stage and cohort.
The numbers and proportions of ADA-positive patients and ADA-negative patients 
during both the treatment and follow-up periods will be summarized by safety run-in and 
randomization phase, and by cohort and study arm.  Patients are considered to be ADA 
positive if they are ADA negative or missing data at baseline but develop an ADA 
response following study drug administration (treatmentinduced ADA response), or if 
they are ADA positive at baseline and the titer of one or more post-baseline samples is 
at least 4-fold greater (i.e., 0.60 titer units) than the titer of the baseline sample 
(treatmentenhanced ADA response).  Patients are considered to be ADA negative if 
they are ADA negative or missing data at baseline and all post-baseline samples are 
negative, or if they are ADA positive at baseline but do not have any post-baseline 
samples with a titer that is at least 4-fold greater than the titer of the baseline sample 
(treatment unaffected).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported descriptively via subgroup analyses.
6.8
EXPLORATORY BIOMARKER ANALYSES
The biomarker readout and the relation to clinical activity will be summarized as 
warranted by the sample size. 
The efficacy of Arm A, Arm B, and Arm C will be correlated to biomarkers such as MAPK 
hyperactivation (including RAS mutation), t(11;14) translocations, and pretreatment 
immune contexture. Data will be analyzed and summarized separately for the safety 
run-in phase and the randomization phase; data will not be combined across phases.
In the three study arms different biomarkers will be evaluated, including those 
associated with disease biology, the mechanism of action of cobimetinib, the resistance 
to study drugs, pharmacodynamics, and prognosis.  Furthermore, the available 
biomarkers will be assessed for the improvement of diagnostic assays.  
MRD will be evaluated and correlated with patient response and survival
(Kumar et al. 2016).
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 


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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.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
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.


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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
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.
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 Clinical Study Report has been 
completed 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. 


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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 a Child’s Informed 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 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 


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each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
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 
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.


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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 Roche 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.
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
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.


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9.4
ADMINISTRATIVE STRUCTURE
This study is sponsored by F. Hoffmann-La Roche Ltd.  This study will enroll a total of 
approximately 72 patients.  The Sponsor will provide clinical operations oversight, data 
management support, and medical monitoring. 
Randomization will occur through an interactive voice or Web-based response system
(IxRS).  Efficacy assessments and other specified laboratory tests throughout the study 
will be conducted in accredited local laboratories; local laboratory ranges will be 
collected. Central facilities will be used for the assessment of biomarker and PK
objectives. Plasma and serum will be sent to a central laboratory for analysis and 
sample storage.  Routine sample analysis will be performed by an accredited external 
vendor; local laboratory ranges will be collected.
Following the completion of the safety run-in phase, further accrual to the randomization 
phase will be temporarily halted while the study team reviews the totality of clinical data 
to determine safety and tolerability of all regimens. Only after the regimens have
demonstrated acceptable safety, the randomization phase can be initiated.  As it is 
estimated that it will take several months to complete enrollment of the safety run-in 
phase, the safety review should contain data from patients who have been receiving the 
regimen for a minimum of one cycle of treatment.
Stopping rules for patient safety are provided in Section 3.1.1.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical
Study Information at the following Web site:
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.


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The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Schedule of Activities
Screening a
Study Regimen Treatment Period b
Treatment 
Discontinuation c
Follow-up
Visits d
Complete 
Response
Cycle 1
Cycle 2
Cycle 3
Days
28 to 1
1
15
22
1
15
22
1
15
22
Informed consent e
x
Demographic data
x
Medical history
x
Vital signs f, g
x
x
x
x
x
x
x
x
Height (on Cycle 1, Day 1 
only) and weight
x
x
x
x
x
ECOG Performance Status
x
x
x
x
x
Physical examination h
x
x
x
x
x
x
x
x
ECHO or MUGA scan i
x
x
x
x
12-lead ECG
x
x
SPEP, UPEP, SIFE, UIFE j
x
x
x
x
x
sFLCs k
x
x
x
x
x
Skeletal survey/assessment of 
lytic disease
x a
As clinically indicated (X-ray, whole-body low-dose CT, MRI, or PET scan)
Plasmacytoma assessment l
x
x
Serum β-2 microglobulin 
x
Quantitative immunoglobulins 
(including IgA, IgG, IgM)
x
x
x
x
x
Hematology m
x
x
x
x
x
x
x
x
Coagulation (PT, aPTT, INR)
x
x


Appendix 1 Schedule of Activities (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
157/Protocol BO39813, Version 7
Screening a
Study Regimen Treatment Period b
Treatment 
Discontinuation c
Follow-up
Visits d
Complete 
Response
Cycle 1
Cycle 2
Cycle 3
Days
28 to 1
1
15
22
1
15
22
1
15
22
Chemistry n
x
x
x
x
x
x
x
x
Viral serology (HIV, HBsAg, 
hepatitis B surface antibody, 
total HBcAb, HCV antibody) o
x
Thyroid function test  p
x
x
x
Urinalysis q
x
x
x
x
x
Pregnancy test r
x
Monthly and as clinically indicated
Ophthalmic exams s
x
x
x
x
Cobimetinib dispensing
x
x
x
Atezolizumab administration t
x
x
x
x
x
x
Venetoclax dispensing
x
x
x
Concomitant medications
Continuous from time of signed ICF until 90 days after last study treatment dose
Adverse events u
Continuous from time of signed ICF until 90 days after last study treatment dose
ADA sample
See Appendix 2
PK sample
See Appendix 2
Biomarker bone marrow 
biopsy v
x
x v
Biomarker bone marrow 
aspirate sample w
x
x
x
x
Serum samples for analysis of 
autoantibodies
x
Perform if an atezolizumab-treated patient experiences
a suspected immune-mediated adverse event
Biomarker blood sample x
x
x
x
x
x
x
x


Appendix 1 Schedule of Activities (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
158/Protocol BO39813, Version 7
Screening a
Study Regimen Treatment Period b
Treatment 
Discontinuation c
Follow-up
Visits d
Complete 
Response
Cycle 1
Cycle 2
Cycle 3
Days
28 to 1
1
15
22
1
15
22
1
15
22
Biomarker serum sample y
x
x
x
x
x
Biomarker plasma sample z
x
x
x
x
x
x
x
Survival assessment
x d
ADAanti-drug antibody; ALPalkaline phosphatase; CRcomplete response; CTcomputed tomography; ECHOechocardiogram; 
ECOGEastern Cooperative Oncology Group; eCRF electronic Case Report Form; HBcAbhepatitis B core antibody; HBsAghepatitis B 
surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; ICFInformed Consent Form; LVEFleft ventricular ejection fraction; 
MRDminimal residual disease; MRImagnetic resonance imaging; MUGAmultiple-gated acquisition (scan); PDprogressive disease; 
PET positron emission tomography; PKpharmacokinetic; sFLCserum free light chain; SIFEserum immunofixation electrophoresis; 
SPEPserum protein electrophoresis; T4thyroxine; T3triiodothyronine; TSHthyroid-stimulating hormone; UIFEurine immunofixation
electrophoresis; UPEPurine protein electrophoresis.
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to Day 1 may be 
used; such tests do not need to be repeated for screening, except for extramedullary disease and skeletal survey in which a 35-day window is 
allowed.
b A time window of 2 days is allowed for all study assessments unless otherwise specified.  Pneumococcal vaccination may be considered 
during the initiation of screening procedures for all patients who have not previously received the vaccine.  At the investigator's discretion, 
inactive influenza vaccination may also be considered (live attenuated vaccines are not permitted) during the initiation of screening procedures 
and during study treatment.
c Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit within 30 (7) days after the last dose of study 
drug. The visit at which response assessment shows PD may be used as the treatment discontinuation visit.
d Required follow-up information will be collected via telephone calls and/or clinic visits every 3 months until death, withdrawal of consent, the 
patient is lost to follow-up, or study termination by the Sponsor, whichever occurs first.
e Informed consent must be documented before and study-specific screening procedure is performed and may be obtained up to 28 days before 
initiation of study treatment.
f
Includes respiratory rate, heart rate, temperature, and systolic and diastolic blood pressure while the patient is in a seated position.  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.


Appendix 1 Schedule of Activities (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
159/Protocol BO39813, Version 7
g For patients receiving atezolizumab, either with the triplet regimen (Arm C) or in those patients in which atezolizumab is added on cobimetinib 
monotherapy upon PD (Arm A), vital signs will be collected at screening and thereafter as follows during each atezolizumab administration.  
For the first infusion (Cycle 1), vital signs will be measured and recorded within 60 minutes prior to the infusion, every 15 (5) minutes during
the infusion, and 30 (10) minutes after the infusion.  For subsequent cycles, vital signs will be measured and recorded within 60 minutes 
prior to the infusion, every 15 (5) minutes during the infusion, and 30 (10) minutes after the infusion.
h A complete physical examination should be performed at screening and should include an evaluation of the head, eyes, ears, nose, throat, 
neck, and lymph node regions, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 
neurological systems.  Any abnormality identified at baseline should be recorded on the General Medical History and Baseline Conditions 
eCRF.  At subsequent visits (or as clinically indicated), limited, symptom-directed physical examinations should be performed.  Changes from 
baseline abnormalities should be recorded in patient notes.  New or worsened clinically significant abnormalities should be recorded as 
adverse events on the Adverse Event eCRF. 
i
All patients will undergo evaluation of left ventricular dysfunction, either by ECHO or MUGA screening.  Evaluation of LVEF by ECHO or 
MUGA scan (using the same method for each patient) must be performed at the following time points: 

Day 1 of Cycle 2 (1 week)

After Day 1 of Cycle 2, every three treatment cycles (Day 1 of Cycles 5, 8, 11, etc.) 2 weeks until treatment discontinuation.

Evaluation of LVEF does not need to be performed at the treatment discontinuation visit if an evaluation has been performed within the last 
12 weeks and there are no clinically significant findings and/or changes from baseline.
j
Assessments performed at screening, Day 1 of each treatment cycle (SPEP and UPEP), to confirm sCR or CR (SIFE and UIFE), and at 
treatment discontinuation. SIFE and UIFE to be performed only if electrophoresis shows no measurable protein.
k sFLCs performed at screening, Day 1 of each treatment cycle, and treatment discontinuation; also when sCR or CR is suspected or 
maintained.
l
If clinically indicated at screening by radiologic imaging (CT scan or MRI) and thereafter every 12 weeks.
m Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, and other cells).
n Chemistry panel (serum or plasma) includes sodium, potassium, magnesium, chloride, bicarbonate (or total CO2), glucose, BUN or urea, 
creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, AST, LDH, CPK, lipase, and amylase.  Serum chemistry 
includes serum cholesterol and triglycerides at baseline. On Cycle 1 Day 1, the chemistry panel should be repeated at 46 hours after the first 
treatment with venetoclax. 
o If a patient has a negative HBsAg test result and a positive total HBcAb test result at screening, an HBV DNA test must be performed to rule 
out active HBV infection based on HBV viral load per local guidelines.  If a patient has a positive HCV antibody test result at screening, an 
HCV RNA test should be performed to rule out active HCV infection prior to initiation of study treatment.  For patients with unknown HIV 
status, HIV testing must be performed at screening if not in contradiction with local regulations.


Appendix 1 Schedule of Activities (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
160/Protocol BO39813, Version 7
p Thyroid function testing (TSH, free T3, or total T3 where T3 is not performed, free T4) collected on Day 1 of Cycle 1, and Day 1 of every fourth 
cycle thereafter.
q Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, bacteria).
r
All women of childbearing potential will have a serum pregnancy test performed at screening (within 7 days prior to initiation of study drug), 
and then monthly and as clinically indicated.  After study treatment discontinuation, a monthly pregnancy test should be performed (in women 
of childbearing potential) for at least 3 months after the last dose of cobimetinib, 1 month after the last dose of venetoclax, and 5 months after 
the last dose of atezolizumab.
s Ophthalmic examination includes visual acuity testing, intraocular pressure measurements by tonometry, slitlamp ophthalmoscopy, indirect 
ophthalmoscopy, and optical coherence tomography (spectral- or time-domain).
All patients must undergo ophthalmic examination at screening and at the following timepoints:

Day 1 of Cycle 2 (1 week)

Day 1 of Cycles 5, 8, and 11 (every three treatment cycles; 2 weeks)

Day 1 of Cycles 15, 19, and 23 (every four treatment cycles; 2 weeks)

On Day 1 of Cycles 29, 35, 41, 47, etc. (every six treatment cycles; 2 weeks)

Treatment discontinuation visit
t
Atezolizumab IV will be administered at a fixed dose of 840 mg IV on Days 1 and Day 15 (3 days) in of each 28-day cycle (note:  Cycle 1 of 
the safety run-in phase does not include the 3-day window).
u After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 90 days after the last dose of study drug.  
After the end of the adverse event reporting period if the investigator becomes aware of a serious adverse event that is believed to be related 
to prior study drug treatment, the event should be reported through use of the Adverse Event eCRF.  The investigator should follow each 
adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related to study 
drug or trial-related procedures until a final outcoe can be reported.
v Biomarker bone marrow biopsy to be collected at screening (mandatory) and Day 1 of Cycle 4 (optional).
w Bone marrow aspirate to be collected at screening, on Day 15 of Cycle 2, Day 1 of Cycle 4, and at CR, CR 3 months, and CR 6 months.
x Whole blood to be collected on Days 1 and 15 of Cycle 1, Days 1 and 15 of Cycle 2, Day 1 of Cycle 4, Day 1 of Cycle 7, at treatment 
discontinuation, and at CR, CR 3 months, and CR 6 months.
y Serum sample to be collected on Day 1 of Cycle 1, Day 1 of Cycle 2, Day 1 of Cycle 4, Day 1 of Cycle 7, at treatment discontinuation, and at 
CR, CR 3 months, and CR 6 months (SIFE interference assay for atezolizumab).


Appendix 1 Schedule of Activities (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
161/Protocol BO39813, Version 7
z Plasma sample to be collected on Days 1 and 15 of Cycle 1, Days 1 and 15 of Cycle 2, Day 1 of Cycle 4, Day 1 of Cycle 7, at treatment 
discontinuation, and at CR, CR3 months, and CR6 months.


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
162/Protocol BO39813, Version 7
Appendix 2
Schedule of Pharmacokinetic and Immunogenicity Samples
ARM A (COBIMETINIB) 
Study Visit
Timepoint
Sample Type
Cycle 1 Day 1
24 hour post-dose
Cobimetinib PK (plasma)
Cycle 1 Day 15
Pre-dose (within 1 hour prior to dose)
Cobimetinib PK (plasma)
24 hour post-dose
Cobimetinib PK (plasma)
PKpharmacokinetic.
Note:  Except for Day 1 of Cycle 1, all other study visits and assessments during the treatment 
period should be performed within 3 days of the scheduled date.  Study assessments may be 
delayed or moved ahead of the window to accommodate holidays, vacations, and unforeseen 
delays.  Ensure dose times are accurately recorded on PK sampling day and the day prior to 
PK sampling.  Ensure all sampling times are accurately recorded.
ARM B (COBIMETINIBVENETOCLAX) 
Study Visit
Timepoint
Sample Type
Cycle 1 Day 1
24 hour postdose
Cobimetinib PK (plasma)
6 hour postdose (20 min)
Venetoclax PK (plasma)
Cycle 1 Day 15
Predose (within 1 hour prior to dose)
Venetoclax PK (plasma)
Cobimetinib PK (plasma)
2 hour postdose
Venetoclax PK (plasma)
Cobimetinib PK (plasma)
4 hour postdose
Venetoclax PK (plasma)
Cobimetinib PK (plasma)
6 hour postdose (20 min)
Venetoclax PK (plasma)
Cobimetinib PK (plasma)
8 hour postdose (1 hr/20 min), 
if patient is in the clinic
Venetoclax PK (plasma)
Cycle 2 Day 1
Predose (within 1 hour prior to dose)
Venetoclax PK (plasma)
Cycle 3 Day 1
Predose (within 1 hour prior to dose)
Venetoclax PK (plasma)
PKpharmacokinetic.
Note:  Except for Day 1 of Cycle 1, all other study visits and assessments during the treatment 
period should be performed within 3 days of the scheduled date.  Study assessments may be 
delayed or moved ahead of the window to accommodate holidays, vacations, and unforeseen 
delays.  Ensure dose times are accurately recorded on PK sampling day and the day prior to PK 
sampling.  Ensure all sampling times are accurately recorded.


Appendix 2
Schedule of Pharmacokinetic and Immunogenicity
Samples (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
163/Protocol BO39813, Version 7
ARM C (COBIMETINIBVENETOCLAXATEZOLIZUMAB) 
Study Visit
Timepoint
Sample Type
Cycle 1 Day 1
Prior to the first infusion
Atezolizumab PK and ADA 
(serum)
30 (10) minutes following the end of 
atezolizumab infusion
Atezolizumab PK (serum)
24 hour post-cobimetinib dose
Cobimetinib PK (plasma)
6 hour postdose (20 min)
Venetoclax PK (plasma)
Cycle 1 Day 15
Pre-dose (within 1 hour prior to dose)
Venetoclax PK (plasma)
Cobimetinib PK (plasma)
2 hour post-cobimetinib dose
Venetoclax PK (plasma)
Cobimetinib PK (plasma)
4 hour post-cobimetinib dose
Venetoclax PK (plasma)
Cobimetinib PK (plasma)
6 hour postdose (20 min)
Venetoclax PK (plasma)
Cobimetinib PK (plasma)
8 hour postdose (1 hr/+20 min), 
if patient is in the clinic
Venetoclax PK (plasma)
Cycle 2 Day 1
Prior to the first infusion
Atezolizumab PK and ADA 
(serum)
Pre-dose (within 1 hour prior to dose)
Venetoclax PK (plasma)
Cycle 3 Day 1
Prior to the first infusion
Atezolizumab PK and ADA 
(serum)
Pre-dose (within 1 hour prior to dose)
Venetoclax PK (plasma)
Treatment 
discontinuation 
visit a
At visit
Atezolizumab PK and ADA 
(serum)
ADAanti-drug antibody; PKpharmacokinetic.
Note:  Except for Day 1 of Cycle 1, all other study visits and assessments during the treatment 
period should be performed within 3 days of the scheduled date.  Study assessments may be 
delayed or moved ahead of the window to accommodate holidays, vacations, and unforeseen 
delays.  Ensure dose times are accurately recorded on PK sampling day and the day prior to PK 
sampling.  Ensure all sampling times are accurately recorded.
a Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit 
30 (7) days after the last dose of study drug.  The visit at which response assessment shows 
progressive disease may be used as the treatment discontinuation visit.


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
164/Protocol BO39813, Version 7
Appendix 3
Guidelines for the Determination of Prior Lines of Therapy
LINE OF THERAPY
A line of therapy is defined as 1 complete cycle of a single agent, combination regimen 
of several drugs, or a planned sequential therapy of various drugs (e.g., induction 
therapy followed by autologous stem cell transplantation is considered 1 line of therapy).
NEW LINE OF THERAPY
A treatment is considered a new line of therapy if any one of the following three 
conditions is met:
Definition of a New Line of Therapy
Comments
Discontinuation of one treatment regimen 
and start of another
A regimen is considered to have been discontinued 
if all drugs in that given regimen have been stopped.
The reasons for discontinuation, addition, 
substitution or SCT do not influence how lines are 
counted.
Unplanned addition or substitution of 1 or 
more drugs in a regimen
Unplanned addition of a new drug or switching to a 
different drug (or combination of drugs) due to any 
reason is considered a new line of therapy.
In patients undergoing 1 SCT, each 
SCT is considered a new line of therapy
Except in the cases of a planned tandem SCT 
performed 6 months from the first SCT, each 
additional SCT is considered a new line of therapy.
SCT stem cell transplant.
INTERRUPTIONS AND DOSE MODIFICATIONS
If a regimen is interrupted or discontinued for any reason and the same drug or 
combination is restarted without any intervening regimen, then it should be counted as a 
single line.
If a regimen is interrupted or discontinued for any reason and then restarted at a later 
timepoint, but one or more other regimens were administered in between, or the regimen 
is modified through the addition of one or more agents, then it should be counted as 
two lines.


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
165/Protocol BO39813, Version 7
Appendix 4
Eastern Cooperative Oncology Group
Performance Status Scale
Grade
Description
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature (e.g., light housework or 
office work)
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair
5
Dead


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
166/Protocol BO39813, Version 7
Appendix 5
International Myeloma Working Group Uniform Response Criteria (2016)
(Adapted from Durie et al. 2015 and Kumar et al. 2016)
COMPLETE RESPONSE AND OTHER RESPONSE CATEGORIES
Response 
Subcategory
Response Criteria
All response categories require two consecutive assessments made any time before starting any new therapy.
sCR
CR as defined below, plus:
Normal FLC ratio and absence of clonal cells in BM by immunohistochemistry (kappa/lamda ratio 4:1 or 1:2 for kappa and 
lambda patients, respectively after counting 100 plasma cells)  a
CR
No evidence of initial monoclonal protein isotype(s) on immunofixation of the serum and urine, b disappearance of any soft tissue 
plasmacytomas, and 5% plasma cells in BM
VGPR
Serum and urine M-protein detectable by immunofixation but not on electrophoresis; or 90% reduction in serum M-protein plus 
urine M-protein level 100 mg/24 hr
PR
50% reduction of serum M-protein and reduction in 24 hr urinary M-protein by 90% or to 200 mg/24 hr.

If the serum and urine M-protein are unmeasurable, a 50% decrease in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria.

If serum and urine M-protein are unmeasurable and serum FLC assay is also unmeasurable, 50% reduction in plasma cells 
is required in place of M-protein, provided baseline BM plasma cell percentage was 30%.

In addition to the above listed criteria, if present at baseline, a 50% reduction in the size (SPD) c of soft tissue plasmacytomas 
is also required.
MR
25% but 49% reductions of serum M protein and reduction in 24-hour urine M-protein by 50%89%

In addition to the above criteria, if present at baseline, 25%49% reduction in the size (SPD) c of soft tissue plasmacytomas is 
also required.
SD
Not meeting criteria for MR, CR, VGPR, PR, or PD


Appendix 5 International Myeloma Working Group Uniform Response Criteria (2016) (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
167/Protocol BO39813, Version 7
DISEASE PROGRESSION AND RELAPSE
Relapse 
Subcategory
Relapse Criteria
PD d, e
Any increase of 25% from lowest response value in any one of the following:

Serum M-protein (absolute increase must be 0.5 g/dL)

Serum M-protein increase 1g/dL, if the lowest M component was ≥ 5g/dL

Urine M-protein (absolute increase must be 200 mg/24 hr)

In patients without measurable serum and urine M-protein levels:  the difference between involved and uninvolved FLC levels 
(absolute increase must be 10 mg/dL)

In patients without measurable serum and urine M-protein levels and without measurable disease by FLC:  BM plasma cell 
percentage irrespective of baseline status (absolute % must be 10%) b

Appearance of new lesion(s), 50% increase from nadir in SPD of 1 lesion, or 50% increase in the longest diameter of a 
previous lesion 1 cm in short axis

50% increase in circulating plasma cells (minimum 200 cells per microliter) if this is the only measure of disease
Clinical 
relapse
Requires one or more of the following:

Direct indications of increasing disease and/or end organ dysfunction (CRAB features) f related to the underlying clonal plasma 
cell proliferative disorder.  It is not used in calculation of time to progression or PFS but is listed here as something that can be 
reported optionally or for use in clinical practice.

Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute progression)

Definite increase in the size of existing plasmacytomas or bone lesions.  A definite increase is defined as a 50% (and 1 cm) 
increase as measured serially by the sum of the products of the cross-diameters of the measurable lesion.

Hypercalcemia 11 mg/dL (2.65 mmol/L)

Decrease in hemoglobin of 2 g/dL (1.25 mmol/L) not related to therapy or other non-myeloma related conditions

Rise in serum creatinine by 2 mg/dL or more (177 µmol/L or more) from the start of therapy and attributable to myeloma

Hyperviscosity related to serum paraprotein


Appendix 5 International Myeloma Working Group Uniform Response Criteria (2016) (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
168/Protocol BO39813, Version 7
Relapse 
Subcategory
Relapse Criteria
Relapse 
from CR (to 
be used 
only if the 
endpoint 
studied is 
PFS) c
Any one or more of the following:

Reappearance of serum or urine M-protein by immunofixation or electrophoresis

Development of 5% plasma cells in the BM

Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion, or hypercalcemia)
BMbone marrow; CRcomplete response; CT computed tomography; FLCfree light chain; M-proteinmonoclonal protein; MRminimal 
response; MRImagnetic resonance imaging; PDprogressive disease; PET positron emission tomography; PFSprogression-free survival; 
PRpartial response; sCR stringent complete response; SDstable disease; SPDsum of the products of diameters; VGPRvery good partial
response.
a Special attention should be given to the emergence of a different M-protein following treatment, especially in the setting of patients having 
achieved a conventional CR, often related to oligoclonal reconstitution of the immune system.  These bands typically disappear over time and in 
some studies have been associated with a better outcome.  Also, appearance of IgGk in patients receiving monoclonal antibodies should be 
differentiated from the therapeutic antibody.
b In some cases it is possible that the original M-protein light-chain isotype is still detected on immunofixation but the accompanying heavy-chain 
component has disappeared; this would not be considered a CR even though the heavy-chain component is not detectable, since it is possible 
that the clone evolved to one that secreted only light chains.  Thus, if a patient has IgA lambda myeloma, then to qualify as CR there should be 
no IgA detectable on serum or urine immunofixation; if free lambda is detected without IgA, then it must be accompanied by a different heavy-
chain isotype (IgG, IgM, etc.).  Modified from Durie et al. 2006.  This requires two consecutive assessments to be carried out at any time before 
the institution of any new therapy (Durie et al. 2015).
c Plasmacytoma measurements should be taken from the CT portion of the PET/CT or MRI scans, or dedicated CT scans where applicable.  For 
patients with only skin involvement, the skin lesions should be measured with a ruler.  Measurement of tumor size will be determined by the SPD.   
d Positive immunofixation alone in a patient previously classified as achieving a CR will not be considered progression. Criteria for relapse from a 
CR should be used only when calculating disease-free survival.
e In the case where a value is felt to be a spurious result per investigator discretion (e.g., a possible laboratory error), that value will not be 
considered when determining the lowest value.
f
CRAB features calcium elevation, renal failure, anemia, lytic bone lesions.  


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
169/Protocol BO39813, Version 7
Appendix 6
Anaphylaxis Precautions
PRECAUTIONS
Equipment needed:

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for subcutaneous, IV, and/or endotracheal use in accordance with 
standard practice

Antihistamines

Corticosteroids

IV infusion solutions, tubing, catheters, 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 medical assistance.
3.
Maintain 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 as required by patient 
status and directed by physician in charge.
6.
Continue to observe the patient and document observations.


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
170/Protocol BO39813, Version 7
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).  Caution should be used when considering 
atezolizumab for patients who have previously experienced a severe or lifethreatening 
skin adverse reaction while receiving another immunostimulatory anti-cancer agent.  
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
Graves 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’s syndrome
Stiff-Person syndrome
Takayasu arteritis
Ulcerative colitis
Vitiligo
Vogt-Koyanagi-Harada 
disease
Wegener granulomatosis


Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
171/Protocol BO39813, Version 7
Appendix 8
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, 
when clinically indicated.
Although most immune-mediated adverse events observed with atezolizumab 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 for a given patient 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. 
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab in this study.
TREATMENT INTERRUPTION
Atezolizumab treatment may be temporarily suspended in patients experiencing 
toxicity considered to be related to study treatment.  If corticosteroids are initiated for 
treatment of the toxicity, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.  If atezolizumab is 
withheld for 12 weeks after event onset, the patient will be discontinued from 
atezolizumab.  However, atezolizumab may be withheld for 12 weeks to allow for 
patients to taper off corticosteroids prior to resuming treatment.  Atezolizumab can be 
resumed after being withheld for 12 weeks if the Medical Monitor agrees that the 
patient is likely to derive clinical benefit.  Atezolizumab treatment may be suspended 
for reasons other than toxicity (e.g., surgical procedures) with Medical Monitor 
approval.  The investigator and the Medical Monitor will determine the acceptable 
length of treatment interruption.


Appendix 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
172/Protocol BO39813, Version 7
MANAGEMENT GUIDELINES
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 also have computed 
tomography (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 Section 5.1.5.13.
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 Section 5.1.5.4.
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.
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Sections 5.1.5.8
and 5.1.5.9.
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 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
173/Protocol BO39813, Version 7
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 1.
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 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency.


Appendix 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
174/Protocol BO39813, Version 7
Table 1 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 10 mg/day oral 
prednisone or equivalent.  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 10 
mg/day oral prednisone or equivalent 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 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
175/Protocol BO39813, Version 7
Table 1
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 12 mg/kg/day IV methylprednisolone 
or equivalent 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 10 mg/day oral 
prednisone or equivalent.  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 10 
mg/day oral prednisone or equivalent 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 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
176/Protocol BO39813, Version 7
Table 1
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 12 mg/kg/day IV methylprednisolone 
or equivalent 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 12 mg/kg/day IV methylprednisolone 
or equivalent 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 10 mg/day oral 
prednisone or equivalent.  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 10 
mg/day oral prednisone or equivalent 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 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
177/Protocol BO39813, Version 7
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Section 5.1.5.7.  Management 
guidelines for ocular events of suspected immune-mediated etiology are provided in 
Table 2.
Table 2
Management Guidelines for Ocular Events of Suspected 
Immune-Mediated Etiology
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 12 mg/kg/day oral prednisone or equivalent.  

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 10 mg/day oral 
prednisone or equivalent.  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 
10 mg/day oral prednisone or equivalent 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 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
178/Protocol BO39813, Version 7
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 3.


Appendix 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
179/Protocol BO39813, Version 7
Table 3
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 12 mg/kg/day IV methylprednisolone or 
equivalent 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 12 mg/kg/day IV methylprednisolone or 
equivalent 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 10 mg/day oral prednisone or equivalent.  
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 10 mg/day oral 
prednisone or equivalent 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.
INFUSION-RELATED REACTIONS AND CYTOKINE RELEASE 
SYNDROME
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 


Appendix 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
180/Protocol BO39813, Version 7
syndrome (CRS) with atezolizumab may receive premedication with antihistamines,
antipyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of 
its potential for causing agranulocytosis.
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity.
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells 
and/or other immune effector cells.  Symptoms can be progressive, always include fever 
at the onset, and may include hypotension, capillary leak (hypoxia), and end-organ 
dysfunction (Lee et al. 2019).  CRS has been well documented with chimeric antigen 
receptor T-cell therapies and bispecific T-cell engager antibody therapies but has also 
been reported with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; 
Adashek and Feldman 2019), including atezolizumab.
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 4.  
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines interleukin (IL)-6, IL-10, IL-2, and IFN-(Merad and Martin 2020).  If a 
patient develops suspected CRS during the study, a differential diagnosis should 
include COVID-19, which should be confirmed or refuted through assessment of 
exposure history, appropriate laboratory testing, and clinical or radiologic evaluations 
per investigator judgment.  If a diagnosis of COVID-19 is confirmed, the disease should 
be managed as per local or institutional guidelines.


Appendix 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
181/Protocol BO39813, Version 7
Table 4
Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome
Event
Management
Grade 1 a
Fever b with or 
without 
constitutional 
symptoms 

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset.

If the infusion is tolerated at the reduced rate for 30 minutes, the infusion 
rate may be increased to the original rate.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment, c including maintenance of IV fluids 
for hydration.

In case of rapid decline or prolonged CRS (2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2.

For subsequent infusions, consider administration of oral premedication 
with antihistamines, anti-pyretics, and/or analgesics, and monitor 
closely for IRRs and/or CRS.
Grade 2 a
Fever b with 
hypotension 
not requiring 
vasopressors
and/or
Hypoxia 
requiring low-
flow oxygen d
by nasal 
cannula or 
blow-by

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus as needed.

Monitor cardiopulmonary and other organ function closely (in the ICU, 
if appropriate).  Administer IV fluids as clinically indicated, and 
manage constitutional symptoms and organ toxicities as per 
institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy.

Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that 
is, hospitalize patient (monitoring in the ICU is recommended), 
permanently discontinue atezolizumab, and contact Medical Monitor. e

If symptoms resolve to Grade 1 or better for 3 consecutive days, the next 
dose of atezolizumab may be administered.  For subsequent infusions, 
consider administration of oral premedication with antihistamines, 
anti-pyretics, and/or analgesics and monitor closely for IRRs and/or CRS.

If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact Medical Monitor.


Appendix 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
182/Protocol BO39813, Version 7
Event
Management
Grade 3 a
Fever b with 
hypotension 
requiring a 
vasopressor 
(with or 
without 
vasopressin)
and/or
Hypoxia 
requiring 
high-flow 
oxygen d by 
nasal cannula, 
face mask, 
non-rebreather 
mask, or 
Venturi mask

Permanently discontinue atezolizumab and contact Medical Monitor. e

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus and vasopressor as needed.

Monitor cardiopulmonary and other organ function closely; monitoring 
in the ICU is recommended.  Administer IV fluids as clinically indicated, 
and manage constitutional symptoms and organ toxicities as per 
institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy.

Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients 
who are refractory to anti-cytokine therapy, experimental treatments 
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor.
Grade 4 a
Fever b with 
hypotension 
requiring 
multiple 
vasopressors 
(excluding 
vasopressin)
and/or
Hypoxia 
requiring 
oxygen by 
positive 
pressure (e.g., 
CPAP, 
BiPAP, 
intubation 
and 
mechanical 
ventilation)

Permanently discontinue atezolizumab and contact Medical Monitor. e

Administer symptomatic treatment. c

Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed.  Monitor other 
organ function closely.  Manage constitutional symptoms and organ 
toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy.  For patients who are refractory to 
anti-cytokine therapy, experimental treatments f may be considered at the 
discretion of the investigator and in consultation with the Medical 
Monitor.

Hospitalize patient until complete resolution of symptoms.


Appendix 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
183/Protocol BO39813, Version 7
Event
Management
ASTCT American Society for Transplantation and Cellular Therapy; BiPAP bi-level 
positive airway pressure; CAR chimeric antigen receptor; CPAP continuous positive 
airway pressure; CRS cytokine-release syndrome; CTCAE Common Terminology Criteria 
for Adverse Events; eCRF electronic Case Report Form; HLH hemophagocytic 
lymphohistiocytosis; ICU intensive care unit; IRR infusion-related reaction; 
MAS macrophage activation syndrome; NCCN National Cancer Comprehensive Network; 
NCI National Cancer Institute.
a Grading system for these management guidelines is based on ASTCT consensus grading 
for CRS.  NCI CTCAE v4.0 should be used when reporting severity of IRRs, CRS, or organ 
toxicities associated with CRS on the Adverse Event eCRF.  Organ toxicities associated 
with CRS should not influence overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is 
no longer required when subsequently determining event severity (grade).  In this case, the 
grade is driven by the presence of hypotension and/or hypoxia.
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as oxygen 
delivered at 6 L/min.
e 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.  For subsequent infusions, administer oral premedication with 
antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs and/or 
CRS.  Premedication with corticosteroids and extending the infusion time may also be 
considered after consulting the Medical Monitor and considering the benefitrisk ratio.
f
Refer to Riegler et al. (2019).


Appendix 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
184/Protocol BO39813, Version 7
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 work-up 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 5.
Table 5
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 10 mg/day oral prednisone or equivalent.
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 12 mg/kg/day 
oral prednisone or equivalent.

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; ULNupper limit of normal.
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 10 mg/day oral prednisone or 
equivalent.  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 10 mg/day 
oral prednisone or equivalent 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 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
185/Protocol BO39813, Version 7
Table 5
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 12 mg/kg/day IV methylprednisolone 
or equivalent 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 12 mg/kg/day IV methylprednisolone 
or equivalent 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 10 mg/day oral prednisone or 
equivalent.  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 10 mg/day 
oral prednisone or equivalent 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. 
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash were mild in severity and self-limiting, with or without pruritus.  
Although uncommon, cases of severe cutaneous adverse reactions such as 
StevensJohnson syndrome and toxic epidermal necrolysis have been reported with 


Appendix 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
186/Protocol BO39813, Version 7
atezolizumab.  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 Section 5.1.5.5.
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 work-up is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 6.
Table 6
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 12 mg/kg/day oral or IV prednisone or 
equivalent.
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 10 mg/day oral prednisone 
or equivalent.  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 10 mg/day 
oral prednisone or equivalent 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 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
187/Protocol BO39813, Version 7
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 7.
Table 7
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 12 mg/kg/day IV methylprednisolone or 
equivalent 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 
etiologies (including prerenal and postrenal causes, and concomitant medications such 
as non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if 


Appendix 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
188/Protocol BO39813, Version 7
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 8.
Table 8
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 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
189/Protocol BO39813, Version 7
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 9.
Table 9
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 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
190/Protocol BO39813, Version 7
Table 9
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 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
191/Protocol BO39813, Version 7
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), which are considered to be potential risks for atezolizumab.  
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.  
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)


Appendix 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
192/Protocol BO39813, Version 7
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 10.
Table 10 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, an immunosuppressive 
agent, and/or anti-cytokine therapy.

If event does not respond to treatment within 24 hours, contact 
Medical Monitor and initiate treatment as appropriate according 
to published guidelines (La Rosée 2015; Schram and Berliner 
2015; La Rosée et al. 2019).

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
HLHhemophagocytic lymphohistiocytosis; MASmacrophage activation syndrome.
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Appendix 8 Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib, Venetoclax, and Atezolizumab—F. Hoffmann-La Roche Ltd
193/Protocol BO39813, Version 7
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