Clinical trial NCT03264066
Conditions: Solid Tumors
Sponsor: Hoffmann-La Roche
Start date: 2017-11-23; Completion date: 2020-06-25
Enrollment: 87 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study to evaluate the efficacy, safety, and pharmacokinetics of cobimetinib plus atezolizumab in participants with advanced solid tumors including the following cohorts: squamous cell carcinoma of the head and neck (SCCHN), urothelial carcinoma (UC), and renal cell carcinoma (RCC).

Detailed description:

Arms: arm 1: In participants with recurrent or advanced / metastatic SSCHN who are anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. arm 2: In participants with advanced / metastatic UC who are anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. arm 3: In participants with metastatic RCC who are anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib will be administered at the approved dose and schedule of 60 milligrams (mg) once daily (QD) for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. arm 4: In participants with SCCHN whose disease has progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. arm 5: In participants with UC whose disease has progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. arm 6: In participants with RCC whose disease has progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. arm 7: In participants with solid non-melanoma, non- hematologic tumors who previously developed primary or secondary resistance to an anti-PD-1 or anti-PD-L1 agent, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle. The first dose of atezolizumab of 840 mg by IV infusions on Day 15 of Cycle 1. Thereafter, they will receive atezolizumab 840 mg IV infusion Q2W on Days 1 and 15 of Cycle 2 and all subsequent cycles.
Interventions: intervention 1: Cobimetinib intervention 2: Atezolizumab intervention 3: Atezolizumab Cohort 7
Intervention descriptions: intervention 1: Participants will receive cobimetinib 60 mg (3 tablets of 20 mg each) orally once a day on Days 1-21 of each 28-day cycle. intervention 2: Atezolizumab will be given at a fixed dose of 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. intervention 3: Only for participants in cohort 7, the first dose of atezolizumab of 840 mg will be given by IV infusion on Day 15 of Cycle 1; thereafter, they will receive atezolizumab 840 mg IV infusion Q2W on Days 1 and 15 of Cycle 2 and all subsequent cycles.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: A Phase II, Open-Label, Multicenter, Multi-Cohort Study to Investigate 
the Efficacy and Safety of Cobimetinib Plus Atezolizumab in Patients 
With Solid Tumors 
NCT Number: NCT03264066 
Document Date: Protocol Version 4: 18-September-2018 
 
 


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 and Atezolizumab—F. Hoffmann-La Roche Ltd
Protocol WO39760, Version 4
PROTOCOL
TITLE:
A PHASE II, OPEN-LABEL, MULTICENTER, 
MULTI-COHORT STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF COBIMETINIB 
PLUS ATEZOLIZUMAB IN PATIENTS WITH
SOLID TUMORS
PROTOCOL NUMBER:
WO39760
VERSION NUMBER:
4
EUDRACT NUMBER:
2017-000794-37
IND NUMBER:
118,753
TEST PRODUCTS:
Cobimetinib (RO5514041),
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  23 February 2017
DATES AMENDED:
Version 2:  20 October 2017
Version 3:  29 March 2018
Version 4:  See electronic date stamp below.
 
18-Sep-2018 22:13:13
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
2/Protocol WO39760, Version 4
PROTOCOL AMENDMENT, VERSION 4:
RATIONALE
Protocol WO39760 is being amended to update the lists of risks for atezolizumab and 
guidelines for managing patients who experience atezolizumab-associated adverse 
events to include nephritis (Section 5.1.2 and Appendix 8).
The following additional changes have been made:

Text has been added to clarify that histologic samples are required for patients with 
squamous cell carcinoma of the head and neck (SCCHN) and renal cell carcinoma 
(RCC), and either cytological or histologic samples are acceptable for patients with 
urothelial carcinoma (UC) (Sections 3.1.1.3.1 and 4.1.1.2).

The inclusion criterion for serum creatinine have been modified to allow patients 
with serum creatinine 1.5ULN or creatinine clearance 50 mL/min by 
Cockcroft-Gault equation or 24-hour urine collection (Section 4.1.1.1).

The coagulation test inclusion criterion has been amended to provide criteria for 
patients receiving therapeutic anticoagulation and those not receiving therapeutic 
anticoagulation (Section 4.1.1.1).

The inclusion criterion that addresses female contraception has been modified to 
specify when women must refrain from donating eggs (Section 4.1.1.2).

Added language to clarify use of samples after withdrawal of patient consent 
(Section 4.5.6.3).

Cobimetinib dose modification has been amended to allow for dose re-escalations 
on a case-by-case basis after discussion with the Medical Monitor or 
 designee 
(Table 4 in Section 5.1.3).  

The Medical Monitor has changed (Section 5.4.1).

Language has been updated to indicate that therapeutic or elective abortions are 
not considered adverse events unless performed because of an underlying maternal 
or embryofetal toxicity.  In such cases, the underlying toxicity should be reported as 
a serious adverse event.  Language has also been added to clarify that all abortions 
are to be reported on the paper Clinical Trial Pregnancy Reporting Form (Section 
5.4.3.3).

Language has been added for consistency with Roche's current data retention 
policy and to accommodate more stringent local requirements (if applicable)
(Section 7.5).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10
PROTOCOL SYNOPSIS .................................................................................... 11
1.
BACKGROUND ........................................................................................... 24
1.1
Background on Solid Tumor Cohorts..................................... 24
1.1.1
Background on Squamous Cell Carcinoma of the 
Head and Neck...................................................................... 24
1.1.2
Background on Urothelial Carcinoma .................................... 25
1.1.3
Background on Renal Cell Carcinoma................................... 26
1.2
Background on Cobimetinib and Atezolizumab ..................... 28
1.2.1
The PD-L1 Pathway .............................................................. 28
1.2.2
The MAPK Signaling Pathway and Regulation of 
the Immune Tumor Microenvironment................................... 28
1.2.3
Background on Cobimetinib Monotherapy............................. 29
1.2.4
Background on Atezolizumab Monotherapy .......................... 29
1.2.5
Combined Inhibition of PD-L1 and MAPK 
Signaling Pathways as Potential Anti-Cancer 
Therapy ................................................................................. 30
1.2.5.1
Rationale for Combining Cobimetinib and 
Atezolizumab for Solid Tumors after Progression 
on AntiPD-1/PD-L1 Therapy................................................ 31
1.2.6
Clinical Data:  Cobimetinib in Combination with 
Atezolizumab......................................................................... 31
1.2.6.1
Phase Ib Study of Cobimetinib and Atezolizumab:  
Study GP28363 ..................................................................... 31
1.2.6.2
Preliminary Results of Study GP28363.................................. 32
34
2.
OBJECTIVES AND ENDPOINTS ................................................................ 34
3.
STUDY DESIGN.......................................................................................... 37
3.1
Description of the Study......................................................... 37
3.1.1
Overview of Study Design ..................................................... 37
3.1.1.1
Cobimetinib and Atezolizumab Treatment 
Schedule................................................................................ 40
3.1.1.2
Tumor Assessments.............................................................. 41


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3.1.1.3
Tumor Biopsies...................................................................... 41
3.1.2
Safety Data Review ............................................................... 43
3.2
End of Study and Length of Study......................................... 43
3.3
Rationale for Study................................................................ 43
3.3.1
Rationale for Study Design.................................................... 43
3.3.2
Rationale for Cobimetinib and Atezolizumab 
Dose and Schedule ............................................................... 43
3.3.2.1
Rationale for the Biopsy Cohort (Cohort 7)............................ 44
3.3.3
Rationale for Patient Population ............................................ 44
3.3.3.1
Rationale for SCCHN............................................................. 44
3.3.3.2
Rationale for Urothelial Carcinoma........................................ 45
3.3.3.3
Rationale for RCC ................................................................. 45
3.3.4
Rationale for Allowing Patients to Continue 
Treatment until Loss of Clinical Benefit.................................. 45
3.3.5
Rationale for the Use of Immune-Modified 
RECIST ................................................................................. 46
3.3.6
Rationale for Pharmacokinetic Sample Collection 
Schedule................................................................................ 46
46
4.
MATERIALS AND METHODS ..................................................................... 47
4.1
Patients.................................................................................. 47
4.1.1
Inclusion Criteria.................................................................... 47
4.1.1.1
General Inclusion Criteria ...................................................... 47
4.1.1.2
Cancer-Related Inclusion Criteria.......................................... 48
4.1.2
Exclusion Criteria................................................................... 49
4.1.2.1
General Exclusion Criteria..................................................... 49
4.1.2.2
Exclusion Criteria based on Organ Function or 
Medical History...................................................................... 51
4.1.2.3
Autoimmune Conditions and Immunomodulatory 
Drugs..................................................................................... 51
4.1.2.4
Exclusions Related to Other Medical Conditions 
or Medications ....................................................................... 52
4.1.3
Cohort-Specific Inclusion and Exclusion Criteria ................... 53
4.1.3.1
SCCHN Cohorts .................................................................... 53
4.1.3.2
UC Cohorts............................................................................ 53


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4.1.3.3
RCC Cohorts ......................................................................... 55
4.1.3.4
Biopsy Cohort 7..................................................................... 56
4.2
Method of Treatment Assignment and Blinding..................... 56
4.3
Study Treatment.................................................................... 56
4.3.1
Formulation, Packaging, and Handling.................................. 57
4.3.1.1
Cobimetinib............................................................................ 57
4.3.1.2
Atezolizumab......................................................................... 57
4.3.2
Dosage, Administration, and Compliance.............................. 57
4.3.2.1
Cobimetinib............................................................................ 57
4.3.2.2
Atezolizumab......................................................................... 57
4.3.3
Investigational Medicinal Product Accountability ................... 59
4.3.4
Post-Trial Access to Cobimetinib and 
Atezolizumab......................................................................... 59
4.4
Concomitant Therapy ............................................................ 60
4.4.1
Permitted Therapy................................................................. 60
4.4.2
Cautionary and Prohibited Therapy....................................... 61
4.4.2.1
Corticosteroids and Tumor Necrosis 
FactorAlpha Inhibitors.......................................................... 61
4.4.2.2
Medications Given with Precaution due to Effects 
Related to Cytochrome P450 Enzymes................................. 62
4.4.2.3
Prohibited Therapy ................................................................ 62
4.4.2.4
Prohibited Food and Herbal Supplements............................. 63
4.5
Study Assessments ............................................................... 63
4.5.1
Informed Consent Forms and Screening Log........................ 63
4.5.2
Medical History and Demographic Data ................................ 63
4.5.3
Physical Examinations........................................................... 64
4.5.4
Vital Signs.............................................................................. 64
4.5.5
Tumor and Response Evaluations......................................... 64
4.5.6
Laboratory, Biomarker, and Other Biologic 
Samples................................................................................. 65
4.5.6.1
Screening (Local Laboratory) ................................................ 65
4.5.6.2
Treatment (Local Laboratory) ................................................ 65
4.5.6.3
Central Laboratory Assessments........................................... 66


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4.5.7
Samples for Optional Whole Genome 
Sequencing............................................................................ 67
4.5.8
Left Ventricular Ejection Fraction........................................... 68
4.5.9
Ophthalmologic Examinations ............................................... 69
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 70
4.6.1
Study Treatment Discontinuation........................................... 70
4.6.2
Patient Discontinuation from Study........................................ 70
4.6.3
Study Discontinuation............................................................ 71
4.6.4
Site Discontinuation............................................................... 71
5.
ASSESSMENT OF SAFETY........................................................................ 71
5.1
Safety Plan ............................................................................ 72
5.1.1
Risks Associated with Cobimetinib........................................ 72
5.1.1.1
Important Identified Risks Associated with 
Cobimetinib............................................................................ 72
5.1.1.2
Potential Risks Associated with Cobimetinib ......................... 74
5.1.1.3
Other Risks with Cobimetinib................................................. 75
5.1.2
Risks Associated with Atezolizumab ..................................... 76
5.1.3
Management of Patients Who Experience 
Specific Adverse Events........................................................ 77
5.1.3.1
Cobimetinib Dose Modifications ............................................ 77
5.1.3.2
Atezolizumab Dose Modifications.......................................... 77
5.1.3.3
Treatment Interruption ........................................................... 77
5.1.3.4
Guidelines for Management of Patients Who 
Experience Adverse Events................................................... 77
5.2
Safety Parameters and Definitions ........................................ 91
5.2.1
Adverse Events ..................................................................... 92
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 92
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 93
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 94
5.3.1
Adverse Event Reporting Period ........................................... 94
5.3.2
Eliciting Adverse Event Information....................................... 95


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5.3.3
Assessment of Severity of Adverse Events ........................... 95
5.3.4
Assessment of Causality of Adverse Events ......................... 95
5.3.5
Procedures for Recording Adverse Events............................ 96
5.3.5.1
Infusion-Related Reactions.................................................... 96
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 96
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 97
5.3.5.4
Persistent or Recurrent Adverse Events................................ 97
5.3.5.5
Abnormal Laboratory Values ................................................. 97
5.3.5.6
Abnormal Vital Sign Values ................................................... 98
5.3.5.7
Abnormal Liver Function Tests.............................................. 99
5.3.5.8
Deaths ................................................................................... 99
5.3.5.9
Preexisting Medical Conditions............................................ 100
5.3.5.10
Lack of Efficacy or Worsening of Cancer............................. 100
5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 100
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 101
5.4.1
Emergency Medical Contacts.............................................. 101
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 102
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 102
5.4.2.2
Events That Occur after Study Drug Initiation...................... 102
5.4.3
Reporting Requirements for Pregnancies............................ 102
5.4.3.1
Pregnancies in Female Patients.......................................... 102
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 103
5.4.3.3
Abortions ............................................................................. 103
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 104
5.4.4
Reporting Requirements for Cases of Overdose, 
Medication Error, Drug Abuse, or Drug Misuse ................... 104
5.5
Follow-Up of Patients after Adverse Events ........................ 106
5.5.1
Investigator Follow-Up......................................................... 106
5.5.2
Sponsor Follow-Up .............................................................. 106
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 106


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5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 107
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN...................... 107
6.1
Determination of Sample Size ............................................. 107
6.2
Summaries of Conduct of Study.......................................... 109
6.3
Summaries of Demographic and Baseline 
Characteristics..................................................................... 110
6.4
Efficacy Analyses ................................................................ 110
6.4.1
Primary Efficacy Endpoint.................................................... 110
6.4.2
Secondary Efficacy Endpoints............................................. 110
6.4.3
Exploratory Efficacy Endpoints............................................ 110
6.5
Safety Analyses................................................................... 111
6.6
Pharmacokinetic Analyses................................................... 111
6.7
Immunogenicity Analyses.................................................... 111
6.8
Biomarker Analyses............................................................. 112
7.
DATA COLLECTION AND MANAGEMENT .............................................. 112
7.1
Data Quality Assurance....................................................... 112
7.2
Electronic Case Report Forms............................................. 113
7.3
Source Data Documentation................................................ 113
7.4
Use of Computerized Systems ............................................ 113
7.5
Retention of Records........................................................... 114
8.
ETHICAL CONSIDERATIONS................................................................... 114
8.1
Compliance with Laws and Regulations .............................. 114
8.2
Informed Consent................................................................ 114
8.3
Institutional Review Board or Ethics Committee.................. 115
8.4
Confidentiality...................................................................... 116
8.5
Financial Disclosure ............................................................ 116
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 117
9.1
Study Documentation .......................................................... 117
9.2
Protocol Deviations.............................................................. 117
9.3
Site Inspections ................................................................... 117


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9.4
Administrative Structure....................................................... 117
9.5
Publication of Data and Protection of 
Trade Secrets...................................................................... 118
9.6
Protocol Amendments ......................................................... 118
10.
REFERENCES ........................................................................................ 120
LIST OF TABLES
33
Table 2
Objectives and Corresponding Endpoints................................... 35
Table 3
Administration of First and Subsequent Atezolizumab 
Infusions...................................................................................... 58
Table 4
Recommended Cobimetinib Dose Modifications......................... 77
Table 5
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab).......... 78
Table 6
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 95
109
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 39
Figure 2
Study Dosing Schema:  Cohorts 16.......................................... 39
Figure 3 
Study Dosing Schema:  Biopsy Cohort 7 .................................... 40
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................. 126
Appendix 2
Schedule of Pharmacokinetic and Immunogenicity Samples..... 131
Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 132
Appendix 4
Immune-Modified Response Evaluation Criteria in Solid 
Tumors (Immune-Modified RECIST)......................................... 142
Appendix 5
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 152
Appendix 6
Preexisting Autoimmune Diseases and Immune Deficiencies ... 153
Appendix 7
Anaphylaxis Precautions............................................................ 154
Appendix 8
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 155


Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
10/Protocol WO39760, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE II, OPEN-LABEL, MULTICENTER, 
MULTI-COHORT STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF COBIMETINIB PLUS 
ATEZOLIZUMAB IN PATIENTS WITH SOLID 
TUMORS
PROTOCOL NUMBER:
WO39760
VERSION NUMBER:
4
EUDRACT NUMBER:
2017-000794-37
IND NUMBER:
118,753
TEST PRODUCTS:
Cobimetinib (RO5514041), 
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 return the signed original of this form to the Sponsor or its designee.  Please retain a 
copy for your study files.








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14/Protocol WO39760, Version 4
Number of Patients
Approximately 20 patients are planned to be enrolled in Cohorts 1–6 with possible expansion up 
to approximately 40 patients in each cohort. Approximately 12 patients are planned to be 
enrolled in Cohort 7 (biopsy cohort). Therefore, up to approximately 250 patients in total are 
planned to be enrolled in this study. 
Target Population
Inclusion Criteria
Patients must meet the following general criteria for study entry:

Signed Informed Consent Form

Age 18 years

Ability to comply with the study protocol, in the investigator's judgment

Eastern Cooperative Oncology group performance status of 0 to 1

Life expectancy 3 months, as determined by the investigator

Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 14 days prior to initiation of study treatment:
ANC 1.5 109/L without granulocyte colony-stimulating factor support 
Lymphocyte count 0.5 109/L
Platelet count 100 109/L without transfusion 
Hemoglobin 90 g/L
–
Patients may be transfused to meet this criterion.
AST and ALT 2.5 upper limit of normal (ULN), with the following exceptions:
–
Patients with documented liver metastases:  AST and ALT 5 ULN
Serum bilirubin 1.5 ULN with the following exception:
–
Patients with known Gilbert disease:  serum bilirubin level 3 ULN
Serum creatinine 1.5 ULN or creatinine clearance 50 mL/min by Cockcroft-Gault 
equation or 24-hour urine collection
Serum albumin 2.5 g/dL
For patients not receiving therapeutic anticoagulation:  INR or aPTT 1.5 ULN
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen and 
INR 3.5
Cancer-Related Inclusion Criteria 
Patients must meet the following cancer-related criteria for study entry:

Patients must have measurable disease by CT or MRI scan per Response Evaluation 
Criteria in Solid Tumors (RECIST v1.1).

Availability to provide a representative tumor specimen biopsy:
Baseline tumor tissue samples will be collected from all patients, preferably by means 
of a biopsy performed at study entry. For patients with SCCHN or RCC, histologic 
samples are required.  For patients with UC, cytological or histologic samples are 
acceptable.  Archival tumor tissue may be submitted after Medical Monitor approval 
has been obtained.
A formalin-fixed, paraffin-embedded tumor specimen in a paraffin block (preferred) or 
at least 15 slides (20 preferred) containing unstained, freshly cut, serial sections is 
recommended to be submitted along with an associated pathology report prior to study 
enrollment.  If a limited number of slides are available, the patient may still be eligible 
for the study, after discussion with and approval by the Medical Monitor.  

Evidence of tumor progression on or after the last treatment regimen received and within 
6 months prior to study enrollment


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
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a non-hormonal contraceptive method with a failure rate of 
1% per year during the treatment period and for at least 5 months after the last dose of 
atezolizumab and within 3 months after the last dose of cobimetinib.  Women must refrain 
from donating eggs during this same period.
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).
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, and copper intrauterine devices.
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.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, 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 barrier method of contraception during the treatment period 
and for at least 3 months after the last dose of cobimetinib.  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.
Cohort-Specific Inclusion Criteria
SCCHN Cohort 1 (AntiPD-1/PD-L1 Treatment-Naive)

Patients must have histologically confirmed recurrent or metastatic SCCHN (oral cavity, 
pharynx, larynx), Stage III/IV, and are not amenable to local therapy with curative intent 
(surgery or radiation, with or without chemotherapy).

Patients must have received at least one platinum-containing therapy in the recurrent or 
metastatic setting and up to a total of two lines of chemotherapy (including the required 
platinum-based regimen), in the recurrent or metastatic SCCHN.

Patients are also eligible if they had recurrence or progression within 6 months of the last 
dose of platinum-containing therapy in the adjuvant (i.e., with radiation after surgery) or 
primary (i.e., with radiation) setting.
SCCHN Cohort 4 (Progression on Anti–PD-1/PD-L1 Therapy)

Patients must have histologically confirmed recurrent or metastatic SCCHN (oral cavity, 
pharynx, larynx), Stage III/IV, and are not amenable to local therapy with curative intent 
(surgery or radiation, with or without chemotherapy).

Progressed on prior anti–PD-1/PD-L1 therapy in the recurrent or metastatic setting
Patients are also eligible if they had disease progression on or within 6 months of the 
last dose of antiPD-1/PD-L1 therapy in the adjuvant setting 

Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies, and 
combinations, including antiCTLA-4, antiPD-1/PD-L1 therapeutic antibodies are allowed
UC Cohort 2 (AntiPD-1/PD-L1 Treatment-Naive)

Histologically or cytologically documented locally advanced (T4b, any N; or any T, N2N3) 
or metastatic (M1, Stage IV) urothelial bladder cancer (also termed transitional cell 
carcinoma, urothelial carcinoma, or carcinoma the urinary tract; including renal pelvis, 
ureters, urinary bladder, and urethra)
Patients with mixed histologies are required to have a dominant transitional cell pattern.


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
Locally advanced bladder cancer must be inoperable on the basis of involvement of pelvic 
sidewall or adjacent viscera (clinical stage T4b) or bulky nodal metastasis (N2N3)
Transurethral resection for bladder tumor (TURBT) specimens must contain a muscle-
invasive component (i.e., T2 or greater) or the bladder tumor as verified by local 
pathology review.  If the TURBT specimens do not contain a muscle-invasive 
component, then specimens obtained at the time of cystectomy, nephroureterectomy, 
or metastatic spread (i.e., a sample from a metastatic lesion) will be required prior to 
enrollment.  

Disease progression during or following treatment with at least one platinum-containing 
regimen for inoperable, locally advanced or metastatic urothelial bladder cancer or disease 
recurrence
Patients who received prior adjuvant/neoadjuvant chemotherapy and progressed 
within 12 months of treatment with a platinum-containing adjuvant or neoadjuvant 
regimen are eligible.
Patients may have received at least one prior regimen but no more than two prior 
regimens of treatment (including the required platinum-based regimen) for advanced 
urothelial bladder cancer.
Patients who have received one cycle of a platinum-containing regimen but 
discontinued because intolerable toxicity may also be eligible.
Patients with disease progression following chemoradiotherapy must demonstrate 
progression outside the prior radiotherapy port.
UC Cohort 5 (Progression on Anti–PD-1/PD-L1 Therapy)

Histologically or cytologically documented locally advanced (T4b, any N; or any T, N2N3) 
or metastatic (M1, Stage IV) urothelial bladder cancer (also termed transitional cell 
carcinoma, urothelial carcinoma, or carcinoma the urinary tract; including renal pelvis, 
ureters, urinary bladder, and urethra)
Patients with mixed histologies are required to have a dominant transitional cell pattern.

Locally advanced bladder cancer must be inoperable on the basis of involvement of pelvic 
sidewall or adjacent viscera (clinical stage T4b) or bulky nodal metastasis (N2N3)
Transurethral resection for bladder tumor (TURBT) specimens must contain a muscle-
invasive component (i.e., T2 or greater) or the bladder tumor as verified by local 
pathology review.  If the TURBT specimens do not contain a muscle-invasive 
component, then specimens obtained at the time of cystectomy, nephroureterectomy, 
or metastatic spread (i.e., a sample from a metastatic lesion) will be required prior to 
enrollment.  

Disease progression during or following treatment with at least one platinum-containing 
regimen for inoperable, locally advanced or metastatic urothelial bladder cancer or disease 
recurrence
Patients who received prior adjuvant/neoadjuvant chemotherapy and progressed 
within 12 months of treatment with a platinum-containing adjuvant or neoadjuvant 
regimen are eligible.
Patients who have received one cycle of a platinum-containing regimen but 
discontinued because intolerable toxicity may also be eligible.
Patients with disease progression following chemoradiotherapy must demonstrate 
progression outside the prior radiotherapy port.

Progression while on a prior anti–PD-1/PD-L1 therapy in the recurrent or metastatic setting
Patients are also eligible if they had disease progression on or within 6 months of the 
last dose of anti–PD-1/PD-L1 therapy in the adjuvant setting

Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies, and 
combinations including anti–CTLA-4, anti–PD-1/PD-L1 therapeutic antibodies are allowed

Patients are eligible if they received no more than three lines of therapy in the advanced, 
metastatic setting
RCC Cohort 3 (AntiPD-1/PD-L1 Treatment-Naive)


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
Histological confirmation of advanced or metastatic RCC with a clear-cell component

Prior cytokine therapy (e.g., IL-2, IFN-), vaccine therapy, or treatment with cytotoxic 
agents is allowed.  

Patients must have received at least one but no more than two total prior systemic 
treatment regimens in the advanced or metastatic setting. 
RCC Cohort 6 (Progression while on AntiPD-1/PD-L1 Therapy):

Patients in RCC Cohort 6 must meet the following criteria for study entry:

Histological confirmation of advanced or metastatic RCC with a clear-cell component

Prior cytokine therapy (e.g., IL-2, IFN-), vaccine therapy, or treatment with cytotoxic 
agents is allowed.  

Progressed while on prior antiPD-1/PD-L1 therapy in the recurrent or metastatic setting
Patients are also eligible if they had disease progression on or within 6 months of the 
last dose of anti–PD-1/PD-L1 therapy in the adjuvant setting.

Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies, and 
combinations including anti–CTLA-4, anti–PD-1/PD-L1 therapeutic antibodies are allowed.

Patients are eligible if they received no more than three lines of therapy in the 
advanced/metastatic setting.
Biopsy Cohort 7

Patients must have histologically confirmed non-melanoma, non-hematologic solid tumor.

Patients must have metastatic or locally advanced disease that is not amenable to local 
treatment with curative intent.

Measurable disease according to RECIST v1.1

Patients in this cohort must have received a minimum of two cycles of anti–PD-1 or anti–
PD-L1 therapy.

Patients in this cohort must have progressed during or after anti–PD-1 or anti–PD-L1 
therapy within 12 weeks before study start.

Patients in this cohort must meet criteria for primary or secondary resistance to an anti–PD-
1 or anti–PD-L1 agent as outlined below:
Primary resistance is defined as progressive disease, according to RECIST v1.1, as 
best response
Secondary resistance is defined as progressive disease after initial confirmed 
response according to RECIST v1.1

Patients in this cohort must have received anti–PD-1 or anti–PD-L1 therapy as the most 
recent treatment.

Patients in this cohort must consent to undergo tumor biopsies of accessible lesions before 
and during treatment for biomarker analyses.

Patients in this cohort must have at least two accessible lesions that are amenable to 
excisional or core-needle biopsy with acceptable risk of a major procedural complication.  
Exceptions may be made following discussion with Medical Monitor. 
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
General Exclusion Criteria

Inability to swallow medications. Other means of intake may be allowed after Medical 
Monitor approval has been obtained.  

Malabsorption condition that would alter the absorption of orally administered medications

Poor peripheral venous access

Prior treatment with cobimetinib or a MEK inhibitor


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
For patients in Cohorts 1, 2, and 3 only:  prior treatment with T-cell co-stimulating or 
immune checkpoint blockade therapies, including antiCTLA-4, antiPD-1, and antiPD-L1 
therapeutic antibodies 

Treatment with investigational therapy within 14 days prior to initiation of study treatment

Any anti-cancer therapy, including chemotherapy or hormonal therapy, within 2 weeks prior 
to initiation of study treatment

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary 
cells 

Known allergy or hypersensitivity to any component of the atezolizumab formulation

Known allergy or hypersensitivity to any component of the cobimetinib formulation

Known allergy or hypersensitivity to any anti–PD-1/PD-L1 therapy

History of serous retinopathy, retinal vein occlusion (RVO), or evidence of ongoing serous 
retinopathy or RVO at baseline

Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study 
treatment, or anticipation of need for a major surgical procedure during the study

Uncontrolled tumor-related pain
Patients requiring narcotic pain medication must be on a stable regimen at study entry.
Intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage
more than once every 28 days
Indwelling drainage catheters (e.g., PleurX®) are allowed.

Uncontrolled hypercalcemia (ionized calcium 1.5 mmol/L, calcium 12 mg/dL, or 
corrected calcium greater than the ULN) or symptomatic hypercalcemia requiring continued 
use of bisphosphonate therapy.
Patients who are receiving bisphosphonate therapy for other reasons (e.g., bone 
metastasis or osteoporosis) and who do not have a history of clinically significant 
hypercalcemia are eligible for the study.

Active or untreated CNS metastases
Patients with treated and asymptomatic CNS metastases are eligible, if they meet all of 
the following:
–
Evaluable or measurable disease outside the CNS
–
No metastases to midbrain, pons, medullar or within 10 mm of the optic nerves 
and chiasm
–
No history or evidence of intracranial hemorrhage or spinal cord hemorrhage
–
No evidence of clinically significant vasogenic edema
–
No corticosteroids for 2 weeks; anti-convulsant medications at a stable dose are 
allowed
–
No evidence of clinical and radiographic disease progression in the CNS for 3 
weeks after radiotherapy or surgery

Pregnancy or breastfeeding, or intending to become pregnant during the study
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to initiation of study treatment.
Exclusion Criteria based on Organ Function or Medical History
Cardiovascular


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
Left ventricular ejection fraction (LVEF) below the institutional lower limit of normal or 50%, 
whichever is lower
Infections

Positive HIV test at screening

Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive 
hepatitis B surface antigen (HBsAg) test at screening
Patients with a past or resolved HBV infection, defined as having a negative HBsAg 
test and a positive total hepatitis B core antibody (HBcAb) test at screening and 
negative HBV DNA, are eligible for the study.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test 
followed by a positive HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive HCV 
antibody test.

Active tuberculosis

Severe infection within 4 weeks 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 2 weeks 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. 
Autoimmune Conditions and Immunomodulatory Drugs

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, 
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
–
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
–
Disease is well controlled at baseline and only requiring low-potency steroids (e.g., 
hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 
0.05%, alclometasone dipropionate 0.05%)

Prior allogeneic stem cell or solid organ transplantation

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 CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.


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Exclusions Related to Other Medical Conditions or Medications

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, or may render the patient at high risk from treatment 
complications

Other active malignancy or a prior malignancy within the past 3 years outside of the primary 
cancer being studied in this study 
Patients with completely resected basal cell carcinoma, cutaneous squamous cell 
carcinoma, cervical carcinoma in-situ, breast carcinoma in-situ, and patients with 
isolated elevation in prostate-specific antigen in the absence of radiographic evidence 
of metastatic prostate cancer are eligible for the study.

Any Grade 3 hemorrhage or bleeding event within 28 days of Day 1 of Cycle 1

History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 
6 months prior to Day 1 of Cycle 1
Cohort-Specific Exclusion Criteria
SCCHN Cohorts 1 and 4

Histologically confirmed recurrent or metastatic carcinoma of the nasopharynx and salivary 
gland or of non-squamous histologies (e.g., mucosal melanoma) 
End of Study
The study will end when all patients enrolled have been followed until death, withdrawal of 
consent, loss to follow-up, or the Sponsor decides to end the trial, whichever occurs first.  
Patients may continue study treatment until the development of progressive disease, 
unacceptable toxicity, and/or withdrawal of consent.  
Length of Study
The total length of the study, from screening of the first patient to last patient, last visit is 
expected to be approximately 3 years.
Investigational Medicinal Products
Test Products (Investigational Drugs)
Cobimetinib
Patients will receive cobimetinib 60 mg (3 tablets of 20 mg each) orally once a day on 
Days 121 of each 28-day cycle in all cohorts.  
Atezolizumab
Atezolizumab will be given at a fixed dose of 840 mg by IV infusion on Days 1 and 15 of each 
28-day cycle.  
Patients in the biopsy cohort, Cohort 7, will receive the first dose of atezolizumab of 840 mg by 
IV infusions on Day 15 of Cycle 1.  Thereafter, they will receive atezolizumab 840 mg IV 
infusion Q2W on Days 1 and 15 of Cycle 2 and all subsequent cycles. 
Statistical Methods
Primary Analysis
This study is designed to explore the preliminary efficacy, safety, pharmacokinetics, 
immunogenicity, and biomarker of cobimetinib plus atezolizumab in seven patient cohorts with 
advanced solid tumors, including SCCHN, urothelial carcinoma, and RCC.
The primary analysis will be conducted once all patients in a particular cohort have been 
followed for a clinically meaningful period of time of approximately 16 weeks.  The statistical 
results will be summarized and presented by cohort.
Determination of Sample Size  
The purpose of this study is for hypothesis generation only.  No formal hypothesis testing or 
inference analysis is planned; hence, no power analysis is conducted.  Approximately 20 
patients are planned to be enrolled in Cohorts 1–6 with possible expansion up to approximately 




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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
21/7
21 days on/7 days off
ADA
anti-drug antibody
CIN
chromosomal instability
CRC
colorectal cancer
CR
complete response
CT
computed tomography
DCR
disease control rate
DOR
duration of response
EC
Ethics Committee
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EMA
European Medicines Agency
FDA
U.S. Food and Drug Administration
HBcAb
hepatitis B core antibody
HBV
hepatitis B virus
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HPV
human papillomavirus
HR
hazard ratio
IC
immune cell
IxRS
interactive voice or Web-based response system
ICH
International Council for Harmonisation
IFN-
interferon-alpha
Ig
immunoglobulin
IL-2
interleukin-2
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IRR
infusion-related response
LPLV
last patient, last visit
LVEF
left ventricular ejection fraction
MDSC
myeloid-derived suppressor cell


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Abbreviation
Definition
MHC
major histocompatibility complex
MRI
magnetic resonance imaging
MSI
microsatellite instability
MSS
microsatellite stable
MUGA
multiple-gated acquisition (scan)
NCI CTCAE v4.0
National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 4.0
NGS
next-generation sequencing
ORR
objective response rate
OS
overall survival
PD-1
programmed death1
PD-L1
programmed death ligand1
PFS
progression-free survival
PK
pharmacokinetic
PO
orally (by mouth)
PR
partial response
QD
once a day
Q2W
every 2 weeks
Q3W
every 3 weeks
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RVO
retinal vein occlusion
SCCHN
squamous cell carcinoma of the head and neck
TCR
T-cell receptor
TIL
tumor-infiltrating lymphocyte
TNF-
tumor necrosis factoralpha
TURBT
UC
transurethral resection for bladder tumor
urothelial carcinoma
ULN
upper limit of normal
VEGFR
vascular endothelial growth factor receptor 
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON SOLID TUMOR COHORTS
1.1.1
Background on Squamous Cell Carcinoma of the Head and Neck
Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common 
nonskin-related cancer (Stransky et al. 2011).  In 2002, head and neck cancers 
comprised approximately 664,000 new cases and 350,000 deaths globally (Siegel et al.
2015).  In the United States, there were more than 61,000 new cases and more than 
13,000 deaths from head and neck cancers in 2016, representing approximately 3.7% of 
all new cancer cases and 2.7% of all cancer deaths in 2016 (Siegel et al. 2016).  More 
men are affected than women with SCCHN in a ratio of 2.5:1, and the median age at 
diagnosis is 60 years old (Siegel et al. 2016). 
Two subclasses of SCCHN tumors have been identified: human papillomavirus 
(HPV)-positive and HPV-negative tumors.  Of patients with SCCHN, 20% have 
HPV-positive tumors and have a more favorable prognosis than the remaining 80% 
patients with HPV-negative tumors. In addition, within the HPV-negative subclass,
patients with low chromosomal instability (CIN) and high CIN have been identified on the 
basis of numerical genetic changes, and CIN prevalence has been estimated at 
15% and 65% of SCCHN, respectively.  Patients with low CIN appear to have a more 
favorable prognosis than patients with high CIN status; however, CIN classification is 
preliminary and is based on limited data (Leemans et al. 2011).
Sixty percent of SCCHN are initially diagnosed at an advanced stage, encompassing 
locally advanced (Stage III and IVA/B) and metastatic tumors (Stage IVC).  The standard 
of care for patients with locally advanced SCCHN consists of multimodality therapy with
surgery and/or chemoradiation, and despite 30% of patients achieving a complete 
response (CR), the majority of patients will relapse, with 20%30% developing distant 
metastases (Vermorken and Specenier 2010).  Although a minority of patients who have 
recurrent disease may be candidates for salvage surgery or re-irradiation, treatment 
options are usually limited to palliative chemotherapy or best-supportive care, depending 
on a patient's performance status.  Platinum-containing combination therapy is 
considered first-line therapy in this setting.  In patients with relapsing or metastatic 
SCCHN that is refractory to platinum-containing regimens, single-agent chemotherapy 
(e.g., taxanes, capecitabine, or methotrexate) or targeted agents (e.g., cetuximab) are 
options but have failed to demonstrate a survival benefit (NCCN 2016; Seiwert et al. 
2016).  The median overall survival (OS) was less than 6 months for these patients 
(Machiels et al. 2015; Ferris et al. 2016a).
Checkpoint inhibitors have demonstrated efficacy in SCCHN.  In 2016, pembrolizumab, 
a programmed death1 (PD-1) inhibitor, received accelerated approval from the U.S. 
Food and Drug Administration (FDA) for patients with recurrent or metastatic SCCHN 
with disease progression during or after platinum-containing chemotherapy. The overall 
response rate was 18% (95% CI: 8%, 23%) with pembrolizumab in this second-line 


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treatment setting for these patients, and median OS was 13.0 months (95% CI:
5 months, not reached).  The most common adverse events included fatigue, pruritus, 
nausea, decreased appetite, and rash.  Grade3 events included increased AST and 
ALT, rash, fatigue, atrial fibrillation, lymphopenia, congestive heart failure, diarrhea, neck 
abscess, hyponatremia, and musculoskeletal pain (Bauml et al. 2016; Seiwert et al.
2016).
Nivolumab, another PD-1 inhibitor, received full approval from the FDA in 2016 for 
patients with recurrent or metastatic SCCHN with disease progression during or after a 
platinum-based therapy.  Patients were randomized to receive nivolumab or 
investigator's choice (single-agent methotrexate, docetaxel, or cetuximab).  The 1-year 
OS rate was 36.0% (95% CI: 28.5%, 43.4%) compared with 16.6% (95% CI: 8.6%, 
26.8%), and the median OS was 7.5 months (95% CI: 5.5, 9.1 months) compared with
5.1 months (95% CI: 4.0, 6.0 months).  The objective response rate (ORR) was 13.3% 
(95% CI: 9.3%, 18.3%) among nivolumab-treated patients compared with 5.8% (95% CI: 
2.4%, 11.6%) in investigator’s choice–treated patients. Overall, the safety profile of 
nivolumab was similar to what was reported in pembrolizumab-treated patients with
SCCHN (Ferris et al. 2016a; Seiwert et al. 2016).
After progression on antiPD-1/PD-L1 therapy, there is no standard-of-care effective 
therapy.  Patients can receive single-agent chemotherapy such as methotrexate or
taxanes or treatment with cetuximab, but these agents have been evaluated only in the 
antiPD-1/PD-L1-naive setting.  Currently, there are no treatment modalities that have 
been studied in the postcheckpoint inhibitor setting.
1.1.2
Background on Urothelial Carcinoma
Globally, urothelial carcinoma (UC) is the ninth most commonly occurring cancer.  There 
were an estimated 429,000 new UC cases and approximately 165,000 deaths in 2012
(Ferlay et al. 2013).  In the United States, there were approximately 76,960 new cases 
and 16,390 deaths in 2016 (Siegel et al. 2016).  More men are affected than women in a 
ratio of 3.5:1, and the median age at diagnosis is 73 years old (Mallin et al. 2011).  UC is 
the most prevalent in Europe, Asia, and Northern Africa (Pelucchi et al. 2006).
Of patients with newly diagnosed UC, approximately 70% present with superficial tumors, 
15% with muscle-invasive tumors, and 12% present with regional or metastatic disease.  
Even with appropriate treatment of superficial tumors, about 50%70% will recur, with 
10%20% presenting as muscle-invasive cancer (Kaufman et al. 2009). For 
muscle-invasive tumors, treatment involves radical cystectomy, with or without 
neoadjuvant or adjuvant chemotherapy (Kaufman et al. 2009; Clark et al. 2016).  Despite 
treatment, approximately 50% of patients will have recurrence and ultimately will die 
from their disease (Grossman et al. 2003).  
For patients with advanced UC, platinum-based chemotherapy has been the standard of 
care, with a median OS of 915 months (von der Maase et al. 2005; Kaufman et al. 


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2009). For patients with metastatic UC, almost all will progress after a first-line platinum-
based therapy (von der Maase et al. 2005).  Until recently, there was no standard of care 
for second-line therapy and treatment involved single-agent chemotherapy, such as 
paclitaxel, gemcitabine, and pemetrexed (Clark et al. 2016).  Median OS is 57 months 
in this population (Bellmunt et al. 2009).  Until the introduction of checkpoint inhibitors, 
no therapies prolonged survival (Sweeney et al. 2006).  
In 2016, atezolizumab received accelerated approval from the FDA in patients with 
locally advanced or metastatic UC who have disease progression during or following 
platinum-containing chemotherapy or have disease progression within 12 months of 
neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.  A Phase II 
study with atezolizumab in patients with advanced UC demonstrated an ORR of 15%, 
median progression-free survival (PFS) of 2.1 months and median OS of 7.9 months
(Rosenberg et al. 2016).  Study drugrelated adverse events were reported in 61% of 
patients, with fatigue and nausea being the most common in patients treated with 
atezolizumab.  Six percent of patients treated with atezolizumab experienced a 
Grade 3 adverse event.  
Other checkpoint inhibitors have also been studied in this setting with similar results.  
Pembrolizumab was studied in patients with advanced urothelial carcinoma and showed 
a median PFS of 2.0 months (95% CI: 1.7, 4.0 months) and median OS of 12.7 months 
(95% CI: 5.0 months, not reached) (Plimack et al. 2015). In previously treated patients 
with metastatic urothelial carcinoma, nivolumab demonstrated a median PFS of 
2.8 months (95% CI: 1.5, 5.9 months) and median OS of 9.7 months (95% CI: 7.3,
16.2 months), with confirmed investigator-assessed objective response of 24.4% (95% 
CI: 15.3%, 35.4%) (Sharma et al. 2016), and has received accelerated approval from the 
FDA. 
In patients who have received checkpoint inhibitors but are chemotherapy naive, 
platinum-based therapy is recommended (NCCN 2018).  There are no therapies that 
have been studied in the postcheckpoint therapy setting for patients who have 
previously received chemotherapy.
1.1.3
Background on Renal Cell Carcinoma
Globally, there were an estimated 338,000 new renal cell carcinoma (RCC) cases and 
approximately 144,000 deaths in 2012 (Ferlay et al. 2013).  In the United States, there 
were approximately 62,700 new cases and 14,240 deaths in 2016 (Siegel et al. 2016).
More men are affected than women with RCC in a ratio of 2:1. RCC is more prevalent in 
North America, Australia, New Zealand, and Europe (Ferlay et al. 2013).
About one-third of RCC patients have metastatic disease at the time of diagnosis, and 
another 30% of patients develop metastatic disease despite surgical treatment for
locoregional disease (Fisher et al. 2013).  For the majority of patients with metastatic 
RCC, treatment is palliative with systemic therapy.  In the first-line setting, several 


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targeted therapies and immunotherapies have been approved, including sunitinib, 
bevacizumab plus interferon-alpha (IFN-), high-dose interleukin-2 (IL-2), pazopanib, 
and temsirolimus (NCCN 2017).  Sunitinib is the most commonly used in the first-line 
treatment setting in metastatic RCC (Hess et al. 2013); however, most patients relapse 
within 1 year and require second-line treatment (Motzer et al. 2007).
Nivolumab has received full approval from the FDA and European Medicines Agency
(EMA); cabozantinib has received full approval from the FDA for the second-line 
treatment of metastatic RCC based on Phase III clinical trial results showing 
improvement in clinical efficacy compared with everolimus (Choueiri et al. 2015; Motzer 
et al. 2015).  Prior to these recent approvals, no second-line therapy had shown an 
improvement in OS (Fisher et al. 2013).
Nivolumab is a PD-1 immune checkpoint inhibitor antibody that was studied in patients 
with metastatic RCC who had previously received one or two regimens of antiangiogenic 
therapy.  The ORR was greater with nivolumab than with everolimus (25% vs. 5% [odds 
ratio5.98; 95% CI: 3.68, 9.72]), and median OS was 25 months (95% CI: 21.8 months,
not evaluable) for nivolumab and 19.6 months (95% CI: 17.6, 23.1 months) for 
everolimus. Programmed deathligand 1 (PD-L1) expression levels did not correlate 
with nivolumab benefit over everolimus.  Study treatment-related adverse events of any 
grade occurred in 79% of patients who were treated with nivolumab, with the most 
common study treatmentrelated adverse events being fatigue, nausea, and pruritus.  
Grade 3 or 4 study treatment-related adverse events occurred in 19% of patients, with 
the most common adverse event being fatigue (2%).
Cabozantinib is a tyrosine kinase inhibitor that targets the vascular endothelial growth 
factor receptor (VEGFR) that was studied in patients with metastatic RCC who received 
at least one VEGFR-targeted tyrosine kinase inhibitor.  Estimated median PFS was 
7.4 months (95% CI: 5.6, 9.1 months) with cabozantinib and 3.8 months (95% CI: 3.7,
5.4 months) with everolimus.  A trend toward longer OS with cabozantinib than with 
everolimus was observed (hazard ratio [HR]0.67; 95% CI: 0.51, 0.89; p0.005) as of 
the interim analysis data cutoff, but median OS is not available yet, owing to the low 
number of events.  All patients experienced any grade adverse event, and 68% of 
patients experienced a Grade 3 or 4 adverse event while receiving cabozantinib.  The 
most common adverse events (20%) were diarrhea (74%), fatigue (56%), nausea 
(50%), decreased appetite (46%), palmarplantar erythrodysesthesia syndrome (42%), 
hypertension (37%), vomiting (32%), decreased weight (31%), constipation (25%), 
dysgeusia (24%), and stomatitis (22%).  The most common Grade 3 or 4 adverse events
(5%) were hypertension (15%), diarrhea (11%), and fatigue (9%).
No treatments have specifically been studied in the postcheckpoint inhibitor setting.  
The Phase III trial of cabozantinib versus everolimus in second and subsequent-line 
mRCC did enroll patients who previously had received nivolumab (Choueiri et. al 2016)
but no therapies are currently approved in this setting.


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1.2
BACKGROUND ON COBIMETINIB AND ATEZOLIZUMAB
1.2.1
The PD-L1 Pathway
Clinical data in the field of tumor immunotherapy have demonstrated that therapies that 
are focused on enhancing T-cell responses against cancer can result in significant 
survival benefit in patients with Stage IV cancer (Hodi and Dranoff 2010; Kantoff et al. 
2010). Therefore, immunomodulation represents a promising new strategy for cancer 
therapy that may result in improved anti-tumor activity.
PD-L1 expression is prevalent in many human tumors (e.g., lung cancer, ovarian cancer, 
melanoma, and colon carcinoma), and its overexpression has been associated with poor 
prognosis in some cancers (Thompson et al. 2006; Hamanishi et al. 2007; Okazaki and 
Honjo 2007; Hino et al. 2010). PD-L1 is one of two ligands (PD-L1 and PD-L2) that 
binds to PD-1. The PD-1 receptor is an inhibitory receptor expressed on T cells 
following T-cell activation in states of chronic stimulation, such as chronic infection or 
cancer (Blank et al. 2005; Keir et al. 2008). Ligation of PD-L1 with PD-1 inhibits T-cell 
proliferation, cytokine production, and cytolytic activity that lead to the functional 
inactivation of T cells.  Aberrant expression of PD-L1 on tumor cells has been reported 
to impede anti-tumor immunity, resulting in immune evasion (Blank and Mackensen 
2007). Therefore, interruption of the PD-L1/PD-1 pathway represents an attractive 
strategy to reinvigorate tumor-specific T-cell immunity.
Blockade of PD-L1 or PD-1 with monoclonal antibodies results in strong and often rapid 
anti-tumor effects in several mouse tumor models (Iwai et al. 2002; Strome et al. 2003) 
and has demonstrated clinical activity with drugs such as atezolizumab (Besse et al. 
2015; Rosenberg et al. 2015; Vansteenkiste et al. 2015).
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets 
PD-L1 and inhibits its interaction with its receptors, PD-1 and B7-1 (also known as 
CD80). Both of these interactions are reported to provide inhibitory signals to T cells.
Atezolizumab was engineered to impair its binding to Fc receptors, thus eliminating 
detectable Fc-effector function and associated antibody-mediated clearance of activated 
effector T cells.
1.2.2
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 (Johnson and Lapadat 
2002; Roberts and Der 2007). Given the central role that the MAPK pathway plays in 
normal cellular development, abnormal regulation of this signaling pathway could lead to 
tumorigenesis through contribution to uncontrolled proliferation, invasion, metastasis, 
and angiogenesis, as well as diminished apoptosis.


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The MAPK pathway has also been implicated in the regulation of the immune
microenvironment of tumors. In in vitro cell lines, blocking the MAPK pathway was
shown to increase antigen expression and enhance reactivity to antigen-specific
T lymphocytes (Boni et al. 2010). Furthermore, pretreatment biopsies in which there 
were increased tumor-infiltrating lymphocytes (TILs) demonstrated a larger increase in
TILs and PD-1 expression after treatment with a BRAF inhibitor and MEK inhibitor 
(Cooper et al. 2015; Kakavand et al. 2015; Liu et al. 2015). The inhibition of the MAPK 
pathway leads to an increase in immune effector cells in the tumor, thus priming the 
microenvironment to enable to immune system to attack the tumor.
Inhibition of the MAPK pathway has focused on the suppression of targets within this
signaling network, such as MEK1 and MEK2. There are multiple upstream activating
signals, but multiple alternative pathways exist to bypass their inhibition and still activate
ERK1 and ERK2. ERK1 and ERK2 can only be activated and phosphorylated by MEK1
and MEK2, which therefore render MEK1 and MEK2 as key targets for the inhibition of 
the MAPK pathway.
Cobimetinib is an orally dosed, potent and highly selective inhibitor of MEK.
1.2.3
Background on Cobimetinib Monotherapy
Cobimetinib is a reversible, potent, and highly selective inhibitor of MEK1 and MEK2, 
key downstream regulators of the MAPK pathway.  MEK1 and MEK2 are responsible for 
activating ERK by phosphorylation.  Cobimetinib inhibits ERK phosphorylation in 
xenograft tumor models to stimulate apoptosis and tumor regression. Cobimetinib has 
been studied alone or with other agents in more than 1000 adult cancer patients; the 
vast majority of patients had been treated with cobimetinib plus other agents, such as 
vemurafenib.  The cobimetinib monotherapy trial is the first-in-human Phase I study 
MEK4592g, an open-label, safety, and pharmacokinetic (PK) dose-escalation study in 
patients with metastatic or unresectable solid tumors (Rosen et al. 2016).  The 
recommended dose was 60 mg daily for 21 days followed by a 7-day break in dosing.  
As a single-agent, cobimetinib demonstrated anti-tumor activity in melanoma.  In 
combination with other agents, cobimetinib has demonstrated anti-tumor activity in other 
tumor types, such as melanoma, lung, colon, and breast cancers (Larkin et al. 2014).
Cobimetinib (Cotellic®) is approved in the United States, European Union, Switzerland, 
and in multiple other countries across the world in combination with vemurafenib for the 
treatment of advanced BRAF-mutated melanoma.
Refer to the Cobimetinib Investigator's Brochure for cobimetinib for details on nonclinical 
and clinical studies.
1.2.4
Background on Atezolizumab Monotherapy
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 


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both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells.
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy.
Atezolizumab (Tecentriq®) is approved in the United States for the treatment of locally 
advanced or metastatic urothelial carcinoma and for the treatment of metastatic 
nonsmall cell lung cancer.
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies.
1.2.5
Combined Inhibition of PD-L1 and MAPK Signaling Pathways 
as Potential Anti-Cancer Therapy 
Although checkpoint inhibitors have shown efficacy in a variety of tumors, only a 
proportion of the tumors are responsive, and most patients eventually progress and die 
from their disease.  Moreover, there are still high unmet needs for patients with tumors 
for which checkpoint inhibitors are ineffective.
One potential mechanism to convert cancers that are otherwise resistant to immune 
checkpoint inhibitors is to recruit immune cells (ICs) to the tumor sites so that
antiPD-L1 can be effective in activating the local immune system against the cancer 
cells. Nonclinical models suggest that MEK inhibition may have pleiotropic effects that 
could impact the tumor immune microenvironment, as the MAPK pathway has been 
implicated in the immune resistance of tumors and inhibition of this pathway can lead to
increase CD8-positive T-cell infiltration (Kakavand et al. 2015; Liu et al. 2015).
Within the tumor, MEK inhibition in tumors increases expression of the checkpoint 
receptor PD-L1, which could counteract the increased presentation of tumor antigens.
MEK inhibition also results in increased major histocompatibility complex (MHC) class I 
expression and tumor antigen presentation, which acts to enhance tumor recognition by 
the immune system. Lastly, the MAPK pathway is known to regulate a number of 
cytokines and chemokines, such as VEGF, IL-6, IL-8, and granulocyte macrophage 
colony-stimulating factor, which may affect recruitment of vascular and other stromal cell 
types, including myeloid-derived suppressor cells (MDSCs), that can inhibit the anti-
tumor activity of T cells (Bancroft et al. 2001, 2002; Sano et al. 2001; Phan et al. 2013).


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Activity of MEK inhibition outside of the tumor cells may further contribute to the 
modulation of the immune microenvironment that could enable a more permissive 
immune reaction against the tumor. These effects include inhibition of tumor vascular 
maturity and integrity, tumor infiltration, activity of MDSCs, neutrophils, increased activity 
of antigen-presentation cells, such as macrophage and dendritic cells, and recruitment 
and activation status of T-cell subsets, including CD8-positive cytolytic and CD4-positive
helper cells (Giordano et al. 2015; Liu et al. 2015; Loi et al. 2015).
Collectively, these effects enable tumors to demonstrate stronger anti-tumor responses
with the combination of a MEK inhibitor and PD-L1/PD-1 blockade in multiple mouse 
models, including colorectal, breast, and melanoma models (Liu et al. 2015; Loi et al. 
2015). Increased anti-tumor activity is associated with increased CD8-positive T-cell 
infiltration of tumors that express markers consistent with tumor-cell cytolytic activity. 
In a mouse model, the MEK inhibitorrescued T cells appeared to be most effective in 
the presence of a PD-L1 blocking antibody; the MAPK axis is a key downstream 
pathway for the T-cell receptor (TCR) triggering.  The TCR-driven death seemed to be 
working in parallel with the PD-1 axis (Ebert et al. 2016).  The data suggest that MEK 
inhibition can modulate the tumor immune microenvironment and enable better tumor 
recognition and killing by the immune system, particularly when paired with a checkpoint 
inhibitor against the PD-1/PD-L1 axis.
1.2.5.1
Rationale for Combining Cobimetinib and Atezolizumab for 
Solid Tumors after Progression on AntiPD-1/PD-L1 Therapy
As detailed in Sections 1.1.11.1.3, although anti–PD-1/PD-L1 therapies have benefited 
patients with certain solid tumors, response rates to anti–PD-1/PD-L1 therapies are low
and patients eventually progress on treatment. Patients who do not respond or achieve 
disease stabilization are defined as having refractory disease or primary resistance, 
whereas patients whose tumors progress after initial response or stabilization are 
defined as having relapsed disease or secondary resistance. The molecular 
mechanisms of primary and secondary resistance to immunotherapy are poorly 
understood. However, the known effects of MAPK inhibitors, including cobimetinib, on 
the tumor microenvironment (see Section 1.2.5) include effects that may enable 
conversion to an immune-responsive phenotype, sensitize refractory tumors to antiPD-
1/PD-L1 agents, and/or re-sensitize relapsed tumors to these agents, leading 
researchers to the hypothesis that combining MEK inhibition with antiPD-1/PD-L1 
therapy may lead to improved efficacy. 
1.2.6
Clinical Data:  Cobimetinib in Combination with Atezolizumab
1.2.6.1
Phase Ib Study of Cobimetinib and Atezolizumab:  
Study GP28363
Study GP28363 is a Phase Ib, open-label, multicenter, global study designed to assess 
cobimetinib and atezolizumab administered in combination to patients with metastatic or 
locally advanced (unresectable) solid tumors. The study has two stages:  Stage 1 (dose 
escalation) and Stage 2 (indication-specific expansion cohorts and serial biopsy cohort).  




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cobimetinib has beneficial immunomodulatory effects at the tumor site that allow for 
immune anti-tumor activity.
Summary of Adverse Events
The safety-evaluable population consists of 150 patients who had received at least one 
dose of atezolizumab.  All patients received cobimetinib. Overall, 96.7% of patients 
experienced at least one adverse event regardless of attribution; 65.3% experienced a 
Grade3 adverse event; and 44.0% experienced a serious adverse event.  There were 
five Grade 5 adverse events (3.3%) (see Table 1).
The most common adverse events (reported in 20% of patients) were diarrhea 
(69.3%), fatigue (52.7%), rash (46.0%), vomiting (38.7%), nausea (34.0%), pruritus 
(32.7%), decreased appetite (30.0%), constipation (28.0%), peripheral edema (26.0%), 
pyrexia (23.3%), acneiform dermatitis (23.3%), increased CPK (22.7%), dyspnea 
(20.0%), and anemia (20.0%).  The most common Grade 3 adverse events (5%) 
were fatigue (9.3%), anemia (8.7%), and diarrhea (8.0%). Overall, 44% of patients 
experienced a serious adverse event. 
 
 
 
 


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2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of cobimetinib plus 
atezolizumab in patients with advanced solid tumors, including the following seven
cohorts:  

Cohort 1:  patients with SCCHN who are antiPD-1 and antiPD-L1 treatment naive

Cohort 2:  patients with UC who are antiPD-1 and antiPD-L1 treatment naive

Cohort 3: Patients with RCC who are antiPD-1 and antiPD-L1 treatment naive

Cohort 4: Patients with SCCHN who have progressed while on antiPD-1 or 
antiPD-L1 therapy

Cohort 5: Patients with UC who have progressed while on antiPD-1 or antiPD-L1 
therapy

Cohort 6: Patients with RCC who have progressed while on antiPD-1 or antiPD-
L1 therapy

Cohort 7: A biopsy cohort comprising patients with solid non-melanoma,
non-hematologic tumors who previously developed primary or secondary resistance 
to an antiPD-1 or antiPD-L1 agent
Specific objectives and corresponding endpoints for the study are outlined in Table 2.








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There are seven patient cohorts in the study: 

Cohort 1: patients with SCCHN who are antiPD-1 and antiPD-L1 treatment 
naive

Cohort 2: patients with UC who are antiPD-1 and antiPD-L1 treatment naive

Cohort 3: patients with RCC who are antiPD-1 and antiPD-L1 treatment naive

Cohort 4: patients with SCCHN whose disease has progressed while receiving 
antiPD-1 or antiPD-L1 therapy

Cohort 5: patients with UC whose disease has progressed while receiving
antiPD-1 or antiPD-L1 therapy

Cohort 6: patients with RCC whose disease has progressed while receiving
antiPD-1 or antiPD-L1 therapy

Cohort 7: a biopsy cohort comprising patients with solid non-melanoma,
non- hematologic tumors who previously developed primary or secondary 
resistance to an antiPD-1 or antiPD-L1 agent  
The primary objective of the study is to evaluate the efficacy of cobimetinib plus 
atezolizumab in different solid tumor types as measured by overall response rate.  The 
study will be conducted globally, and approximately 20 patients will be enrolled in each 
cohort with the opportunity to expand up to approximately 40 patients per cohort. 
Approximately 12 patients will be enrolled in Cohort 7. 
The Sponsor will monitor the enrollment for each region (North America, Europe, and
Pacific/Asia). To ensure balanced global enrollment, the Sponsor may institute
temporary limitations on enrollment in certain regions in the event of disproportionate
accrual of patients.
A schedule of activities is provided in Appendix 1.
After signing informed consent, patients will undergo screening procedures that include 
laboratory tests (e.g., hematology, chemistries, liver function tests); left ventricular 
function evaluation (echocardiogram [ECHO] or multiple-gated acquisition [MUGA]
scan); contrast-enhanced computed tomography (CT) or magnetic resonance imaging 
(MRI) scan of the chest, abdomen, and pelvis; and ophthalmologic assessments.
Patients can be rescreened.


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Figure 1
Study Schema
DCR disease control rate; DOR duration of response; ORR objective response rate; 
OS overall survival; PFS progression-free survival; RCC renal cell carcinoma; 
SCCHN squamous cell carcinoma of the head and neck; UC urothelial carcinoma.
Figure 2
Study Dosing Schema:  Cohorts 16
Dday; POorally (by mouth).




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
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions

Patient's written consent to acknowledge deferring other treatment options in favor 
of continuing study treatment at the time of initial disease progression
After discontinuation of study treatment, patients may receive any subsequent line of 
therapy as directed by their treating physician.  Patients will continue to be followed after 
discontinuation of study treatment to monitor adverse events, response and duration of 
response, and survival (see Section 4.6.1).
3.1.1.2
Tumor Assessments
Tumor response will be evaluated by either CT scan or MRI scan according to RECIST 
v1.1, as determined by the investigator (see Appendix 3). Any evaluable and 
measurable disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Immune-modified RECIST will also be evaluated at the 
same time (see Appendix 4), as determined by the investigator. Investigators will 
assess tumor response at 8-week intervals, regardless of any dose delays or treatment 
cycles. 
Patients who discontinue treatment for reasons other than disease progression
(e.g., toxicity) will continue scheduled tumor assessments until disease progression,
withdrawal of consent, study termination by Sponsor, or death, whichever occurs first.
In the absence of disease progression, tumor assessments should continue every 
8 weeks regardless of whether patients start a new anti-cancer therapy, unless consent 
is withdrawn.
All patients will be followed for survival unless consent is withdrawn.  In patients who are 
treated beyond progression, tumor assessments will be performed until discontinuation 
of treatment.
3.1.1.3
Tumor Biopsies
3.1.1.3.1
Non-Biopsy Cohorts (Cohorts 16)
Baseline tumor tissue samples will be obtained from all patients, preferably by means of 
a biopsy performed at study entry.  If a biopsy is not deemed feasible by the investigator, 
archival tumor tissue may be submitted after Medical Monitor approval has been 
obtained.
These samples will be utilized for biomarker research (see 
 
and details on tissue sample collection in Section 4.5.5). 
Patients will be asked to provide an optional biopsy during treatment on Day 15 of
Cycle 1 (5 days), provided the patient's disease is easily accessible and tumor biopsies 
can be performed with minimal risk and discomfort. The biopsy is for exploratory 
research on biomarkers associated with the MAP kinase pathway and immune-related 


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pathways, and for DNA and RNA extraction on non-inherited biomarkers (including, but 
not limited to, cancer-related genes).
Patients will undergo mandatory tumor biopsy sample collection, unless not clinically 
feasible, as assessed and documented by the investigator, at the time of first evidence 
of radiographic disease progression according to RECIST v1.1, within 14 days after 
radiographic progression, or prior to the start of new anti-cancer treatment, whichever is 
sooner.  These samples will be analyzed to evaluate the utility of the biopsy in 
distinguishing pseudoprogression (caused by tumor-infiltrating ICs) from true 
progression.  In addition, tumor tissue biomarkers related to resistance, disease 
progression, and clinical benefit of atezolizumab may be analyzed.
For biopsies obtained during screening (fresh or archival) and during the conduct of the 
trial, histologic samples are required for patients with SCCHN or RCC.  For patients 
with UC, cytological or histologic samples are acceptable.
3.1.1.3.2
Biopsy Cohort (Cohort 7)
Patients enrolled in Cohort 7, the biopsy cohort, must have at least two (preferably three) 
accessible lesions that meet the requirements specified in the eligibility criteria. 
Exceptions may be made if a patient has only one lesion that allows multiple biopsies 
following discussion with Medical Monitor.  One pre-treatment, two on-treatment biopsies, 
and possibly one post-progression biopsy will be performed. If more than one biopsy will 
be obtained from one lesion, the lesion should be large enough to permit successive 
biopsies1 cm apart. Investigators are strongly encouraged to obtain two on-treatment 
biopsies as described below.  At a minimum, the biopsy obtained between Day 10 and 
14 of Cycle 1 should be obtained to test for possible immunologic effects of cobimetinib 
alone. 
Patients in the biopsy cohort will undergo biopsies according to the following schedule:

A pre-dose biopsy will be taken before Day 1, Cycle 1 (not required if a fresh biopsy 
was provided during screening)

On Day 1, Cycle 1, patients will start treatment with cobimetinib alone

A mandatory on-treatment biopsy will be obtained between Days 10 and 14 of Cycle 
1

Patients will receive their first atezolizumab dose on Day 15 of Cycle 1

A mandatory second on-treatment biopsy will be obtained during Cycle 2, 
46 weeks after the first dose of atezolizumab to assess the combined effects of 
cobimetinib and atezolizumab

An optional, post-treatment biopsy will be obtained at the time of radiographic 
progression
Patients in the tumor biopsy cohort whose tissue sample is not evaluable may receive 
study treatment but may be replaced for the purpose of serial biopsy assessment. 


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3.1.2
Safety Data Review
The Sponsor's study team will review adverse events, serious adverse events, the 
frequency of deaths from all causes, and any other safety data in the study on an 
ongoing basis.
It is the responsibility of the study team to review accumulating safety data, to assess 
and monitor ongoing safety in patients, to evaluate potential changes to the clinical study 
protocol, and ultimately, to safeguard patient safety.
3.2
END OF STUDY AND LENGTH OF STUDY
The study will end when all patients enrolled have been followed until death, withdrawal 
of consent, loss to follow-up, or the Sponsor decides to end the trial, whichever occurs 
first. Patients may continue study treatment until the development of progressive 
disease, unacceptable toxicity, and/or withdrawal of consent.  Patients who discontinue 
study treatment for any reason will be followed for safety according to protocol, followed 
for disease progression, and followed for survival until death, withdrawal of consent, or 
loss to follow-up, whichever occurs first.  Patients who start a subsequent anti-cancer 
treatment after study treatment discontinuation will be followed for survival as well as 
disease progression, per protocol.  
The total length of the study, from screening of the first patient to last patient, last visit 
(LPLV) is expected to be approximately 3 years. 
3.3
RATIONALE FOR STUDY
3.3.1
Rationale for Study Design
This Phase II study is designed to assess the efficacy and safety of cobimetinib plus 
atezolizumab in a variety of solid tumors. 
 
 
 
 
 
 In 
light of the nonclinical and clinical data, and the high unmet need of the tumors proposed 
in this study, the study is designed to evaluate whether this combination may benefit 
these patient populations.
3.3.2
Rationale for Cobimetinib and Atezolizumab Dose 
and Schedule
Concomitant administration of cobimetinib and atezolizumab was studied in 
Study GP28363.  Cobimetinib and atezolizumab in combination were found to be safe 
and tolerable with cobimetinib on the approved dose and schedule of 60 mg QD 21/7


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(Days 121 of a 28-day cycle), and atezolizumab 800 mg IV Q2W, which is equivalent in 
exposure to the approved dose and schedule for the treatment of bladder cancer of 1200 
mg IV every 3 weeks (Q3W).
Cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 
21 days and 7 days off of each 28-day cycle.  For administration with cobimetinib in this
28-day cycle, a dose of 840 mg atezolizumab will be administered Q2W.  The 840-mg 
dose is expected to be similar to the 800-mg dose of atezolizumab and was selected in 
this study to simplify dose administration.  Atezolizumab is formulated at a concentration 
of 60 mg/mL; thus, 800 mg corresponds to a volume of 13.33 mL.  To ensure consistent, 
precise, and clinically feasible administration in this study, the volume was rounded up to 
14 mL, corresponding to a dose of 840 mg. The 840-mg dose is not expected to result 
in meaningfully different exposures compared with the 800-mg dose.
In addition, the atezolizumab dose of 840 mg Q2W is equivalent to an average body 
weightbased dose of 15 mg/kg Q3W, the recommended Phase II dosage for 
atezolizumab based on nonclinical and clinical studies, and it has been used in multiple
atezolizumab Phase III studies in other indications.
3.3.2.1
Rationale for the Biopsy Cohort (Cohort 7)
Cohort 7 is designed to allow assessment of the biological effects of cobimetinib on 
immune therapy. In this cohort, in Cycle 1 only, cobimetinib will be given for 14 days 
before initiation of atezolizumab treatment. Biopsies obtained before treatment start and 
between Days 10 and 14 of cobimetinib monotherapy period will allow elucidation of the 
effects of cobimetinib on tumor immune contexture. Additional biopsies taken during the 
combination treatment period and at radiographic progression will support evaluation of 
the effects of combination treatment on the tumor microenvironment and the 
identification of potential mechanisms of resistance to combination therapy. 
During Cycle 2 and all subsequent cycles, patients in Cohort 7 will receive cobimetinib 
60 mg QD 21/7 and atezolizumab 840 mg IV Q2W, the same dose and schedule as in 
Cohorts 16.
3.3.3
Rationale for Patient Population
3.3.3.1
Rationale for SCCHN
Recurrent or metastatic SCCHN is a disease of high unmet medical need for which the
5-year survival is less than 5%.  In patients with recurrent or metastatic SCCHN whose 
disease has progressed on platinum-containing regimens, treatment options are limited 
and median OS is less than 6 months.  Recently pembrolizumab and nivolumab, both
checkpoint inhibitors, have received accelerated approval from the FDA for patients who 
have had disease progression during or following platinum-containing chemotherapy for 
recurrent or metastatic cancer; however, median OS remains short at about 8 months.  
 
 


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3.3.3.2
Rationale for Urothelial Carcinoma
Advanced urothelial carcinoma is a disease of high unmet medical need with an overall 
5-year survival rate of 5%.  Chemotherapy with platinum-containing regimens remains 
the standard-of-care treatment for initial treatment of advanced disease, but median OS 
ranges from 9 to 15 months.  Recently, atezolizumab received accelerated approval 
from the FDA for patients who have had disease progression during or following 
platinum-containing chemotherapy for advanced urothelial carcinoma, but median OS 
remains short at approximately 8 months.  
 
 
 
 
3.3.3.3
Rationale for RCC
Metastatic RCC is a disease of high unmet medical need with the majority of patients 
receiving palliative systemic therapy and dying of their disease. Nivolumab is an 
antiPD-1 antibody that is approved by the FDA and the EMA for patients with 
metastatic RCC who have previously received one or two previous regimens of 
antiangiogenic therapy. 
 
 
 
3.3.4
Rationale for Allowing Patients to Continue Treatment until 
Loss of Clinical Benefit
In studies of immunotherapeutic agents, a CR, a PR, and stable disease have each 
been shown to occur after radiographic evidence of an apparent increase in tumor 
burden.  This initial increase in tumor burden caused by IC infiltration in the setting of a 
T-cell response has been termed pseudoprogression (Hales et al. 2010). 
 
 
 Because of the potential for a response after 
pseudoprogression, this study will allow all patients to continue treatment after apparent 
radiographic progression per RECIST v1.1, provided the benefitrisk ratio is judged to 
be favorable by the investigator (for the criteria, see Section 3.1.1).  Patients should be 
discontinued for unacceptable toxicity or symptomatic deterioration attributed to disease 
progression, as determined by the investigator, after an integrated assessment of 
radiographic and biochemical data, biopsy results (if available), and clinical status.


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3.3.5
Rationale for the Use of Immune-Modified RECIST
Increasing clinical experience indicates that traditional response criteria 
(e.g., RECIST v1.1 and World Health Organization criteria) may not adequately assess 
the activity of immunotherapeutic agents because initial radiographic evidence of 
disease progression does not necessarily reflect therapeutic failure.  Patients can 
experience a response in the presence of new lesions or after an increase in tumor 
burden.  Thus, this study will employ immune-modified RECIST for tumor assessments 
to account for the possible appearance of new lesions and allow radiographic 
progression to be confirmed at a subsequent assessment (see Appendix 4).  It is 
required that radiographic progression be confirmed at a subsequent tumor assessment 
to take into account the potential for pseudoprogression (caused by IC infiltration).  
Given the proposed immunomodulatory mechanism of action of atezolizumab and the 
possibility of observing delayed responses, use of immune-modified RECIST criteria will 
allow for the capture of a greater proportion of potential responses and allow patients to 
derive maximum clinical benefit.  
3.3.6
Rationale for Pharmacokinetic Sample Collection Schedule
The proposed PK sampling scheme for assessment of 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 (e.g., maximum 
and minimum concentrations [Cmax and Cmin]) of each compound.
 
 
 
 
 
  
The pharmacokinetics of each compound will be compared with single-agent data for 
each molecule from previous studies.  Plasma samples will be collected as outlined in 
Appendix 2.
 
 
 
  


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4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 20 patients in each cohort of advanced solid tumors will be enrolled in this 
study with a possibility of expanding to approximately 40 patients in each cohort.  
Approximately 12 patients are planned to be enrolled in Cohort 7.  The seven cohorts of 
patients are described in Section 2.
4.1.1
Inclusion Criteria
4.1.1.1
General Inclusion Criteria
Patients must meet the following general criteria for study entry:

Signed Informed Consent Form

Age 18 years

Ability to comply with the study protocol, in the investigator's judgment

ECOG performance status of 0 to 1 (see Appendix 5)

Life expectancy 3 months, as determined by the investigator

Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days prior to initiation of study treatment:
ANC 1.5109/L without granulocyte colony-stimulating factor support
Lymphocyte count 0.5109/L
Platelet count 100109/L without transfusion 


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Hemoglobin 90 g/L
–
Patients may be transfused to meet this criterion.
AST and ALT 2.5upper limit of normal (ULN), with the following exceptions:
–
Patients with documented liver metastases:  AST and ALT 5ULN
Serum bilirubin 1.5ULN with the following exception:
–
Patients with known Gilbert disease:  serum bilirubin level 3ULN
Serum creatinine 1.5 ULN or creatinine clearance 50 mL/min by 
Cockcroft-Gault equation or 24-hour urine collection
Serum albumin 2.5 g/dL
For patients not receiving therapeutic anticoagulation:  INR or 
aPTT 1.5 ULN
For patients receiving therapeutic anticoagulation:  stable anticoagulant 
regimen and INR 3.5
4.1.1.2
Cancer-Related Inclusion Criteria 
Patients must meet the following cancer-related criteria for study entry (for
cohort-specific inclusion criteria, see Section 4.1.3):

Patients must have measurable disease by CT or MRI scan per RECIST v1.1.

Availability to provide a representative tumor specimen biopsy:
Baseline tumor tissue samples will be collected from all patients, preferably by 
means of a biopsy performed at study entry.  For patients with SCCHN or 
RCC, histologic samples are required.  For patients with UC, cytological or 
histologic samples are acceptable.  Archival tumor tissue may be submitted after 
Medical Monitor approval has been obtained.
A formalin-fixed, paraffin-embedded tumor specimen in a paraffin block 
(preferred) or at least 15 slides (20 preferred) containing unstained, freshly cut, 
serial sections is recommended to be submitted along with an associated 
pathology report prior to study enrollment.  If a limited number of slides are 
available, the patient may still be eligible for the study, after discussion with and 
approval by the Medical Monitor.  

Evidence of tumor progression on or after the last treatment regimen received and 
within 6 months prior to study enrollment

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a non-hormonal contraceptive method with a 
failure rate of 1% per year during the treatment period and for at least 5 months 
after the last dose of atezolizumab and within 3 months after the last dose of 
cobimetinib. Women must refrain from donating eggs during this same period.
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).


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Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, and copper intrauterine devices.
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.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, 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 barrier method of contraception during the 
treatment period and for at least 3 months after the last dose of cobimetinib.  
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
4.1.2.1
General Exclusion Criteria
Patients who meet any of the following general exclusion criteria will be excluded from 
study entry:

Inability to swallow medications. Other means of intake may be allowed after 
Medical Monitor approval has been obtained.  

Malabsorption condition that would alter the absorption of orally administered 
medications

Poor peripheral venous access

Prior treatment with cobimetinib or a MEK inhibitor

For patients in Cohorts 1, 2, and 3 only: prior treatment with T-cell co-stimulating or
immune checkpoint blockade therapies, including antiCTLA-4, antiPD-1, and 
antiPD-L1 therapeutic antibodies 

Treatment with investigational therapy within 14 days prior to initiation of 
study treatment

Any anti-cancer therapy, including chemotherapy or hormonal therapy, within 
2 weeks prior to initiation of study treatment

History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins

Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster 
ovary cells 

Known allergy or hypersensitivity to any component of the atezolizumab formulation

Known allergy or hypersensitivity to any component of the cobimetinib formulation


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
Known allergy or hypersensitivity to any anti–PD-1/PD-L1 therapy

History of serous retinopathy, retinal vein occlusion (RVO), or evidence of ongoing 
serous retinopathy or RVO at baseline

Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of 
study treatment, or anticipation of need for a major surgical procedure during the 
study

Uncontrolled tumor-related pain
Patients requiring narcotic pain medication must be on a stable regimen at 
study entry.
Intractable pain with further growth (e.g., epidural metastasis that is not 
currently associated with spinal cord compression) should be considered for
loco-regional therapy if appropriate prior to enrollment.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated
drainage more than once every 28 days
Indwelling drainage catheters (e.g., PleurX®) are allowed.

Uncontrolled hypercalcemia (ionized calcium 1.5 mmol/L, calcium 12 mg/dL, or 
corrected calcium greater than the ULN) or symptomatic hypercalcemia requiring 
continued use of bisphosphonate therapy.
Patients who are receiving bisphosphonate therapy for other reasons 
(e.g., bone metastasis or osteoporosis) and who do not have a history of 
clinically significant hypercalcemia are eligible for the study.

Active or untreated CNS metastases
Patients with treated and asymptomatic CNS metastases are eligible, if they 
meet all of the following:
–
Evaluable or measurable disease outside the CNS
–
No metastases to midbrain, pons, medullar or within 10 mm of the optic 
nerves and chiasm
–
No history or evidence of intracranial hemorrhage or spinal cord 
hemorrhage
–
No evidence of clinically significant vasogenic edema
–
No corticosteroids for 2 weeks; anti-convulsant medications at a stable 
dose are allowed
–
No evidence of clinical and radiographic disease progression in the CNS 
for 3 weeks after radiotherapy or surgery

Pregnancy or breastfeeding, or intending to become pregnant during the study
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment.


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4.1.2.2
Exclusion Criteria based on Organ Function or Medical History
Cardiovascular
Patients who meet the following cardiovascular exclusion criterion will be excluded from 
study entry:

Left ventricular ejection fraction (LVEF) below the institutional lower limit of normal
or 50%, whichever is lower
Infections
Patients who meet any of the following infection exclusion criteria will be excluded from 
study entry:

Positive HIV test at screening

Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a 
positive hepatitis B surface antigen (HBsAg) test at screening
Patients with a past or resolved HBV infection, defined as having a negative 
HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at 
screening and negative HBV DNA, are eligible for the study.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody 
test followed by a positive HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive HCV 
antibody test.

Active tuberculosis

Severe infection within 4 weeks 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 2 weeks 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. 
4.1.2.3
Autoimmune Conditions and Immunomodulatory Drugs
Patients who meet any of the following exclusion criteria for autoimmune conditions and 
immunomodulatory drugs will be excluded from study entry:

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 6 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.


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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
–
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
–
Disease is well controlled at baseline and only requiring low-potency 
steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, 
flucinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)

Prior allogeneic stem cell or solid organ transplantation

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 CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
4.1.2.4
Exclusions Related to Other Medical Conditions or Medications
Patients who meet any of the following exclusion criteria related to other medical 
conditions or medications will be excluded from study entry:

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect 
the interpretation of the results, or may render the patient at high risk from treatment 
complications

Other active malignancy or a prior malignancy within the past 3 years outside of the 
primary cancer being studied in this study
Patients with completely resected basal cell carcinoma, cutaneous squamous cell 
carcinoma, cervical carcinoma in-situ, breast carcinoma in-situ, and patients with 
isolated elevation in prostate-specific antigen in the absence of radiographic 
evidence of metastatic prostate cancer are eligible for the study.

Any Grade3 hemorrhage or bleeding event within 28 days of Day 1 of Cycle 1

History of stroke, reversible ischemic neurological defect, or transient ischemic 
attack within 6 months prior to Day 1 of Cycle 1


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4.1.3
Cohort-Specific Inclusion and Exclusion Criteria
4.1.3.1
SCCHN Cohorts
Inclusion Criteria for SCCHN Cohort 1 (AntiPD-1/PD-L1 Treatment-Naive 
Patients):
Patients in SCCHN Cohort 1 must meet the following criteria for study entry:

Patients must have histologically confirmed recurrent or metastatic SCCHN (oral 
cavity, pharynx, larynx), Stage III/IV, and are not amenable to local therapy with 
curative intent (surgery or radiation, with or without chemotherapy).

Patients must have received at least one platinum-containing therapy in the 
recurrent or metastatic setting and up to a total of two lines of chemotherapy 
(including the required platinum-based regimen), in the recurrent or metastatic 
SCCHN.

Patients are also eligible if they had recurrence or progression within 6 months of 
the last dose of platinum-containing therapy in the adjuvant (i.e., with radiation after 
surgery) or primary (i.e., with radiation) setting.
Inclusion Criteria for SCCHN Cohort 4 (Progression while on Anti–PD-1/PD-
L1 Therapy)

Patients in SCCHN Cohort 4 must meet the following criteria for study entry:

Patients must have histologically confirmed recurrent or metastatic SCCHN (oral 
cavity, pharynx, larynx), Stage III/IV, and are not amenable to local therapy with 
curative intent (surgery or radiation, with or without chemotherapy).

Progressed on prior anti–PD-1/PD-L1 therapy in the recurrent or metastatic setting
Patients are also eligible if they had disease progression on or within 6 months 
of the last dose of antiPD-1/PD-L1 therapy in the adjuvant setting 

Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies,
and combinations, including antiCTLA-4, antiPD-1/PD-L1 therapeutic antibodies 
are allowed
Exclusion Criteria for SCCHN Cohorts 1 and 4:
Patients in the SCCHN cohorts who meet the following exclusion criterion will be 
excluded from study entry:
Histologically confirmed recurrent or metastatic carcinoma of the nasopharynx and 
salivary gland or of non-squamous histologies (e.g., mucosal melanoma) 
4.1.3.2
UC Cohorts
Inclusion Criteria for UC Cohort 2 (AntiPD-L1/PD-1 Treatment-Naive 
Patients):
Patients in UC Cohort 2 must meet the following criteria for study entry:

Histologically or cytologically documented locally advanced (T4b, any N; or any T, 
N2N3) or metastatic (M1, Stage IV) urothelial bladder cancer (also termed 
transitional cell carcinoma, urothelial carcinoma, or carcinoma the urinary tract; 
including renal pelvis, ureters, urinary bladder, and urethra)


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Patients with mixed histologies are required to have a dominant transitional cell 
pattern.

Locally advanced bladder cancer must be inoperable on the basis of involvement of 
pelvic sidewall or adjacent viscera (clinical stage T4b) or bulky nodal metastasis 
(N2N3)
Transurethral resection for bladder tumor (TURBT) specimens must contain a 
muscle-invasive component (i.e., T2 or greater) or the bladder tumor as verified 
by local pathology review.  If the TURBT specimens do not contain a 
muscle-invasive component, then specimens obtained at the time of 
cystectomy, nephroureterectomy, or metastatic spread (i.e., a sample from a 
metastatic lesion) will be required prior to enrollment.  

Disease progression during or following treatment with at least one 
platinum-containing regimen for inoperable, locally advanced or metastatic urothelial 
bladder cancer or disease recurrence
Patients who received prior adjuvant/neoadjuvant chemotherapy and 
progressed within 12 months of treatment with a platinum-containing adjuvant
or neoadjuvant regimen are eligible.
Patients may have received at least one prior regimen but no more than two
prior regimens of treatment (including the required platinum-based regimen) for
advanced urothelial bladder cancer.
Patients who have received one cycle of a platinum-containing regimen but 
discontinued because intolerable toxicity may also be eligible.
Patients with disease progression following chemoradiotherapy must 
demonstrate progression outside the prior radiotherapy port.
Inclusion Criteria for UC Cohort 5 (Progression while on
Anti–PD-1/PD-L1 Therapy):

Patients in UC Cohort 5 must meet the following criteria for study entry:

Histologically or cytologically documented locally advanced (T4b, any N; or any T, 
N2N3) or metastatic (M1, Stage IV) urothelial bladder cancer (also termed 
transitional cell carcinoma, urothelial carcinoma, or carcinoma the urinary tract; 
including renal pelvis, ureters, urinary bladder, and urethra)
Patients with mixed histologies are required to have a dominant transitional cell 
pattern.

Locally advanced bladder cancer must be inoperable on the basis of involvement of 
pelvic sidewall or adjacent viscera (clinical stage T4b) or bulky nodal metastasis 
(N2N3)
Transurethral resection for bladder tumor (TURBT) specimens must contain a 
muscle-invasive component (i.e., T2 or greater) or the bladder tumor as verified 
by local pathology review.  If the TURBT specimens do not contain a 
muscle-invasive component, then specimens obtained at the time of 
cystectomy, nephroureterectomy, or metastatic spread (i.e., a sample from a 
metastatic lesion) will be required prior to enrollment.  


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
Disease progression during or following treatment with at least one 
platinum-containing regimen for inoperable, locally advanced or metastatic urothelial 
bladder cancer or disease recurrence
Patients who received prior adjuvant/neoadjuvant chemotherapy and 
progressed within 12 months of treatment with a platinum-containing adjuvant 
or neoadjuvant regimen are eligible.
Patients who have received one cycle of a platinum-containing regimen but 
discontinued because intolerable toxicity may also be eligible.
Patients with disease progression following chemoradiotherapy must 
demonstrate progression outside the prior radiotherapy port.

Progression while on a prior anti–PD-1/PD-L1 therapy in the recurrent or metastatic 
setting
Patients are also eligible if they had disease progression on or within 6 months 
of the last dose of anti–PD-1/PD-L1 therapy in the adjuvant setting

Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies,
and combinations including anti–CTLA-4, anti–PD-1/PD-L1 therapeutic antibodies 
are allowed

Patients are eligible if they received no more than three lines of therapy in the 
advanced, metastatic setting
4.1.3.3
RCC Cohorts
Inclusion Criteria for RCC Cohort 3 (AntiPD-1/PD-L1 Treatment-Naive 
Patients):
Patients in RCC Cohort 3 must meet the following criteria for study entry:

Histological confirmation of advanced or metastatic RCC with a clear-cell 
component

Prior cytokine therapy (e.g., IL-2, IFN-), vaccine therapy, or treatment with 
cytotoxic agents is allowed.  

Patients must have received at least one but no more than two total prior systemic 
treatment regimens in the advanced or metastatic setting.
Inclusion Criteria for RCC Cohort 6 (Progression while on AntiPD-1/PD-L1
Therapy):

Patients in RCC Cohort 6 must meet the following criteria for study entry:

Histological confirmation of advanced or metastatic RCC with a clear-cell 
component

Prior cytokine therapy (e.g., IL-2, IFN-), vaccine therapy, or treatment with 
cytotoxic agents is allowed.  

Progressed while on prior antiPD-1/PD-L1 therapy in the recurrent or metastatic 
setting
Patients are also eligible if they had disease progression on or within 6 months 
of the last dose of anti–PD-1/PD-L1 therapy in the adjuvant setting.


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
Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies,
and combinations including anti–CTLA-4, anti–PD-1/PD-L1 therapeutic antibodies 
are allowed.

Patients are eligible if they received no more than three lines of therapy in the 
advanced/metastatic setting.
4.1.3.4
Biopsy Cohort 7

Patients must have histologically confirmed non-melanoma, non-hematologic solid 
tumor.

Patients must have metastatic or locally advanced disease that is not amenable to 
local treatment with curative intent.

Measurable disease according to RECIST v1.1

Patients in this cohort must have received a minimum of two cycles of anti–PD-1 or 
anti–PD-L1 therapy.

Patients in this cohort must have progressed during or after anti–PD-1 or anti–PD-
L1 therapy within 12 weeks before study start.

Patients in this cohort must meet criteria for primary or secondary resistance to an 
anti–PD-1 or anti–PD-L1 agent as outlined below:
Primary resistance is defined as progressive disease, according to RECIST 
v1.1, as best response
Secondary resistance is defined as progressive disease after initial confirmed 
response according to RECIST v1.1

Patients in this cohort must have received anti–PD-1 or anti–PD-L1 therapy as the 
most recent treatment.

Patients in this cohort must consent to undergo tumor biopsies of accessible lesions 
before and during treatment for biomarker analyses.

Patients in this cohort must have at least two accessible lesions that are amenable 
to excisional or core-needle biopsy with acceptable risk of a major procedural 
complication. Exceptions may be made following discussion with Medical Monitor. 
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label trial. After written informed consent has been obtained and 
eligibility has been established, each patient will be assigned an identification number 
and be enrolled to the appropriate cohort through use of an interactive voice or
Web-based response system (IxRS).
4.3
STUDY TREATMENT 
The investigational medicinal products (IMPs) for this study are cobimetinib and 
atezolizumab.


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4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Cobimetinib
Cobimetinib will be supplied as 20-mg, film-coated tablets packaged in blister packs 
(21 tablets per pack; 3 packs per box) for oral administration.  
For information on the formulation and handling of cobimetinib, see the Cobimetinib 
Investigator's Brochure and pharmacy manual. 
4.3.1.2
Atezolizumab
Atezolizumab will be supplied as sterile liquid in single-use, 20-mL glass vials.  The vial 
is designed to deliver 20 mL (1200 mg) of atezolizumab solution, but it may contain more 
than the stated volume to enable delivery of the entire 20-mL volume. Administration of 
14 mL of atezolizumab solution from a 1200-mg vial contains an 840-mg dose.
For information on the formulation and handling of atezolizumab, refer to the 
Atezolizumab Investigator's Brochure and pharmacy manual.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Cobimetinib
Patients will receive cobimetinib 60 mg (3 tablets of 20 mg each) orally QD on 
Days 121 of each 28-day cycle in all cohorts.  This 4-week period is considered a 
treatment cycle.
Cobimetinib should be taken at the same time every 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, 
patients may resume dosing with the next scheduled dose.
Guidelines for dosage modification and treatment interruption or discontinuation of 
cobimetinib are provided in Section 5.1.3.1.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of overdose, medication error, drug abuse, or drug 
misuse, along with any associated adverse events, should be reported as described in 
Section 5.4.4.  
4.3.2.2
Atezolizumab
Atezolizumab will be given at a fixed dose of 840 mg by IV infusion on Days 1 and 15 of 
each 28-day cycle.  A 28-day period is considered a treatment cycle.
Patients in the biopsy cohort, Cohort 7, will receive the first dose of atezolizumab of 840 
mg by IV infusions on Day 15 of Cycle 1. Thereafter, they will receive atezolizumab 840 
mg IV infusion Q2W on Days 1 and 15 of Cycle 2 and all subsequent cycles. 
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 


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manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 7.  
Atezolizumab infusions will be administered per the instructions outlined in Table 3.
Table 3
Administration of First and Subsequent Atezolizumab Infusions
First Infusion
Subsequent Infusions
Premedication is not allowed.
If patient experienced IRR during any previous 
infusion, pre-medication with antihistamines, 
antipyretics, and/or analgesics may be 
administered for subsequent doses at the 
discretion of the treating physician.
Record vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) within 
60 minutes before starting infusion.
Record patient's vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before starting 
infusion.
Infuse atezolizumab (one vial in 250 mL of
NaCl) over 60 (15) minutes.
If the patient tolerated the first infusion well 
without infusion-associated adverse events, the 
second infusion may be delivered over 
30 (10) minutes.
Record vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) during the 
infusion or after the infusion if clinically 
indicated.
If the patient had an IRR during the previous 
infusion, the subsequent infusion must be 
delivered over 60 (15) minutes.
Patients will be informed about the possibility of 
delayed post-infusion symptoms and instructed 
to contact their study physician if they develop 
such symptoms.
Record patient's vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) during the infusion or after the 
infusion if clinically indicated or if the patient 
experienced symptoms during the previous 
infusion.
If no reaction occurs, continue subsequent 
infusions over 30 (10) minutes using the
same schedule for recording vital signs.
IRRinfusion-related reaction; NaClsodium chloride. 
Dose modifications to atezolizumab are not permitted.  Guidelines for treatment 
interruption of atezolizumab are provided in Section 5.1.3.3, and the management of 
specific adverse events associated with cobimetinib and atezolizumab are provided in 
Section 5.1.3.4. For information regarding management of atezolizumab-associated 
adverse events, refer to Appendix 8.
For anaphylaxis precautions, see Appendix 7. 
See the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 
with any associated adverse events, should be reported as described in Section 5.4.4.  


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4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (cobimetinib and atezolizumab) will be 
provided by the Sponsor where required by local health authority regulations.  The study 
site will acknowledge receipt of IMPs, using the IxRS to confirm the shipment condition 
and content.  Any damaged shipments will be replaced.
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.
4.3.4
Post-Trial Access to Cobimetinib and Atezolizumab
The Sponsor will offer post-trial access to the study drug cobimetinib 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 study drug after completing the study if all of the 
following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being.

There are no appropriate alternative treatments available to the patient.

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them.
A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met:

The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or 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 the particular solid tumor depending on the cohort.

The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for the particular solid tumor, depending on the cohort.

Provision of study drug is not permitted under the laws and regulations of the 
patient's country.


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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
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to initiation of study drug to the study completion or
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:

Hormonal therapy with gonadotropin-releasing hormone agonists for prostate 
cancer

Oral contraceptives

Hormone-replacement therapy

Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin).  However, caution should be used in 
patients on anticoagulation therapy because of the risk of hemorrhage events with 
cobimetinib.

Inactivated influenza vaccinations

Megestrol administered as an appetite stimulant 

Mineralocorticoids (e.g., fludrocortisone)

Corticosteroids administered for chronic obstructive pulmonary disease or asthma

Low-dose corticosteroids administered for orthostatic hypotension or 
adrenocortical insufficiency

Palliative radiotherapy (e.g., treatment of known bone metastases or symptomatic
relief of pain) as outlined below:
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of the tumor target lesions.  


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
Radiotherapy to the brain as outlined below:
Patients whose extracranial tumor burden is stable or responding to study 
treatment and who are subsequently found to have three or fewer brain 
metastases may receive radiotherapy to the brain (either stereotactic 
radiosurgery or whole-brain radiation therapy) provided that all of the following 
criteria are met:
–
The patient has no evidence of progression or hemorrhage after 
completion of CNS-directed therapy.
–
The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease.
Patients who require corticosteroid therapy for more than 7 days after 
completion of radiotherapy must be discontinued from study treatment.
–
Anti-convulsant therapy, if required, is administered at a stable dose.
Premedication with antihistamines, antipyretic medications, and/or analgesics may be 
administered for the second and subsequent atezolizumab infusions only, at the 
discretion of the investigator.  Anti-emetic and anti-diarrheal medications should not be 
administered prophylactically before initial treatment with study drugs. At the discretion 
of the investigator, prophylactic anti-emetic and anti-diarrheal medication(s) may be 
used per standard clinical practice before subsequent doses of study drugs. 
Hematopoietic growth factors should not be administered prophylactically before initial 
treatment with study drugs. Hematopoietic growth factors may be administered 
according to local guidelines if indicated during the study. 
In general, investigators should manage a patient's 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 7).
4.4.2
Cautionary and Prohibited Therapy
4.4.2.1
Corticosteroids and Tumor Necrosis FactorAlpha Inhibitors
Systemic corticosteroids and tumor necrosis factoralpha (TNF-) inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab.  
Therefore, in situations in which systemic corticosteroids or TNF-inhibitors would be 
routinely administered, alternatives, including antihistamines, should be considered.  If 
the alternatives are not feasible, systemic corticosteroids and TNF-inhibitors may be 
administered at the discretion of the investigator.


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Systemic corticosteroids are recommended, at the discretion of the investigator, for the 
treatment of specific adverse events when associated with atezolizumab therapy (refer 
to the guidelines in Appendix 8 for details).
4.4.2.2
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes
Concomitant use of strong and moderate inhibitors of CYP3A (e.g., clarithromycin, 
itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole) should be 
used with caution during cobimetinib treatment because cobimetinib is a sensitive 
substrate of CYP3A and exposures will be increased in presence of these agents 
(approximately 7-fold increase in presence of itraconazole in healthy subjects).
Strong and moderate CYP3A inducers (e.g., rifampin, phenytoin, carbamazepine, and 
phenobarbital) should be avoided during cobimetinib treatment because they increase 
the metabolism of cobimetinib.  Strong inducers of CYP3A4 should be avoided, or 
selection of an alternate concomitant medicinal product with no or minimal potential to 
induce CYP3A4 should be considered.
The above lists of cautionary medications are not necessarily comprehensive.  The 
investigator should consult the prescribing information when determining whether a 
concomitant medication can be safely administered with study treatment.  In addition, 
the investigator should contact the Medical Monitor if questions arise regarding 
medications not listed above.
4.4.2.3
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below:

Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited during 
study treatment until disease progression is documented and the patient has 
discontinued study treatment, with the exception of palliative radiotherapy and 
radiotherapy to the brain.

Investigational therapy (other than protocol-mandated study treatment) is prohibited
during study treatment.

Treatment with live, attenuated vaccines (e.g., FluMist) are prohibited within 
4 weeks prior to initiation of study treatment, during treatment with atezolizumab, 
and for 5 months after the last dose of atezolizumab

Systemic immunostimulatory agents (including, but not limited to, interferons and 
IL-2) are prohibited within 4 weeks or 5 half-lives of the drug, whichever is longer, 
prior to initiation of study treatment and during study treatment because these 
agents could potentially increase the risk for autoimmune conditions when given in 
combination with atezolizumab.


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
Systemic immunosuppressive medications (including, but not limited to, prednisone, 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents) 
are prohibited within 2 weeks of Cycle 1, Day 1 and during study treatment because 
these agents could potentially alter the efficacy and safety of atezolizumab.

Systemic corticosteroids may not be administered as premedication to patients with 
an allergy to contrast agents used for tumor scans (see Appendix 3 for information 
on tumor scans for patients with contrast allergies).
4.4.2.4
Prohibited Food and Herbal Supplements
Consumption of potent CYP3A4 enzyme inhibitors such as grapefruit juice and potent 
CYP3A4 enzyme inducers such as St. John's wort are prohibited starting 7 days prior to 
Day 1 of Cycle 1, during the study, and for 30 days after the last dose of study treatment.
4.5
STUDY ASSESSMENTS 
Refer to Appendix 1 for the schedule of activities to be performed during the study.  All 
activities must be performed and documented for each patient.  Patients will be closely 
monitored for safety and tolerability throughout the study.  Patients should be assessed 
for toxicity prior to each dose; dosing will occur only if the clinical assessment and local 
laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment. The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, prior surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history,
use of alcohol, and drugs of abuse.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 7 days prior to initiation of study treatment will 
be recorded.  At the time of each follow-up physical examination, an interval medical 
history should be obtained and any changes in medications and allergies should be 
recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.  Baseline 
disease characteristics data will include ECOG performance status, date of diagnosis of 
first metastatic disease, site of primary disease, RAS status, history of metastectomy, 
and location of metastasis at enrollment.


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4.5.3
Physical Examinations
A complete physical examination should be performed at screening and at treatment 
discontinuation and should include an evaluation of the head, eyes, ears, nose, and 
throat, 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.
In addition, patients will be asked specifically about vision-related changes as part of 
each physical examination in addition to interval medical history.  (Note:  If physical 
examinations are performed within 7 days of Day 1, Cycle 1, they do not have to be 
repeated on Day 1 of Cycle 1.)
4.5.4
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, and blood pressure
while the patient is in a seated position (after a 5-minute rest period), and temperature
(measured in degrees Centigrade).
Vital signs will be measured and recorded at the timepoints outlined in the schedule of 
activities (see Appendix 1).
For patients who experienced an infusion-related reaction (IRR) during the previous 
atezolizumab infusion, refer to Section 4.3.2.2.
4.5.5
Tumor and Response Evaluations 
All measurable and non-measurable lesions must be documented at screening (within 
28 days prior to initiation of study treatment) and re-assessed at each subsequent tumor 
evaluation. Response will be assessed by the investigator based on CT or MRI scans, 
using RECIST v1.1, and immune-modified RECIST (see Appendix 3 and Appendix 4).  
An objective response should be confirmed by repeat assessments 4 weeks after initial 
documentation. The same radiographic procedure used to assess disease sites at 
screening should be used throughout the study (e.g., the same contrast protocol for CT 
scans).  Assessments should be performed by the same evaluator to ensure internal 
consistency across visits.
Radiographic scans should include chest, abdomen, and pelvic scans; radiographic
scans of the head and/or neck should be included in the SCCHN cohort or if clinically 
indicated.  At the investigator's discretion, CT scans may be repeated at any time if 
progressive disease is suspected.


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It is possible that the CT and MRI scans might be collected, sent to and reviewed by an 
independent review committee for response assessments.
4.5.6
Laboratory, Biomarker, and Other Biologic Samples
4.5.6.1
Screening (Local Laboratory)
Samples for the following laboratory tests during screening will be sent to the study site's 
local laboratory for analysis:

Hematology: WBC count, RBC count, CBC, hemoglobin, hematocrit, count with 
differential (neutrophils, eosinophils, basophils, monocytes, and lymphocytes)

Serum chemistry panel:  glucose, BUN or urea, creatinine, sodium, potassium, 
magnesium, calcium, phosphorus, total bilirubin, ALT, AST, ALP, CPK, albumin, and 
others per the schedule of activities (see Appendix 1)

Coagulation (INR and aPTT)

Urinalysis (includes dipstick [pH, specific gravity, glucose, protein, ketones, and 
blood] and microscopic examination [sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, and bacteria])

Serum pregnancy test for women of childbearing potential, including women who 
have had a tubal ligation
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (defined as 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone permanent surgical sterilization (removal of bilateral ovaries and/or 
uterus).

Thyroid-function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) (or 
total T3 for sites where free T3 is not performed), and free thyroxine (also known as 
T4)

HBV serology:  HBsAg, antibodies against HBsAg, anti-HBcAb
HBV DNA should be obtained prior to enrollment if patient has a negative 
serology for HBsAg and a positive serology for anti-HBcAb.

HCV serology:  HCV antibody (anti-HCV)
HCV RNA should be obtained prior to enrollment if patient tests positive for 
anti-HCV.

HIV testing
All patients will be tested for HIV prior to the inclusion into the study and 
HIV-positive patients will be excluded from the study.
4.5.6.2
Treatment (Local Laboratory)
Samples for the following laboratory tests during treatment will be sent to the study site's 
local laboratory for analysis:

Hematology: WBC count, RBC count, CBC, hemoglobin, hematocrit, count with 
differential (neutrophils, eosinophils, basophils, monocytes, and lymphocytes)


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
Serum chemistry panel: glucose, BUN or urea, creatinine, sodium, potassium, 
magnesium, calcium, phosphorus, total bilirubin, ALT, AST, ALP, CPK, and others 
according to the schedule of activities (see Appendix 1)

Urine pregnancy test for women of childbearing potential 

Thyroid function test
4.5.6.3
Central Laboratory Assessments
A central laboratory will coordinate the sample collection of tissue and blood samples for 
research-related testing at central laboratories. Instruction manuals and supply kits will 
be provided for all central laboratory assessments. Serum samples collected for PK and 
immunogenicity (anti-drug antibody [ADA]) analysis may be needed for additional PK 
and ADA assay development and validation, and additional immunogenicity 
characterization; therefore, these samples will be destroyed no later than 5 years after 
the final Clinical Study Report has been completed.  The schedule for sampling is 
presented in Appendix 2.
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.

Blood sample for DNA extraction to enable analysis via next-generation sequencing 
(NGS) and/or optional whole genome sequencing (WGS)

Tumor tissue sample collected during the study for exploratory research on 
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NGS may be performed by Foundation Medicine.  If performed by Foundation Medicine, 
the investigator can obtain results from the samples collected at the time of disease 
progression in the form of an NGS report, which is available upon request directly from 
Foundation Medicine.  The investigator may share and discuss the results with the 
patient, unless the patient chooses otherwise.  The Foundation Medicine NGS assay 
has not been cleared or approved by health authorities.  The NGS report is generated 
for research purposes and is not provided for the purpose of guiding future treatment 
decisions.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Biological samples will be destroyed when the final Clinical Study Report has been 
completed, with the following exceptions:

Plasma and serum samples collected for PK analysis and/or immunogenicity 
analysis will be destroyed no later than 5 years after the final Clinical Study Report
has been completed.

Optional blood samples collected for WGS will be stored until they are no longer 
needed or until they are exhausted.

Blood, plasma, peripheral blood mononuclear cell, urine, and tumor tissue samples 
collected for biomarker research will 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.
4.5.7
Samples for Optional Whole Genome Sequencing 
At participating sites, blood samples will be collected for DNA extraction to enable WGS
 
 
  The blood samples may be sent to one or more 
laboratories for analysis.
Collection and submission of WGS samples is contingent upon the review and approval 
of the exploratory research by each site's Institutional Review Board or Ethics 
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been granted approval for WGS sampling, this section of the protocol (Section 4.5.7) will 
not be applicable at that site.
Genomics is increasingly informing researchers' understanding of disease pathobiology. 
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
Blood samples collected for WGS are to be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
Patient medical information associated with WGS 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 WGS analyses, data derived from
these analyses will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
4.5.8
Left Ventricular Ejection Fraction
For patients receiving cobimetinib, evaluations of LVEF are required.
Evaluation of LVEF by ECHO or MUGA scan must be performed at the following 
timepoints: 

Screening 

Day 1 of Cycle 2 (1 week)

At least every 3 months or as clinically indicated

Treatment discontinuation visit
The treatment discontinuation visit 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.


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
After restarting treatment with a dose reduction of cobimetinib
All patients restarting treatment with a dose reduction of cobimetinib because of 
a decrease in LVEF should have LVEF measurements taken after 
approximately 2 weeks, 4 weeks, 10 weeks, and 16 weeks, and then resume
monitoring of LVEF every three treatment cycles.
Any patient who develops clinical signs or symptoms suspicious of cardiac failure should 
undergo an LVEF assessment.  Evaluation of LVEF must be performed using the same 
method (ECHO or MUGA scan) for each patient.  It is strongly encouraged that the same 
laboratory and operator perform each ECHO or MUGA scan for each individual patient.  
Investigators must be aware of local institution regulations regarding repeat MUGA 
scans. 
4.5.9
Ophthalmologic Examinations
Patients receiving cobimetinib are required to undergo ophthalmologic examinations
because of the risk of serous retinopathy.
An ophthalmologic examination must be performed at the following timepoints:

Screening

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)

Day 1 of Cycles 29, 35, 41, 47, and so on (every six treatment cycles; 2 weeks)

Treatment discontinuation visit
The treatment discontinuation visit evaluation does not need to be performed if 
an evaluation has been performed within the last 12 weeks and there are no 
clinically significant findings and/or changes from baseline.
The objective of baseline ophthalmologic examination is to evaluate for evidence of 
retinal pathology. Ophthalmologic examination must be performed by a qualified 
optometrist or ophthalmologist. 
Baseline and serial surveillance ophthalmologic examination will include visual acuity
testing, intraocular pressure measurements by tonometry, slit-lamp ophthalmoscopy, 
indirect ophthalmoscopy, and spectraldomain optical coherence tomography.  
Spectral-domain optical coherence tomography, if not available, may be substituted with 
time-domain optical coherence tomography.


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4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Disease progression (see Section 3.1.1 for dosing beyond progression)

Symptomatic deterioration attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results, and 
clinical status

Intolerable toxicity related to any study drug

Any medical condition that may jeopardize the patient's safety if he or she continues 
study treatment

Use of another nonprotocol-specified anti-cancer therapy 

Pregnancy
Patients must provide written consent to acknowledge deferring any standard treatment 
options that may exist in favor of continuing treatment at the time of initial progression.
The primary reason for study drug discontinuation should be documented on the 
appropriate eCRF and patients will remain in the study for safety follow-up.
Patients who discontinue study treatment prematurely will not be replaced.
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

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
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.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced.
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status.


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4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
The safety plan is based on results from nonclinical studies, completed and ongoing 
clinical studies, and published data on similar molecules.  Refer to the Atezolizumab 
Investigator's Brochure for a complete summary of atezolizumab safety information.
Cobimetinib (for use with vemurafenib) is approved in the United States and European 
Union as well as other countries for the treatment of metastatic melanoma.  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.  Refer to the Cobimetinib 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.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Patients will undergo 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.  There are separate 
guidelines for the two different study drugs as the toxicities and management guidelines 
are distinct for the two different drugs.  Refer to the specific guidelines for each drug
individually.


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5.1
SAFETY PLAN
The risks associated with cobimetinib and atezolizumab are detailed in Sections 5.1.1
and 5.1.2, respectively.
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.  Administration of atezolizumab will be performed in a 
monitored setting in which there is immediate access to trained personnel and adequate 
equipment and medicine to manage potentially serious reactions.  Adverse events will 
be reported as described in Sections 5.2 5.6.  
5.1.1
Risks Associated with Cobimetinib
Information related to risks attributed to cobimetinib is based on safety data from 
Studies GO28141 and NO25395 (cobimetinib and vemurafenib) and Study MEK4592g 
(cobimetinib monotherapy). For additional information regarding clinical safety, refer to 
the current Cobimetinib Investigator's Brochure.
5.1.1.1
Important Identified Risks Associated with Cobimetinib
5.1.1.1.1
Hemorrhage
Hemorrhage, including major hemorrhages, 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 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 and 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 brain 
metastases, and/or in patients that use concomitant medications that increase the risk of 
bleeding (including antiplatelet or anticoagulant therapy).
Instructions for dose modification for hemorrhagic events are included in Section 5.1.3.4.
5.1.1.1.2
Serous Retinopathy
Serous retinopathy (fluid accumulation within the layers of the retina) is an identified risk 
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.


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Serous retinopathy has been characterized in Study GO28141. The study incorporated 
prospective serial ophthalmologic examinations for all enrolled patients.  Serous 
retinopathy was reported more frequently in patients treated with cobimetinib plus 
vemurafenib than placebo plus vemurafenib (25.5% vs. 2.8%, respectively), and 
approximately half of the events were asymptomatic Grade 1 events. Few patients 
treated 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 ophthalmologic examination to assess for history or evidence of 
retinal pathology that is considered to be a risk factor for or indicative of neurosensory 
retinal detachment, central serous chorioretinopathy, neovascular retinopathy, or 
retinopathy of prematurity.  Patients will also undergo ophthalmologic examinations at 
specified timepoints throughout the study (see Section 4.5.9 and Appendix 1). Details 
regarding baseline and subsequent ophthalmologic 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 5.1.3.
5.1.1.1.3
Left Ventricular Dysfunction
Decreases in LVEF from baseline have been reported in patients receiving cobimetinib. 
Left ventricular dysfunction may occur with signs and symptoms of cardiac failure, or 
reduction in LVEF may be asymptomatic.
Left ventricular dysfunction has been characterized in Study GO28141. The study 
incorporated prospective serial LVEF evaluations in all patients. With active surveillance, 
measured reductions in LVEF 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 decreased LVEF).  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 treated 
with cobimetinib plus vemurafenib improved or resolved with management according to 
dose modification guidelines (see Section 5.1.3). 
5.1.1.1.4
Rhabdomyolysis and Creatine Phosphokinase Elevations
Elevations in CPK have been observed in patients who received cobimetinib 
monotherapy as well as when administered with other agents. Most CPK elevations 
reported were asymptomatic and 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 the 
postmarketing experience.


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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, no patients with 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 5.1.3.
5.1.1.1.5
Pneumonitis
Events of pneumonitis have been reported in cobimetinib clinical studies. Most reported 
events were considered to be non-serious and of low severity grade. In Study GO28141, 
pneumonitis events were reported more frequently in patients treated with cobimetinib 
plus vemurafenib than placebo plus 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 plus vemurafenib.
5.1.1.2
Potential Risks Associated with Cobimetinib
5.1.1.2.1
Liver Laboratory Abnormalities and Severe Hepatotoxicity
Liver laboratory test abnormalities, including increases in ALT, AST, and ALP, 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).
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.
5.1.1.2.2
Impaired Female Fertility 
There is a potential for effects on fertility based on results from nonclinical studies. 
Although no dedicated fertility studies have been conducted with cobimetinib in animals, 
degenerative changes observed in reproductive tissues included increased apoptosis
and 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 treatment.
5.1.1.2.3
Teratogenicity and Developmental 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.


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5.1.1.3
Other Risks with Cobimetinib
5.1.1.3.1
Rash
In 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 (71.7% vs. 66.7%, respectively), although Grade 3 events (reported in 
approximately 16% of patients) and types of rash reported were similar between study 
arms. Specific events in patients treated with cobimetinib plus vemurafenib included 
rash (39% all grade events, 5.9% Grade3 events, and 1.6% serious adverse events) 
and maculopapular rash (14.6% all grade events, 6.3% Grade3 events, and 1.2% 
serious adverse events).
Generally, Grade 3 rash events were effectively managed with dose modification. In 
Study GO28141, approximately 90% of Grade3 rash events resolved in both arms.
5.1.1.3.2
Gastrointestinal Toxicity
A range of gastrointestinal adverse events, including nausea, vomiting, and diarrhea, 
have been reported in all cobimetinib studies in adult patients with cancer.
In Study GO28141, diarrhea was the most common adverse event reported.  Diarrhea 
events of all severity grades were reported in 59.9% of patients, and Grade 3 or 4 events 
were reported in 6.5% of patients treated with cobimetinib plus vemurafenib versus 30.9% 
and 0.8% in the patients treated with placebo plus vemurafenib. No Grade 5 events of 
diarrhea have been reported. Serious adverse events of diarrhea were reported for 1.2% 
of patients treated with cobimetinib plus vemurafenib.
Nausea and vomiting have been reported in association with cobimetinib. Most nausea 
and vomiting events were considered to be non-serious and of low severity grade. In 
Study GO28141, nausea and vomiting events were reported more frequently in the 
active cobimetinib arm than the control arm (nausea, 41.3% vs. 25.2%; vomiting, 24.3% 
vs. 12.6%).  However, of the patients treated with cobimetinib plus vemurafenib, few 
experienced Grade 3 events (nausea, 0.8%; vomiting, 1.2%).
In the Phase I single-agent study (MEK4592g), all grades of nausea and vomiting were 
both reported as 33.9%, with 0.9% reported for Grade 3 nausea events and none were 
reported for vomiting.
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 anti-diarrheal agents and supportive care. Routine anti-emetic 
prophylaxis is not recommended. 


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5.1.1.3.3
Hypersensitivity
There have been few reports of hypersensitivity and/or anaphylaxis in clinical trials with 
patients who have been exposed to cobimetinib monotherapy or cobimetinib when used 
with other agents. These have appeared to be isolated reports, and in some cases, 
occurred in patients with history of drug allergies.  Thus, the relationship of cobimetinib 
to these events is unclear.
In Study GO28141, Grade 3 hypersensitivity events were reported for 3 patients in the 
cobimetinib plus 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 Atezolizumab
Atezolizumab has been associated with risks such as IRRs and immune-related hepatitis, 
pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism,
adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, meningoencephalitis, myocarditis, and nephritis.  In addition, 
systemic immune activation is a potential risk associated with atezolizumab.  Refer to 
Section 6 of the Atezolizumab Investigator's Brochure for a detailed description of 
anticipated safety risks for atezolizumab.
Systemic immune activation is a rare condition characterized by an excessive immune 
response.  Given the mechanism of action of atezolizumab, systemic immune activation 
is a potential risk when administered in combination with other immunomodulating 
agents.  Systemic immune activation should be included in the differential diagnosis for 
patients who, in the absence of an alternative etiology, develop a sepsis-like syndrome 
after administration of atezolizumab, and the initial evaluation should include the 
following:

CBC with peripheral smear

PT, PTT, fibrinogen, and D-dimer

Ferritin

Triglycerides

AST, ALT, and total bilirubin

LDH

Complete neurologic and abdominal examination (assess for hepatosplenomegaly)
If systemic immune activation is still suspected after the initial evaluation, contact the 
Medical Monitor for additional recommendations.


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5.1.3
Management of Patients Who Experience Specific 
Adverse Events
5.1.3.1
Cobimetinib Dose Modifications
Cobimetinib dose modifications are provided in Table 4.
Table 4
Recommended Cobimetinib Dose Modifications
Grade 
(NCI CTCAE v4.0) 
Recommended Cobimetinib Dose
Grade 1 or Grade 2 
(tolerable)
No dose reduction. Maintain cobimetinib at the same dose of 60 mg QD 
(3 tablets).
Grade 2 (intolerable) 
or Grade 3 or 4 (any)
First appearance
Interrupt treatment until Grade 1, restart treatment at 40 mg QD 
(2 tablets).
Second appearance
Interrupt treatment until Grade 1, restart treatment at 20 mg QD 
(1 tablet).
Third appearance
Consider permanent discontinuation.
NCI CTCAE v4.0National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4.0; QDonce a day.
Note:  Cobimetinib dose re-escalation is permitted on a case-by-case basis after discussion with 
the Medical Monitor or 
 designee.
5.1.3.2
Atezolizumab Dose Modifications
There will be no dose reduction for atezolizumab in this study.
5.1.3.3
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 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.  If atezolizumab is withheld for 
105 days, the patient will be discontinued from atezolizumab.  However, atezolizumab
may be withheld for 105 days to allow for patients to taper off corticosteroids prior to 
resuming treatment.  Atezolizumab can be resumed after being withheld for 105 days 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.
5.1.3.4
Guidelines for Management of Patients Who Experience 
Adverse Events
Toxicities associated or possibly associated with cobimetinib plus atezolizumab 
treatment should be managed according to standard medical practice.  


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Refer to Table 5 for management of cobimetinib- and atezolizumab-specific toxicities, 
including gastrointestinal toxicity, hepatotoxicity, dermatologic toxicity, pulmonary toxicity, 
potential eye toxicity, LVEF reduction, rhabdomyolysis and elevated CPK, hemorrhage, 
and systemic immune activation. Refer to Appendix 8 for detailed management
guidelines for atezolizumab-specific adverse events.
Table 5
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab)
Event
Action to Be Taken
General guidance for dose 
modifications and treatment 
delays and discontinuation
There will be no dose modifications for atezolizumab.  
If atezolizumab is withheld and corticosteroids are initiated for 
an atezolizumab-related toxicity, corticosteroids must be 
tapered over 1 month to 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. a, b
The dose of cobimetinib can be reduced by 20 mg (1 dose 
level) up to 2 times (i.e., from 60 mg to 40 mg and then from 
40 mg to 20 mg).  If further dose reduction is indicated after 
two dose reductions, the patient must discontinue cobimetinib 
but may continue treatment with atezolizumab at the 
investigator's discretion.
If atezolizumab is discontinued, treatment with cobimetinib 
may be continued at the investigator's discretion and after
discussion with the Medical Monitor.
If cobimetinib is withheld for 28 days because of toxicity, the 
patient should be discontinued from cobimetinib, unless 
resumption of treatment is approved by the Medical Monitor
after discussion with the investigator. 
IRRs, anaphylaxis, and 
hypersensitivity reaction
Guidelines for management of IRRs are provided in
Appendix 8.
For anaphylaxis precautions, see Appendix 7.
For severe hypersensitivity reactions, permanently discontinue 
all study treatment.
IRRinfusion-related reaction.
a Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for 
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.
b Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event.  Patients can be rechallenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


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Table 5
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.)
Event
Action to Be Taken
Gastrointestinal toxicity
Gastrointestinal events:  
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-related colitis.
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: 
–
Initiate loperamide dose with 4 mg and then 4 mg/6 hr around 
the clock, alternating with Lomotil.
–
Dispense Lomotil (diphenoxylate and atropine) 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 of 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 encourage eating small 
meals. 
– Suggest the BRAT (banana, rice, apples, toast) diet, without fiber 
(other vegetables and fruits). 
– Encourage adequate hydration with salt-containing liquids, such 
as broth or Gatorade®.
Diarrhea, Grade 1 or 
Grade 2 (tolerable)
Continue atezolizumab and cobimetinib.
Investigate etiology, referring patient to GI specialist for evaluation
of possible colitis if appropriate.
Initiate supportive care and monitor patient closely. 
GIgastrointestinal; LLNlower limit of normal.


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Table 5
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.)
Event
Action to Be Taken
Gastrointestinal toxicity (cont.)
Diarrhea, Grade 2 
(intolerable) or Grade 3
Withhold atezolizumab and cobimetinib.
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., NSAIDs) 
while investigating etiology.
Investigate etiology, referring patient to GI specialist for evaluation
of possible colitis, including biopsy if appropriate.
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.
Diarrhea, 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) 
while investigating etiology.
Rule out bowel perforation.
Investigate etiology, referring patient to GI specialist for evaluation
of possible colitis, including biopsy if appropriate.
Colitis, Grade 1
Continue atezolizumab and cobimetinib.
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., 
NSAIDs).
Refer patient to GI specialist for evaluation and confirmatory biopsy 
if symptoms persist for 7 days.
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 
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-related event.  Patients can be rechallenged with atezolizumab 
only after approval has been documented by both the investigator (or an appropriate delegate) 
and the Medical Monitor.


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Table 5
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.)
Event
Action to Be Taken
Gastrointestinal toxicity (cont.)
Colitis, Grade 2
Withhold atezolizumab and cobimetinib.
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis 
(e.g., NSAIDs).
Refer patient to GI 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.
Colitis, Grade 3
Withhold atezolizumab and cobimetinib.
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis 
(e.g., NSAIDs).
Refer patient to GI 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.
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 
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-related event.  Patients can be rechallenged with atezolizumab 
only after approval has been documented by both the investigator (or an appropriate delegate) 
and the Medical Monitor.


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Table 5
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.)
Event
Action to Be Taken
Gastrointestinal toxicity (cont.)
Colitis, Grade 4
Permanently discontinue atezolizumab and cobimetinib, and 
contact Medical Monitor. a
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., NSAIDs).
Refer patient to GI 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.
GIgastrointestinal; NSAID non-steroidal anti-inflammatory drug.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event.  Patients can be rechallenged with atezolizumab 
only after approval has been documented by both the investigator (or an appropriate delegate) 
and the Medical Monitor.


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Table 5
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.)
Event
Action to Be Taken
Dermatologic toxicity
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 atezolizumab and cobimetinib.
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 atezolizumab and cobimetinib.
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 12 weeks, 
resume atezolizumab at fixed dose.  If not, permanently 
discontinue atezolizumab and cobimetinib. a, b
Permanently discontinue atezolizumab and cobimetinib and 
contact Medical Monitor if event does not resolve to Grade 1 
or better within 12 weeks. a, b, c
If event resolves to Grade 2 or better within 28 days, resume 
cobimetinib with dose reduced by one level.  If not, 
permanently discontinue cobimetinib.
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 atezolizumab and cobimetinib, and 
contact Medical Monitor. c
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 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-related event.  Patients can be rechallenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


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Table 5
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.)
Event
Action to Be take
Elevations in ALT, AST, 
and/or bilirubin
AST/ALT ULN to3ULN 
with total bilirubin2ULN
(Grade 1)
Continue atezolizumab and cobimetinib.
Continue with the standard monitoring plan (i.e., LFTs Q4W 
before dosing).
AST/ALT 3baseline values 
to5ULN with total 
bilirubin2ULN
(Grade 2)
Continue all study treatment.
Monitor LFTs at least weekly.  
Consider referral to a hepatologist and liver biopsy.
For suspected immune-related 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 atezolizumab and cobimetinib if 
event does not resolve to Grade 1 or better within 
12 weeks. a, b, c
AST/ALT 5baseline values 
to10ULN with total 
bilirubin2ULN
(Grade 3)
Continue all study treatment.
Monitor LFTs at least weekly.  
Consider referral to a hepatologist and liver biopsy.
For suspected immune-related 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 atezolizumab and cobimetinib if 
event does not resolve to Grade 1 or better within 
12 weeks. a, b, c
LFTliver function test; Q4W every 4 weeks; 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-related event.  Patients can be rechallenged 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 for 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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Table 5
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.)
Event
Action to Be Taken
Elevations in ALT, AST, 
and/or bilirubin (cont.)
AST/ALT 3ULN with 
bilirubin2 ULN
Withhold atezolizumab and cobimetinib.
Consult hepatologist and consider liver biopsy.
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 mofetil 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
Permanently discontinue atezolizumab and cobimetinib for 
life-threatening hepatic events, and contact the Medical Monitor.
AST/ALT 10ULN
Permanently discontinue atezolizumab and cobimetinib. c
Consult hepatologist and consider liver biopsy.
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 mofetil 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; TNF-tumor necrosis factoralpha; ULNupper limit of normal.
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 
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-related event.  Patients can be rechallenged with atezolizumab 
only after approval has been documented by both the investigator (or an appropriate delegate) 
and the Medical Monitor.


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Table 5
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.)
Event
Action to Be Taken
Pulmonary events
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.
Pneumonitis, Grade 1 
(asymptomatic)
Continue atezolizumab and cobimetinib.
Re-evaluate on serial imaging.
Consider patient referral to pulmonary specialist.
Pneumonitis, Grade 2
Withhold atezolizumab and cobimetinib.
Refer patient to pulmonary and infectious disease specialists 
and consider bronchoscopy or BAL. 
If bronchoscopy is consistent with immune-related etiology, 
initiate treatment with 1−2 mg/kg/day oral prednisone or 
equivalent. 
Resume atezolizumab and cobimetinib if event resolves to 
Grade 1 or better within 12 weeks. a, b
Permanently discontinue atezolizumab and cobimetinib 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.
Pneumonitis, Grade 3 or 4
Permanently discontinue atezolizumab and cobimetinib. c
Refer patient to pulmonary and infectious disease specialists 
and consider bronchoscopy or BAL. 
If bronchoscopy is consistent with immune-related etiology, 
initiate treatment with 1−2 mg/kg/day oral prednisone or 
equivalent. 
If pulmonary event does not improve within 48 hours or 
worsens, consider adding an immunosuppressive agent 
(e.g., infliximab, cyclophosphamide, IVIg, or mycophenolate).
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
BAL bronchoscopic alveolar lavage; IVIg intravenous immunoglobulin.
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 
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-related event.  Patients can be rechallenged with atezolizumab 
only after approval has been documented by both the investigator (or an appropriate delegate) 
and the Medical Monitor.


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Table 5
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.)
Event
Action to Be Taken
Ocular toxicity
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-related 
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 treatment 
discontinuation. 

RVO has been reported in patients treated with MEK 
inhibitors other than cobimetinib.
Serous retinopathy
Severity grade assessment 
based on NCI CTCAE v4.0
"Eye Disorders–Other" scale a, 
b, c, d
Serous retinopathy, Grade 1 a or 2 b (tolerable): 
Continue cobimetinib and atezolizumab without dose change.
Follow the monitoring schedule 
Serous retinopathy, Grade 2 b (intolerable) or Grade 3 or 4:c, d
Interrupt cobimetinib until Grade1. 
Continue atezolizumab as clinically indicated.
Consult ophthalmology and undergo complete ophthalmologic 
examination, which includes visual acuity testing, intra-ocular 
pressure measurements, slitlamp ophthalmoscopy, indirect 
ophthalmoscopy, visual field, and OCT.  Consider a fluorescein 
angiogram and/or indocyanine green angiogram, if clinically 
indicated.
Follow the monitoring schedule detailed in Section 4.5.9.
The dose of cobimetinib should be reduced by one dose level 
when restarting. 
Consider permanent discontinuation of cobimetinib if serous 
retinopathy recurs despite two dose level reductions.
ADLactivities of daily living; NCI CTCAE v4.0National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.0; 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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Table 5
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.)
Event
Action to Be Taken
Ocular toxicity (cont.)
Potential immune-related
ocular toxicity (e.g., uveitis,
iritis, episcleritis, or retinitis)
Follow guidelines provided in Appendix 8.
Continue cobimetinib as clinically indicated.
RVO (any grade)
If RVO (any grade) is diagnosed, cobimetinib dosing should be 
permanently discontinued and RVO treated per institutional 
guidelines.
Continue atezolizumab.
RVOretinal vein occlusion.


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Table 5
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.)
LVEF Decrease from Baseline
Patient
LVEF
Value
Recommended
Action with Cobimetinib 
and Atezolizumab
LVEF Value
following 
Treatment Break
Recommended
Cobimetinib 
Daily Dose
Asymptomatic
50%
(or 
40%49% 
and10% 
absolute 
decrease 
from 
baseline)
Continue atezolizumab 
and cobimetinib at current 
dose.
NA
NA
40% (or 
40%49% 
and 
10% 
absolute 
decrease 
from 
baseline)
Interrupt cobimetinib 
treatment for 2 weeks.
Continue atezolizumab as 
clinically indicated.
10% absolute 
decrease from 
baseline
First 
occurrence:
40 mg
Second
occurrence:
20 mg
Third 
occurrence: 
permanent 
discontinuation
40% (or 10% 
absolute decrease 
from baseline)
Permanent 
discontinuation
Symptomatic
NA
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 
baseline
First 
occurrence:
40 mg 
Second
occurrence:
20 mg
Third 
occurrence: 
permanent 
discontinuation
Asymptomatic and 
40% (or 10% 
absolute decrease 
from baseline)
Permanent 
discontinuation
Symptomatic 
regardless of 
LVEF
Permanent 
discontinuation
LVEFleft ventricular ejection fraction; NAnot applicable.


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Table 5
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.)
Event
Action to Be Taken
Rhabdomyolysis or CPK elevation
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 intramuscular injections. 
For Grade3 CPK elevations 
that are asymptomatic and 
deemed not clinically significant
Cobimetinib and atezolizumab 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 cobimetinib and atezolizumab treatment. 
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 atezolizumab may be considered in patients 
who are deriving benefit.
Rhabdomyolysis or symptomatic 
CPK elevations
Interrupt cobimetinib and atezolizumab treatment.  
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 atezolizumab may be considered in patients 
who are deriving benefit after discussion with the Medical 
Monitor. 


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Table 5
Guidelines for Management of Patients Who Experience 
Specific Adverse Events (Cobimetinib and Atezolizumab) (cont.)
Event
Action to Be Taken
Hemorrhage
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.
Grade 3 or 4 or intolerable 
Grade 2 treatment-related 
toxicities not described above 
and in Table 4 (dose 
modifications for cobimetinib)
Withhold all study treatment.
If event resolves to Grade 1 or better within 12 weeks, resume 
atezolizumab at fixed dose. If not, permanently discontinue 
atezolizumab. 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.
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 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-related event.  Patients can be rechallenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
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.


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5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to 
the Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

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)


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The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 [NCI 
CTCAE v4.0]; see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Severe hepatic events 
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)
Hepatitis, including AST or ALT 10ULN

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

Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, 
hypothyroidism or hyperthyroidism

Systemic lupus erythematosus

Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome, 
myasthenia gravis, and meningoencephalitis

Nephritis

Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, influenza-like illness, systemic inflammatory response syndrome, or 
systemic immune activation


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
Ocular toxicities
Uveitis or retinitis
Serous retinopathy, including events of retinal detachment, retinal pigment 
epithelium detachment, neurosensory retinal detachment, and central serous 
chorioretinopathy
Retinal vein occlusion

Myositis

Cardiac disorders
Grade 2 atrial fibrillation, myocarditis, or pericarditis
Symptomatic heart failure or Grade 3 LVEF reduction 

Vasculitis

Rhabdomyolysis, Grade 3 CPK elevation, or myopathies

Grade 3 hemorrhage or any grade cerebral hemorrhage

Grade 3 rash

Grade 3 diarrhea

Colitis
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 30 days after the 
last dose of study drug.


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Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE v4.0 will be used for 
assessing adverse event severity.  Table 6 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE v4.0.
Table 6
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.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)


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
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.
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.


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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
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified adverse event reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of cancer 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.  If the cause of death is unknown and 
cannot be ascertained at the time of reporting, "unexplained death" should be recorded 
on the Adverse Events 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 Cancer
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1 or immune-modified RECIST.  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
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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
5.4
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)

Overdoses, medication errors, drug abuse, or drug misuse (see Section 5.4.4 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
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. (Primary)
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 


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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 30 days after the last dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the 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 
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 30 days 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 to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the last 
dose of study drug.  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 


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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 
90 days after the last dose of cobimetinib.  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.  
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study drug.  The pregnant partner 
will need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  After the authorization has been 
signed, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  
If a therapeutic or elective abortion was performed because of an underlying maternal 
or embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
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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).
5.4.4
Reporting Requirements for Cases of Overdose, Medication 
Error, Drug Abuse, or Drug Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose}

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse: intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm}

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self administered by the patient, drug misuse could 
involve the drug being administered to someone other than the patient.}
Special situations are not in themselves adverse events, but may result in adverse 
events.  All special situations associated with atezolizumab or cobimetinib, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event).  Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.


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
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.
Each adverse event associated with a special situation should be recorded separately 
on the Adverse Event eCRF.  If the associated adverse event fulfills seriousness criteria, 
the event should be reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event; see Section 5.4.2).  Adverse events associated with special 
situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.


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
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
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.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 30 days after the last 
dose of study drug), all deaths, regardless of cause, should be reported through use of 
the Long-Term Survival Follow-Up eCRF.  In addition, if the investigator becomes aware 
of a serious adverse event that is believed to be related to prior exposure to study drug, 
the event should be reported through use of the Adverse Event eCRF.  However, if the 
EDC system is not available, the investigator should report these events directly to the 
Sponsor or its designee, either by faxing or by scanning and emailing the paper Clinical 
Trial Serious Adverse Event/Adverse Event of Special Interest Reporting Form using the 
fax number or email address provided to investigators.




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6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE
CHARACTERISTICS
Patient demographics, baseline, and disease characteristics will be summarized
descriptively using mean (standard deviation), median (interquartile range), or number 
and percent. 
6.4
EFFICACY ANALYSES
The analysis population for efficacy will include all patients enrolled in the study who 
received at least one dose of both study drugs.
6.4.1
Primary Efficacy Endpoint
ORR is the primary endpoint for all cohorts. Objective response is defined as a CR or a 
PR on two consecutive tumor assessments4 weeks apart, as determined by the 
investigators using RECIST v1.1.
The number of patients included in the analysis and the number of patients with a CR or 
a PR will be summarized by cohort. The cohort-specified ORR and the corresponding 
95% Clopper-Pearson CIs will be calculated.
6.4.2
Secondary Efficacy Endpoints
OS, defined as the time from enrollment to death from any cause, will be analyzed for all 
cohorts. The cohort specific results will be summarized as median survival times 
obtained using Kaplan-Meier methods and their corresponding 95% CIs for median 
constructed using the Brookmeyer and Crowley method.
PFS, DOR, and DCR will be summarized. PFS is defined as the time from enrollment to 
the first occurrence of disease progression as determined by the investigator(s) using 
RECIST v1.1 or to death from any cause, whichever occurs first. DOR is defined as the 
time from the first occurrence of a documented, confirmed objective response to disease 
progression as determined by the investigator using RECIST v1.1 or to death from any 
cause, whichever occurs first. DCR is defined as the proportion of patients with a CR, a 
PR, or stable disease at 16 weeks as determined by the investigator using RECIST v1.1.
For PFS and DOR, cohort-specified median PFS and DOR will be obtained using 
Kaplan-Meier method, and the corresponding 95% CIs for median will be constructed 
using the Brookmeyer and Crowley method. Cohort-specified DCR will be summarized 
as frequency and percentages and the corresponding 95% Clopper-Pearson Cis will be 
reported.
6.4.3
Exploratory Efficacy Endpoints
For patients with measurable disease in each cohort, ORR, PFS, DOR, and DCR as 
determined by the investigator according to immune-modified RECIST will be analyzed 
using the same methods as described above. 


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6.5
SAFETY ANALYSES
The safety population will include all enrolled patients who received at least one dose of 
study drug. The number of patients for safety population will be specified by cohort.
Adverse events, changes in vital signs, changes in laboratory test results, and study 
treatment exposure will be summarized by cohort. 
For each cohort, the occurrence of all adverse events observed during or after the first 
study drug dose, their severity and verbatim description will be summarized by mapped 
terms and appropriate thesaurus levels and graded according to NCI CTCAE v4.0.  In 
addition, the incidence and percentages as well as exposure adjusted event rates will be 
reported for serious adverse events, severe adverse events (Grades 3), adverse 
events of special interest, and adverse events leading to study drug discontinuation or 
interruption within each cohort.  If a patient experiences the same event several times, 
the occurrence of the event will be counted once at the maximum severity.  The 
causality of all adverse events in relation to the study drug as determined by investigator 
will also be summarized. 
For each cohort, study drug exposure, including treatment duration, number of doses, 
and dose intensity, will be summarized descriptively. 
All deaths and causes of death will be reported as frequency and percentages.  
Relevant laboratory data and vital signs will be summarized over time. Abnormal values 
for laboratory and vital sign data will be identified and summarized.
6.6
PHARMACOKINETIC ANALYSES
The PK analysis population will consist of patients with sufficient data to enable 
estimation of key parameters, with patients grouped according to treatment received.
PK samples will be collected in this study as outlined in Appendix 2. Cobimetinib and 
atezolizumab maximum and minimum concentration data (Cmax and Cmin, respectively) 
will be tabulated and summarized by study day, as data permit. Summary statistics will 
include mean, standard deviation, coefficient of variation, median, range, geometric 
mean, and geometric mean coefficient of variation, as appropriate.
Additional PK and pharmacodynamic analyses will be conducted, as appropriate, based 
on available data.
6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analyses will include patients with any ADA assessment, with 
patients grouped according to treatment received.


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The number and proportion of ADA-positive patients and ADA-negative patients during 
both the treatment and follow-up periods will be summarized by treatment group.  
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, have a post-
baseline ADA result, 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
BIOMARKER ANALYSES
Descriptive statistics will be used to explore the biomarkers and their relations to 
response or escape of combined treatment in patients, 
 
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data. Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data. Other electronic non-eCRF 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.


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7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered on 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 




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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 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S.
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 


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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 IIND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective 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 


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course of the study and for 1 year after completion of the study (i.e., 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.
9.4
ADMINISTRATIVE STRUCTURE
This study is sponsored by F. Hoffmann-La Roche Ltd.  Approximately 20 study centers 
will participate in this study globally and enroll up to approximately 250 patients.  
The Sponsor will provide clinical operations oversight, data management support, and 
medical monitoring.
An IxRS will be used to manage site drug supply and to enroll patients in the study.  For 
patients not previously tested for tumor mutational status, testing will be performed at 
screening.  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 or the center's local laboratory; central and local laboratory ranges will be 
collected.


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9.5
PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
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 


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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 (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
127/Protocol WO39760, Version 4
Assessment/Procedure
(Day Window)
Screening
a
Cycle 1
Cycle 2
Cycle3
Tx
Discon b
ADA 
Visit c
Survival 
FU d
Days
–28 to –1
Day 1 
(3)
Day 15
(3)
Day 1 
(3)
Day 15
(3)
Day 1 
(3)
Day 15
(3)
30 ( 3)
Days after 
Last Dose
>90 Days
( 3) after 
Last Dose 
Every 3 
Months
(3 days)
ECHO or MUGA scan k
x
x
x k
Optional WGS 
x
Tumor assessments l
x
Tumor assessments occur every 8 weeks.
Serology m
x
Thyroid function n
x
x
x
x n
x
Ophthalmologic exam o
x
x
x o
x
Pregnancy test p
x
x
x
x p
x
Urinalysis q
x
Concomitant medications r
x r
x r
x
x
x r
Adverse events s
x s
x s
x
x
x
x
x
x s
x s
Tumor biopsy (Cohorts 16)  t
x
x
x
Tumor biopsy (Cohort 7 only)
x u
x v
x w
x x
Biomarker blood samples y
x
x
x
x
x
Biomarker PBMC samples y
x
x
x
x
x
Biomarker plasma samples y
x
x
x
Biomarker urine samples y, z
x
x
x
Atezolizumab administration aa
x bb
x
x
x
x aa
x
Dispense cobimetinib cc
x
x
x
Survival and anti-cancer therapy 
follow-up
x d


Appendix 1
Schedule of Activities (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
128/Protocol WO39760, Version 4
ADAanti-drug antibody; Discondiscontinuation; ECHOechocardiogram; ECOGEastern Cooperative Oncology Group; eCRFelectronic 
Case Report Form; FUfollow-up; HBcAbhepatitis B core antibody; HBsAghepatitis B surface antigen; HBVhepatitis B  virus; 
HCVhepatitis C virus; IRRinfusion-related reactions; LVEFleft ventricular ejection fraction; MUGAmultiple-gated acquisition; 
PBMCperipheral blood mononuclear cell; PKpharmacokinetic; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; 
T3triiodothyronine; T4thyroxine; Tx treatment; WGSwhole genome sequencing.
Notes:  All assessments should be performed within 3 days of the scheduled visit, unless otherwise specified.  On treatment days, all 
assessments should be performed prior to dosing, unless otherwise specified. On treatment days, pre-infusion laboratory samples should be 
drawn 0–4 hours before the start of infusion, and post-infusion laboratory samples should be drawn 030 minutes after the end of infusion, 
unless otherwise specified.
Assessments shaded in gray should be performed as scheduled, but the associated data do not need to be recorded on the eCRF (except in the 
case of an adverse event). 
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.  
b Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit within 30 (3) days after the last dose.  The
visit at which response assessment shows progressive disease may be used as the study discontinuation visit.
c Visit not specified by the protocol.  Assessments should be performed as clinically indicated.
d Required follow-up information will be collected via telephone calls and/or clinic visits every 3 months until death, loss to follow-up, or study 
termination by the Sponsor.
e Informed consent must be documented before any study-specific screening procedure is performed and may be obtained up to 28 days before 
initiation of study treatment.
f
Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and 
temperature. Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, 
record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
g Vital signs will be recorded within 60 minutes prior to the infusion and otherwise as clinically indicated during or after the infusion.
h Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.  If physical examinations are assessed within 7 days of the Day 1, Cycle 1 visit, they do not have to 
be repeated on Day 1.
i
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, and lymphocytes).
j
Chemistry panel (serum) includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, magnesium, 
phosphorus, calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, CPK, and uric acid.  Albumin will be assessed at screening 
only.


Appendix 1
Schedule of Activities (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
129/Protocol WO39760, Version 4
k Evaluation of LVEF by ECHO or MUGA scan must be performed at the following timepoints only for patients on cobimetinib:  at screening; on Day 1 
of Cycle 2 (1 week); on Day 1 of Cycles 5, 8, 11, 14, 17, and every 3 treatment cycles thereafter (i.e., Cycles 20, 23, 26, etc.; 2 weeks for each); 
and at treatment discontinuation visit evaluation (unless evaluation performed within the previous 12 weeks showed no clinically significant findings 
and/or changes from baseline).
l
Tumor assessments will continue until disease progression per RECIST v1.1 or immune-modified RECIST unless patient continued treatment, loss 
of clinical benefit (for patients who continue treatment after disease progression according to RECIST v1.1 or immune-modified RECIST), 
withdrawal of consent, study termination by the Sponsor, or death, whichever occurs first. Patients who discontinue treatment for reasons other 
than disease progression (e.g. toxicity) will continue scheduled tumor assessments until disease progression, withdrawal of consent, study 
termination by Sponsor, or death, whichever occurs first.
m All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the study. HBV serology will 
include HBsAg, antibodies against HBsAg, and total HBcAb antibody (anti-HBcAb).  HBV DNA should be obtained prior to enrollment if patient has 
a negative serology for HBsAg and a positive serology for anti-HBcAb.  HCV serology will include HCV antibody (anti-HCV).  HCV RNA should be 
obtained prior to enrollment if patient tests positive for anti-HCV.
n Thyroid-function testing (thyroid-stimulating hormone, free T3 [or total T3 for sites where free T3 is not performed], and free T4) collected on Day 1 
of Cycles 15, and every 2 cycles thereafter (i.e., Day 1 of Cycles 7, 9, 11, etc.) for patients on atezolizumab.
o Ophthalmologic examination must be performed at the following timepoints only for patients on cobimetinib:  at screening; on Day 1 of Cycle 2 
(1 week); on Day 1 of Cycles 5, 8, and 11 (every 3 treatment cycles; 2 weeks); on Day 1 of Cycles 15, 19, and 23 (every 4 treatment cycles;
2 weeks); on Day 1 of Cycles 29, 35, 41, 47, and every 6 treatment cycles thereafter (i.e., Cycles 53, 59, 65, etc.; 2 weeks for each); and at 
treatment discontinuation visit evaluation (unless evaluation performed within the previous 12 weeks showed no clinically significant findings and/or 
changes from baseline).
p All women of childbearing potential will have a serum pregnancy test at screening.  Urine pregnancy tests will be performed on Day 1 (2 weeks) of 
every cycle.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
q Includes dipstick (pH, specific gravity, glucose, protein, ketones, and blood) and microscopic examination (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, and bacteria).
r
Includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to initiation of study drug until 30 days after the last dose of study drug.
s 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 30 days after the last dose of study drug or 
initiation of new anti-cancer therapy, whichever occurs first.  After this period, all deaths, regardless of cause, should be reported.  After this period, 
the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior study drug 
treatment (see Section 5.6).  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 or adverse events of special interest considered to be related to study drug or trial-related procedures until a final outcome 
can be reported.


Appendix 1
Schedule of Activities (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
130/Protocol WO39760, Version 4
t
Biopsy schedule for patients in Cohorts 16.  Please see different biopsy schedule listed in the table for the biopsy cohort (Cohort 7). Fresh 
baseline tumor tissue collected during screening (or archival if fresh tumor biopsy cannot be performed); optional on-treatment biopsy at Cycle 1, 
Day 15 (5 days); mandatory biopsy at progression if clinically feasible.
u Mandatory pre-treatment biopsy
v Biopsy Cohort 7, mandatory tumor biopsy done between Days 10 and 14 of Cycle 1. 
w Biopsy Cohort 7, second (mandatory) on-treatment biopsy will be done during Cycle 2, approximately 4–6 weeks after the first dose of 
atezolizumab.  
x Biopsy Cohort 7, optional post-treatment biopsy at the time of radiographic progression.
y Biomarkers are collected until Cycle 3, Day 1 (including that visit) and then at treatment discontinuation.
z Urine samples will be collected for urothelial carcinoma patients only:  screening on Day 1 of Cycle 1; on Day 1 of Cycle 3; and at treatment 
discontinuation visit only.
aaThe initial dose of atezolizumab will be delivered over 60 (15) minutes.  If the first infusion is well tolerated, all subsequent infusions will be 
delivered over 30 (10) minutes until loss of clinical benefit.  Study drug administration may be 7 days.
bb For patients in Cohorts 1–6 only.
ccAll patients will receive cobimetinib at a dose of 60 mg (three 20-mg tablets) orally once a day on Days 121 of each 28-day cycle.  At least 7 days 
off cobimetinib are required prior to starting a new treatment cycle.  Cobimetinib should be taken approximately the same time each day, and no 
later than 4 hours after the scheduled time.  


Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
131/Protocol WO39760, Version 4
Appendix 2
Schedule of Pharmacokinetic and Immunogenicity Samples
Visit
Timepoint
Sample Type(s)
Day 1 of Cycle 1
(Cohorts 16 only)
Prior to atezolizumab infusion
Atezolizumab PK and ADA
(serum)
30 (10) minutes following 
end of atezolizumab infusion
Atezolizumab PK (serum)
Day 15 of Cycle 1 
(Cohort 7 only)
Prior to atezolizumab infusion
Atezolizumab PK and ADA 
(serum)
30 (10) minutes following 
end of atezolizumab infusion
Atezolizumab PK (serum)
Day 1 of Cycles 2, 4, 
8, 12, and 16
Prior to atezolizumab infusion
Atezolizumab PK and ADA 
(serum)
Day 15 of Cycle 3 
Prior to atezolizumab infusion
Atezolizumab PK and ADA 
(serum)
Prior to cobimetinib dose
Cobimetinib PK (plasma)
30 (10) minutes following 
end of atezolizumab infusion
Atezolizumab PK and ADA 
(serum)
24 hours after cobimetinib 
dose
Cobimetinib PK (plasma)
Atezolizumab 
treatment 
discontinuation visit
At visit
Atezolizumab PK and ADA 
(serum)
>90 days after last 
atezolizumab infusion
At visit
Atezolizumab PK and ADA 
(serum)
ADAanti-drug antibody; NAnot applicable; PKpharmacokinetic.
Notes: 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.


Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
132/Protocol WO39760, Version 4
Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) (Eisenhauer et al. 2009), are presented below, with slight modifications 
from the original publication and the addition of explanatory text as needed for clarity.1
TUMOR MEASURABILITY
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression.
DEFINITION OF MEASURABLE LESIONS
Tumor Lesions
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes
To be considered pathologically enlarged and measurable, a lymph node must be 
15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be 5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters").
                                           
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made.


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
133/Protocol WO39760, Version 4
DEFINITION OF NON-MEASURABLE LESIONS
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 mm but 15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions:

Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
134/Protocol WO39760, Version 4
METHODS FOR ASSESSING LESIONS
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option.
CLINICAL LESIONS
Clinical lesions will only be considered measurable when they are superficial and 
10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested.
CHEST X-RAY
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.
CT AND MRI SCANS
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is 5 mm.  When CT scans 
have slice thickness of 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV 
contrast because of allergy or renal insufficiency, the decision as to whether a non-
contrast CT or MRI (without IV contrast) will be used to evaluate the patient at baseline 
and during the study should be guided by the tumor type under investigation and the 
anatomic location of the disease.  For patients who develop contraindications to contrast 
after baseline contrast CT is done, the decision as to whether non-contrast CT or MRI 
(enhanced or non-enhanced) will be performed should also be based on the tumor type 
and the anatomic location of the disease, and should be optimized to allow for 
comparison with the prior studies if possible.  Each case should be discussed with the 
radiologist to determine if substitution of these other approaches is possible and, if not, 
the patient should be considered not evaluable from that point forward.  Care must be 
taken in measurement of target lesions and interpretation of non-target disease or new 


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
135/Protocol WO39760, Version 4
lesions on a different modality, since the same lesion may appear to have a different 
size using a new modality.
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
utilized for objective tumor evaluation.
ASSESSMENT OF TUMOR BURDEN
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline. This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be considered non-target lesions.  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
136/Protocol WO39760, Version 4
as the node measurement.  All other pathological nodes (those with short axis 10 mm 
but 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
10 mm are considered non-pathological and should not be recorded or followed.
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or 
"multiple liver metastases").
CALCULATION OF SUM OF DIAMETERS
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden.
Measuring Lymph Nodes
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to 10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response (CR) criteria are met, since a normal lymph node is defined as 
having a short axis of 10 mm.
Measuring Lesions That Become Too Small to Measure
During the study, all target lesions (lymph node and nonlymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
137/Protocol WO39760, Version 4
assigned in this circumstance as well and "too small to measure" should also be 
ticked).
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is 5 mm, and in that case "too small to measure" should 
not be ticked.
Measuring Lesions That Split or Coalesce on Treatment
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion.
EVALUATION OF NON-TARGET LESIONS
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to 10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis 10 mm), this should be captured on the eCRF as part of the assessment of 
non-target lesions.
RESPONSE CRITERIA
CRITERIA FOR TARGET LESIONS
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below:

CR:  Disappearance of all target lesions
Any pathological lymph nodes must have reduction in short axis to 10 mm.

Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR

Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters on study (including 
baseline)
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of 5 mm.


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
138/Protocol WO39760, Version 4

Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD
CRITERIA FOR NON-TARGET LESIONS
Definitions of the criteria used to determine the tumor response for the group of non-
target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedule of activities.

CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits

PD:  Unequivocal progression of existing non-target lesions
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS
Patients with Measurable and Non-Measurable Disease
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare.
Patients with Non-Measurable Disease Only
For patients with non-measurable disease only, the same general concepts apply as 
noted above.  However, in this instance there is no measurable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden.  Because 
worsening in non-measurable disease cannot be easily quantified (by definition, if all 
lesions are truly non-measurable), a useful test that can be applied when assessing 
patients for unequivocal progression is to consider if the increase in overall disease 
burden based on the change in non-measurable disease is comparable in magnitude to 
the increase that would be required to declare PD for measurable disease, that is, an 
increase in tumor burden representing an additional 73% increase in volume (which is 
equivalent to a 20% increase in diameter in a measurable lesion).  Examples include an 
increase in a pleural effusion from "trace" to "large" or an increase in lymphangitic 
disease from localized to widespread. If unequivocal progression is seen, the patient 


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
139/Protocol WO39760, Version 4
should be considered to have had overall PD at that point.  While it would be ideal to 
have objective criteria to apply to non-measurable disease, the very nature of that 
disease makes it impossible to do so; therefore, the increase must be substantial.
NEW LESIONS
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient's baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a
"new" cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared using the date of the 
initial scan.
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline.


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
140/Protocol WO39760, Version 4
Table 1
Criteria for Overall Response at a Single Timepoint: 
Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a "Non-CR/non-PD" is preferred over "stable disease" for non-target 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some trials; thus, assigning "stable disease"
when no lesions can be measured is not advised.
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that timepoint, 
unless a convincing argument can be made that the contribution of the individual missing 
lesions would not change the assigned timepoint response.  This would be most likely to 
happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm with 
three measured lesions and during the study only two lesions were assessed, but those 
gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 
SPECIAL NOTES ON RESPONSE ASSESSMENT
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions as shown in Table 1.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
141/Protocol WO39760, Version 4
REFERENCE
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847.  
doi: 10.1016/j.ejca.2008.10.026.


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142/Protocol WO39760, Version 4
Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST)
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents like atezolizumab, which can produce delayed 
responses that may be preceded by initial apparent radiographic progression, including 
the appearance of new lesions.  Therefore, immune-modified response criteria have 
been developed to incorporate new lesions into the assessment of total tumor burden 
and allow radiographic progression to be confirmed at a subsequent assessment.  
Immune-modified Response Evaluation Criteria in Solid Tumors (RECIST), as described 
within this appendix, were adapted from RECIST, Version 1.1 (v1.1) (Eisenhauer et al 
2009), in the same manner that immune-related response criteria were adapted from 
WHO criteria (Wolchok et al. 2009) and RECIST v1.0 (Nishino et al. 2014).  When not 
otherwise specified, RECIST v1.1 conventions will apply.  Differences between 
immune-modified RECIST and RECIST v1.1 are summarized in Table 1.
Table 1
Comparison of RECIST v1.1 and Immune-Modified RECIST
RECIST v1.1
Immune-Modified RECIST
Measurable new lesions
Always represent progression
Incorporated into the total tumor 
burden a and followed
Non-measurable new 
lesions
Always represent progression
Do not represent progression, but 
preclude CR
Non-target lesions
Contribute to defining CR, PR, 
SD, and PD
Contribute to defining CR only
CR
Disappearance of all lesions
Disappearance of all lesions
PR
30% decrease in sum of 
diameters of target lesions, in 
the absence of CR, new 
lesions, and unequivocal 
progression in non-target 
lesions
30% decrease in tumor burden, a
in the absence of CR
PD
20% increase in sum of 
diameters of target lesions, 
unequivocal progression in 
non-target lesions, and/or 
appearance of new lesions
20% increase in tumor burden a
SD
Neither sufficient shrinkage to 
qualify for CR or PR nor 
sufficient increase to qualify for 
PD
Neither sufficient shrinkage to 
qualify for CR or PR nor sufficient 
increase to qualify for PD
CRcomplete response; PDprogressive disease; PRpartial response; RECIST Response
Evaluation Criteria in Solid Tumors; SDstable disease.
a Tumor burden is the sum of diameters of target lesions and measurable new lesions.


Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
143/Protocol WO39760, Version 4
TUMOR MEASURABILITY
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression.  
DEFINITION OF MEASURABLE LESIONS
Tumor Lesions
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes
To be considered pathologically enlarged and measurable, a lymph node must be 
15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be 5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions," "New Lesions," and 
"Calculation of Sum of Diameters").
DEFINITION OF NON-MEASURABLE LESIONS
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 mm but 15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.


Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
144/Protocol WO39760, Version 4
Bone Lesions:

Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  
METHODS FOR ASSESSING LESIONS
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option.
CLINICAL LESIONS
Clinical lesions will only be considered measurable when they are superficial and 
10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested.


Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
145/Protocol WO39760, Version 4
CHEST X-RAY
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.
CT AND MRI SCANS
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is 5 mm.  When CT scans 
have slice thickness of 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV 
contrast because of allergy or renal insufficiency, the decision as to whether a non-
contrast CT or MRI (without IV contrast) will be used to evaluate the patient at baseline 
and during the study should be guided by the tumor type under investigation and the 
anatomic location of the disease.  For patients who develop contraindications to contrast 
after baseline contrast CT is done, the decision as to whether non-contrast CT or MRI 
(enhanced or non-enhanced) will be performed should also be based on the tumor type 
and the anatomic location of the disease, and should be optimized to allow for 
comparison with the prior studies if possible.  Each case should be discussed with the 
radiologist to determine if substitution of these other approaches is possible and, if not, 
the patient should be considered not evaluable from that point forward.  Care must be 
taken in measurement of target lesions and interpretation of non-target disease or new 
lesions on a different modality, since the same lesion may appear to have a different 
size using a new modality.
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
utilized for objective tumor evaluation.
ASSESSMENT OF TUMOR BURDEN
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.


Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
146/Protocol WO39760, Version 4
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be considered non-target lesions.  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis 10 mm 
but 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
10 mm are considered non-pathological and should not be recorded or followed.
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or 
"multiple liver metastases").


Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
147/Protocol WO39760, Version 4
NEW LESIONS
New lesions identified after baseline will be evaluated for measurability with use of the 
same criteria applied to prospective target lesions at baseline per RECIST (e.g., 
nonlymph node lesions must be 10 mm on the longest diameter; new lymph nodes 
must be 15 mm on the short axis [see note below]).  All new lesions (measurable or 
non-measurable) must be assessed and recorded at the time of identification and at all 
subsequent tumor assessment timepoints. 
Up to a maximum of five measurable new lesions total (and a maximum of two lesions 
per organ) can be included in the calculation of tumor burden that is performed as part of 
the tumor response evaluation.  New lesion types that would not qualify as target lesions 
per RECIST cannot be included in the calculation of tumor burden and thus will not 
affect overall tumor response evaluation.  New lesions that are not measurable at first 
appearance but meet measurability criteria at a subsequent timepoint can be included in 
the tumor response evaluation from that point on, if the maximum number of measurable 
new lesions has not been reached.
Note regarding new lymph node lesions:  If at first appearance the short axis of a lymph 
node lesion is 15 mm, it will be considered a measurable new lesion.  If at first 
appearance the short axis of a lymph node lesion is 10 mm and 15 mm, the lymph 
node will not be considered measurable but will still be considered a new lesion and 
should be identified as a non-measurable new lesion.  If at first appearance the short 
axis of a lymph node is 10 mm, the lymph node should not be considered pathological 
and should not be considered a new lesion.  A lymph node can subsequently become 
measurable, when the short axis is 15 mm.
CALCULATION OF SUM OF DIAMETERS
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline as a measure of 
tumor burden.  At each subsequent tumor assessment, a sum of the diameters (longest 
diameter for non-lymph node lesions, short axis for lymph node lesions) will be 
calculated for all target lesions plus measurable new lesions (up to five new lesions, with 
a maximum of two new lesions per organ) that have emerged after baseline.  Hence, 
each net percentage change in tumor burden per assessment accounts for the size and 
growth kinetics of both old lesions and new lesions as they appear.
Measuring Lymph Nodes
If at first appearance the short axis of a new lymph node lesion is 15 mm, it will be 
considered a measurable new lesion and may be included in the sum of the diameters.  
If the new lymph node lesion is included in the sum of diameters, it will continue to be 


Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
148/Protocol WO39760, Version 4
measured and included in the sum of diameters at subsequent timepoints, even if the 
short axis decreases to 15 mm (or even 10 mm).  However, if it subsequently 
decreases to 10 mm and all other lesions are no longer detectable or have also 
decreased to a short axis of 10 mm (if lymph nodes), a response assessment of 
complete response (CR) may be assigned.
Lymph nodes should always have the actual short axis measurement recorded 
(measured in the same anatomical plane as the baseline examination), even if the node 
regresses to 10 mm during the study.  Thus, when lymph nodes are included in the 
sum of diameters, the sum may not be zero even if CR criteria are met, since a normal 
lymph node is defined as having a short axis of 10 mm.
Measuring Lesions That Become Too Small to Measure
During the study, all target lesions and up to five measurable new lesions (lymph node 
and nonlymph node) should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., 2 mm).  However, sometimes 
lesions or lymph nodes become so faint on CT scan that the radiologist may not feel 
comfortable assigning an exact measurement and may report them as being too small to 
measure.  When this occurs, it is important that a value be recorded on the CRF, as 
follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked).
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is 5 mm, and in that case "too small to measure" should 
not be ticked.
Measuring Lesions That Split or Coalesce on Treatment
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 


Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
149/Protocol WO39760, Version 4
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion.
EVALUATION OF NON-TARGET LESIONS AND NON-MEASURABLE NEW 
LESIONS
Measurements are not required for non-target lesions or non-measurable new lesions.  
Non-target lesions should be noted at baseline, and non-measurable new lesions should 
be noted at the time of identification.  At subsequent evaluations, non-target lesions and 
non-measurable new lesions will be categorized as "present" or "absent."
After baseline, changes in non-target lesions or non-measurable new lesions (or 
measurable new lesions in excess of five total or two per organ) will contribute only in 
the assessment of CR (i.e., a CR is attained only with the complete disappearance of all 
tumor lesions, including non-target lesions and non-measurable new lesions) and will not 
be used to assess progressive disease (PD).
RESPONSE CRITERIA
Definitions of the criteria used to determine objective tumor response are provided below:

CR:  Disappearance of all lesions
Any pathological lymph nodes must have reduction in short axis to 10 mm.

Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions plus measurable new lesions (up to a maximum of five total or two per 
organ), taking as reference the baseline sum of diameters, in the absence of CR

PD:  At least a 20% increase in the sum of diameters of all target lesions plus 
measurable new lesions (up to a maximum of five total or two per organ), taking as 
reference the smallest sum of diameters on study (including baseline)
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of 5 mm.
New lesions alone do not qualify as PD.  However, their contribution to total 
tumor burden is factored into the sum of the diameters, which is used to 
determine the overall immune-modified RECIST tumor response.

Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT
Table 2 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline.


Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
150/Protocol WO39760, Version 4
Table 2
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions)
Target Lesions and 
Measurable New Lesions a
Non-Target Lesions and 
Non-Measurable New Lesions b
Overall Response
CR
Absent
CR
CR
Present or not all evaluated
PR
PR
Any
PR
SD
Any
SD
Not all evaluated
Any
NE
PD
Any
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial 
response; SDstable disease.
a Up to a maximum of five measurable new lesions total (and a maximum of two lesions 
per organ) can be included in the calculation of tumor burden, in addition to the target 
lesions identified at baseline.
b Also includes measurable new lesions in excess of five total or two per organ.
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target or 
measurable new lesions at a timepoint, usually the case is also considered not evaluable 
at that timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesions would not change the assigned timepoint response.  This 
would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 
SPECIAL NOTES ON RESPONSE ASSESSMENT
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions, as well as new lesions, as shown in Table 2.


Appendix 4
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST) (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
151/Protocol WO39760, Version 4
REFERENCES
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847.  
doi: 10.1016/j.ejca.2008.10.026.
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Can Res 
2009;15:741220. doi: 10.1158/1078-0432.CCR-09-1624. Epub: 24 November 
2009.
Nishino M, Gargano M, Suda M, et al. Optimizing immune-related tumor response 
assessment: does reducing the number of lesions impact response assessment in 
melanoma patients treated with ipilimumab? J Immunother Can 2014;2:17.
doi: 10.1186/2051-1426-2-17.


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


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Appendix 6
Preexisting Autoimmune Diseases and Immune Deficiencies
Subjects 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 for whom the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Contact the Medical Monitor regarding any 
uncertainty about 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 syndrome
Stiff-Person syndrome
Takayasu arteritis
Ulcerative colitis
Vitiligo
Vogt-Koyanagi-Harada 
disease
Wegener granulomatosis


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Appendix 7
Anaphylaxis Precautions
EQUIPMENT NEEDED

Tourniquet

Oxygen

Epinephrine for subcutaneous, IV, and/or endotracheal use in accordance with 
standard practice

Antihistamines

Corticosteroids

IV infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1.
Stop the study treatment infusion.
2.
Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
treatment.  Do not obstruct arterial flow in the limb.
3.
Maintain an adequate airway.
4.
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge.
5.
Continue to observe the patient and document observations


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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.
Although most immune-related adverse events observed with immunomodulatory agents 
have been mild and self-limiting, such events should be recognized early and treated 
promptly to avoid potential major complications.  Discontinuation of atezolizumab may 
not have an immediate therapeutic effect, and in severe cases, immune-related toxicities 
may require acute management with topical corticosteroids, systemic corticosteroids, or 
other immunosuppressive agents. 
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  In patients who have met 
the criteria for permanent discontinuation, resumption of atezolizumab may be 
considered if the patient is deriving benefit and has fully recovered from the 
immune-related event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and 
the Medical Monitor. 
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will 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 5.1.3.4.


Appendix 8
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
156/Protocol WO39760, Version 4
HEPATIC EVENTS
Immune-related 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 
5.1.3.4.
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-related colitis has been associated with the administration of atezolizumab.  
Management guidelines for gastrointestinal events are provided in Section 5.1.3.4.
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. 
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 


Appendix 8
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
157/Protocol WO39760, Version 4
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency.
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-related 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-related 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 and Atezolizumab—F. Hoffmann-La Roche Ltd
158/Protocol WO39760, Version 4
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.

Initiate treatment with insulin if needed.

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-related 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 and Atezolizumab—F. Hoffmann-La Roche Ltd
159/Protocol WO39760, Version 4
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-related 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. 
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 2.


Appendix 8
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
160/Protocol WO39760, Version 4
Table 2
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 

Continue atezolizumab.

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Ocular event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to ophthalmologist.

Initiate treatment with 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-related 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 and Atezolizumab—F. Hoffmann-La Roche Ltd
161/Protocol WO39760, Version 4
IMMUNE-RELATED MYOCARDITIS
Immune-related myocarditis has been associated with the administration of 
atezolizumab.  Immune-related myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not limited to, 
dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  
Immune-related 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 and Atezolizumab—F. Hoffmann-La Roche Ltd
162/Protocol WO39760, Version 4
Table 3
Management Guidelines for Immune-Related Myocarditis
Event
Management
Immune-related 
myocarditis, Grade 1

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines.
Immune-related 
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-related 
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-related 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 and Atezolizumab—F. Hoffmann-La Roche Ltd
163/Protocol WO39760, Version 4
INFUSION-RELATED REACTIONS
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) with Cycle 1 of 
atezolizumab may receive premedication with antihistamines or antipyretics/analgesics 
(e.g., acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited in 
treating atezolizumab-associated IRRs because of its potential for causing 
agranulocytosis.
Guidelines for medical management of IRRs during Cycle 1 are provided in Table 4.  For 
subsequent cycles, IRRs should be managed according to institutional guidelines.
Table 4
Management Guidelines for Infusion-Related Reactions
Event
Management
IRR, Grade 1 

Reduce infusion rate to half the rate being given at the time of 
event onset.

After the event has resolved, the investigator should wait for 30 
minutes while delivering the infusion at the reduced rate.

If the infusion is tolerated at the reduced rate for 30 minutes after 
symptoms have resolved, the infusion rate may be increased to 
the original rate.
IRR, Grade 2

Interrupt atezolizumab infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic medication, glucocorticoids, 
epinephrine, bronchodilators, oxygen).

After symptoms have resolved to baseline, resume infusion at half 
the rate being given at the time of event onset.

For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or analgesics 
and monitor closely for IRRs.
IRR, Grade 3 or 4

Stop infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen).

Permanently discontinue atezolizumab and contact Medical 
Monitor. a
IRRinfusion-related reaction.
a Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related 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 and Atezolizumab—F. Hoffmann-La Roche Ltd
164/Protocol WO39760, Version 4
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

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent.
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.
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-related 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 and Atezolizumab—F. Hoffmann-La Roche Ltd
165/Protocol WO39760, Version 4
Table 5
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-related 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-related 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-related 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 limited, with or without pruritus.  A 


Appendix 8
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
166/Protocol WO39760, Version 4
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 5.1.3.4.
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.


Appendix 8
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
167/Protocol WO39760, Version 4
Table 6
Management Guidelines for Neurologic Disorders
Event
Management
Immune-related 
neuropathy, 
Grade 1

Continue atezolizumab.

Investigate etiology.
Immune-related 
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-related 
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-related 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. 
IMMUNE-RELATED MENINGOENCEPHALITIS
Immune-related meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-related 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 


Appendix 8
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
168/Protocol WO39760, Version 4
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-Related 
Meningoencephalitis
Event
Management
Immune-related 
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-related 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-related nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function, and 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 
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.


Appendix 8
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Cobimetinib and Atezolizumab—F. Hoffmann-La Roche Ltd
169/Protocol WO39760, Version 4
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-related 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.