Conditions: Colorectal Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 96
Healthy volunteers: no

Brief summary:
A phase Ib/II, open-label, multicenter, randomized study designed to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of immunotherapy-based treatment combinations in patients with metastatic colorectal cancer (mCRC) that became refractory to first- and second-line standard therapies. Eligible patients will be assigned to one of several treatment arms.

Detailed description:

Arms:
arm 1: Participants will receive treatment until unacceptable toxicity or disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. arm 2: Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. arm 3: Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. arm 4: Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. arm 5: Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. arm 6: Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. arm 7: Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. arm 8: Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

Interventions: intervention 1: Regorafenib intervention 2: Atezolizumab intervention 3: Imprime PGG intervention 4: Bevacizumab intervention 5: Isatuximab intervention 6: Selicrelumab intervention 7: Idasanutlin intervention 8: AB928 intervention 9: LOAd703
Intervention descriptions: intervention 1: Regorafenib will be administered orally on Days 1-21 of each 28-day cycle. intervention 2: Atezolizumab will be administered by intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of 21-day cycles, with the exception of the Atezolizumab + Selicrelumab + Bevacizumab, Atezolizumab + Idasanutlin, Atezolizumab + Regorafenib and Atezolizumab + Regorafenib + AB928 arms where the Atezolizumab will be administered by IV infusion every 2 weeks (Q2W) on Days 1 and 15 of each 28-day cycle. intervention 3: Imprime PGG will be administered by IV infusion weekly on Days 1, 8, and 15 of each 21-day cycle. intervention 4: Bevacizumab will be administered by IV infusion on Day 1 of each 21-day cycle for the Atezolizumab + Imprime PGG + Bevacizumab arm, and on Day 1 and Day 15 of each 28-day cycle for the Atezolizumab + Selicrelumab + Bevacizumab arm. intervention 5: Isatuximab will be administered on Day 1, 8 and 15 of cycle 1 and on day 1 of all subsequent cycles. Cycles will be 21 days long. intervention 6: Selicrelumab will be administered by subcutaneous (SC) injection on Day 1 of cycles 1-4 and every third cycle thereafter. Cycles will be 28 days long. intervention 7: Idasanutlin will be administered orally on Days 1-5 of each 28-day cycle. intervention 8: AB928 will be administered orally once daily on Days 1-28 of each 28-day cycle. intervention 9: LOAd703 will be administered by intratumoral injection on Day 1 of each 21-day cycle.

Protocol document:
Prot_SAP_000.pdf: 


CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
2/Protocol CO39612, Version 11
PROTOCOL HISTORY
Protocol
Version
Date Final
11
See electronic date stamp 
on title page.
10
30 August 2021
9
16 February 2021
8
16 January 2021
7
22 March 2020
6 (France, 
Switzerland, 
United Kingdom)
10 January 2020
5 (United States, 
Australia, South 
Korea) 
12 November 2019
4 (France)
29 October 2019
3
10 July 2019
2
16 October 2018
1
15 March 2018


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PROTOCOL AMENDMENT, VERSION 11:
RATIONALE
Protocol CO39612 has been amended primarily to update risks and management 
guidelines for atezolizumab to align with the latest Atezolizumab Investigator's Brochure
(Version 18).  Changes to the protocol, along with a rationale for each change, are 
summarized below:

The information on the atezolizumab, Imprime PGG, and bevacizumab arm, has 
been removed because enrollment and patient follow-up have been completed for 
this arm (Sections 1.3, 3.1.1, 3.1.1.1, 4.1.2, 4.2, 4.3.1, and 5.7, Appendices 8 and 
15).

The Modified RECIST v1.1 for Immune-Based Therapeutics (iRECIST) appendix 
(former Appendix 2) has been removed as the Sponsor no longer plans to perform 
these analyses (Sections 2, 3.1.3, 4.5.6, and 6.4.3; Section 3.3.3 has been deleted 
and subsequent sections have been renumbered).

Text has been added to clarify that, if tumor assessment scans for an experimental 
arm are submitted for evaluation by an Independent Review Facility, scans for the 
corresponding control arm will also be submitted (Section 3.1.3).

The inclusion criterion “Tumor accessible for biopsy” has been removed from 
Section 4.1.1.2 (Inclusion Criteria for Stage 1 and Stage 2), as it is redundant with 
existing criteria in Section 4.1.1.1 (Inclusion Criteria for Stage 1) and Section 4.1.1.3 
(Inclusion Criteria for Stage 2).

It has been clarified that during visits when a patient will undergo a tumor 
assessment, the physical examination should include an evaluation of the presence 
and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly
(Section 4.5.4; Section 6 in Appendix 14).

Text has been updated to align with current Roche protocol template language on 
genomic testing of blood and tissue samples for exploratory biomarker research 
(Section 4.5.7; and new Section 4.5.9 has been added and subsequent sections 
have been renumbered).

The procedures for reporting infusion-related reactions (IRRs) have been modified 
to include reporting of cytokine release syndrome (CRS), as there may be significant 
overlap in signs and symptoms of IRRs and CRS (Section 5.3.5.1).

The backup Medical Monitor for this study has changed and new contact information 
has been added (Section 5.4.1).

Text has been revised to note that 95% confidence intervals will be calculated using 
normal approximation of the binomial distribution (Sections 6.4.1 and 6.4.2).

The responsibilities of the investigator and the role of the Medical Monitor in 
determining patient eligibility have been clarified (Sections 3.1.3, 4.1.1.1, and 4.5.7; 
Appendices 4 and 6; Section 1.1.2 in Appendix 7; Sections 4.1.2 and 
5.1.4.15.1.4.3 in Appendix 11; Sections 4.1.2 and 5.1.4.15.1.4.3 in Appendix 12; 
Sections 4.1.2 and 5.1.5.15.1.5.3 in Appendix 13; Sections 4.1.2, 5.1.4.2, and 
5.1.4.3 in Appendix 14; Appendix 15).


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
The medical term “primary biliary cirrhosis” has been replaced by the term “primary 
biliary cholangitis” to align with the updated preferred term in Medical Dictionary for 
Regulatory Activities (Appendix 4).

The adverse event management guidelines have been updated to align with the 
Atezolizumab Investigator’s Brochure, Version 18 (Appendix 6; Section 5.1.4.3 in 
Appendices 11 and 12; Section 5.1.5.3 in Appendix 13).

To provide additional flexibility for patients and study sites, it has been clarified that 
the 96-hour window for laboratory testing is prior to dosing during the treatment 
period.  An additional footnote has been added to note assessments that may be 
performed within 24 hours prior to dosing during the treatment period. 
(Appendices 7, 1114).

Guidance on concomitant administration of coronavirus disease 2019 vaccines has 
been added (Section 4.2.1 in Appendices 1114).

Immunosuppressive medications have been removed from the prohibited therapy 
section (Section 4.2.3 in Appendices 1114) and added to the cautionary therapy 
section to align with management guidelines that permit use of immunosuppressive 
medications for the treatment of corticosteroid-refractory immune-mediated adverse 
events (Section 4.2.2 in Appendices 1114).

Safety and adverse event management guidelines have been updated to include 
CRS (Section 5.1.4.3 in Appendices 11 and 12; Section 5.1.5.3 in Appendix 13).

It has been clarified that urinalysis may be performed up to 72 hours prior to Day 1 
of each cycle, as results must be available prior to treatment administration
(Section 6 in Appendices 12 and 13).

The frequency of urinalysis assessments has been adjusted to as clinically indicated 
for the Atezo+LOAd703 Arm (Section 6 in Appendix 14).
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.


CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 33
1.1
Background on Colorectal Cancer......................................... 33
1.2
Treatment for Metastatic Colorectal Cancer .......................... 34
1.3
Study Rationale and Benefit–Risk Assessment..................... 35
1.4
Covid-19 BenefitRisk Assessment....................................... 37
2.
OBJECTIVES AND ENDPOINTS ............................................................... 39
3.
STUDY DESIGN......................................................................................... 43
3.1
Description of the Study......................................................... 43
3.1.1
Stage 1 .................................................................................. 45
3.1.1.1
Safety Evaluation Phase........................................................ 48
3.1.1.2
Mandatory Serial-Biopsy Arms .............................................. 49
3.1.2
Stage 2 .................................................................................. 50
3.1.3
Assessments and Monitoring................................................. 50
3.1.4
Internal Monitoring Committee............................................... 51
3.1.5
Scientific Oversight Committee.............................................. 52
3.2
End of Study and Length of Study......................................... 52
3.3
Rationale for Study Design.................................................... 52
3.3.1
Rationale for Patient Population ............................................ 52
3.3.2
Rationale for Immunotherapy-Based Treatment 
beyond Initial Radiographic Progression ............................... 52
3.3.3
Rationale for Biomarker Assessments................................... 53
4.
MATERIALS AND METHODS .................................................................... 54
4.1
Patients.................................................................................. 54
4.1.1
Inclusion Criteria.................................................................... 54
4.1.1.1
Inclusion Criteria for Stage 1 ................................................. 54
4.1.1.2
Inclusion Criteria for Stage 1 and Stage 2 ............................. 55
4.1.1.3
Inclusion Criteria for Stage 2 ................................................. 56
4.1.2
Exclusion Criteria................................................................... 56


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4.1.2.1
Exclusion Criteria for Stage 1 ................................................ 57
4.1.2.2
Exclusion Criteria for Stage 1 and Stage 2............................ 57
4.1.2.3
Additional Exclusion Criteria for 
Idasanutlin-Containing Arm during Stage 1 ........................... 61
4.1.2.4
Additional Exclusion Criteria for 
AB928-Containing Arm during Stage 1.................................. 61
4.1.2.5
Additional Exclusion Criteria for 
LOAd703-Containing Arm during Stage 1 ............................. 62
4.2
Method of Treatment Assignment.......................................... 63
4.3
Study Treatment.................................................................... 64
4.3.1
Investigational Medicinal Product Accountability ................... 64
4.3.2
Post-Trial Access to Study Treatment ................................... 64
4.4
Concomitant Therapy and Prohibited Food ........................... 64
4.5
Study Assessments ............................................................... 64
4.5.1
Informed Consent Forms and Screening............................... 65
4.5.2
Prescreen Testing for TP53 Mutation Status for 
Atezo Idasa Arm ................................................................. 65
4.5.3
Medical History, Molecular Profile, Concomitant 
Medication, and Demographic Data ...................................... 65
4.5.4
Physical Examinations........................................................... 66
4.5.5
Vital Signs.............................................................................. 66
4.5.6
Tumor and Response Evaluations......................................... 66
4.5.7
Laboratory, Biomarker, and Other Biologic 
Samples................................................................................. 68
4.5.8
Electrocardiograms................................................................ 72
4.5.9
Blood Samples for Whole Genome Sequencing 
or Whole Exome Sequencing (Patients at 
Participating Sites)................................................................. 72
4.5.10
Optional Tumor Biopsies ....................................................... 73
4.5.11
Optional Samples for Research Biosample 
Repository ............................................................................. 74
4.5.11.1
Overview of the Research Biosample Repository.................. 74
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 74
4.5.11.3
Sample Collection.................................................................. 74
4.5.11.4
Confidentiality........................................................................ 75


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4.5.11.5
Consent to Participate in the Research 
Biosample Repository............................................................ 75
4.5.11.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 76
4.5.11.7
Monitoring and Oversight....................................................... 76
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 77
4.6.1
Study Treatment Discontinuation........................................... 77
4.6.2
Patient Discontinuation from Study........................................ 78
4.6.3
Study Discontinuation............................................................ 78
4.6.4
Site Discontinuation............................................................... 78
5.
ASSESSMENT OF SAFETY....................................................................... 78
5.1
Safety Plan ............................................................................ 78
5.2
Safety Parameters and Definitions ........................................ 79
5.2.1
Adverse Events ..................................................................... 79
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 79
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 80
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 80
5.3.1
Adverse Event Reporting Period ........................................... 80
5.3.2
Eliciting Adverse Event Information....................................... 81
5.3.3
Assessment of Severity of Adverse Events ........................... 81
5.3.4
Assessment of Causality of Adverse Events ......................... 82
5.3.5
Procedures for Recording Adverse Events............................ 83
5.3.5.1
Infusion-Related or Injection-Site Reactions and 
Cytokine Release Syndrome ................................................. 83
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 84
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 84
5.3.5.4
Persistent or Recurrent Adverse Events................................ 84
5.3.5.5
Abnormal Laboratory Values ................................................. 85
5.3.5.6
Abnormal Vital Sign Values ................................................... 86
5.3.5.7
Abnormal Liver Function Tests.............................................. 86


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5.3.5.8
Deaths ................................................................................... 86
5.3.5.9
Preexisting Medical Conditions.............................................. 87
5.3.5.10
Lack of Efficacy or Worsening of Metastatic 
Colorectal Cancer.................................................................. 87
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 87
5.3.5.12
Reporting Requirements for Cases of Overdose, 
Medication Error, Drug Abuse, or Drug Misuse ..................... 88
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 90
5.4.1
Emergency Medical Contacts................................................ 91
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 91
5.4.2.1
Events That Occur prior to Study Treatment 
Initiation ................................................................................. 91
5.4.2.2
Events That Occur after Study Treatment 
Initiation ................................................................................. 91
5.4.3
Reporting Requirements for Pregnancies.............................. 92
5.5
Follow-Up of Patients after Adverse Events .......................... 92
5.5.1
Investigator Follow-Up........................................................... 92
5.5.2
Sponsor Follow-Up ................................................................ 92
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 92
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 93
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 93
6.1
Determination of Sample Size ............................................... 94
6.2
Summaries of Conduct of Study............................................ 94
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 95
6.4
Efficacy Analyses .................................................................. 95
6.4.1
Primary Efficacy Endpoint...................................................... 95
6.4.2
Secondary Efficacy Endpoints............................................... 95
6.4.3
Exploratory Efficacy Endpoints.............................................. 96
6.5
Safety Analyses..................................................................... 96
6.6
Pharmacokinetic Analyses..................................................... 96


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6.7
Immunogenicity Analyses...................................................... 97
6.8
Shedding Analyses................................................................ 97
6.9
Biomarker Analyses............................................................... 97
6.10
Interim Analyses .................................................................... 97
7.
DATA COLLECTION AND MANAGEMENT ............................................... 98
7.1
Data Quality Assurance......................................................... 98
7.2
Electronic Case Report Forms............................................... 98
7.3
Source Data Documentation.................................................. 99
7.4
Use of Computerized Systems .............................................. 99
7.5
Retention of Records........................................................... 100
8.
ETHICAL CONSIDERATIONS.................................................................. 100
8.1
Compliance with Laws and Regulations .............................. 100
8.2
Informed Consent................................................................ 100
8.3
Institutional Review Board or Ethics Committee.................. 101
8.4
Confidentiality...................................................................... 102
8.5
Financial Disclosure ............................................................ 102
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 103
9.1
Study Documentation .......................................................... 103
9.2
Protocol Deviations.............................................................. 103
9.3
Site Inspections ................................................................... 103
9.4
Administrative Structure....................................................... 103
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 103
9.6
Protocol Amendments ......................................................... 104
10. REFERENCES ......................................................................................... 105
LIST OF TABLES
Table 1
Target and Proposed Mechanism-of-Action Classification for 
Experimental Investigational Medicinal Products........................ 36
Table 2
Objectives and Corresponding Endpoints for Stage 1 ................ 39
Table 3
Objectives and Corresponding Endpoints for Stage 2 ................ 41
Table 4
Stage 1 Treatment Regimens ..................................................... 46


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Table 5
Treatment Arms with Completed Enrollment and Patient 
Follow-Up.................................................................................... 48
Table 6
Stage 2 Treatment Regimens ..................................................... 50
Table 7
Arm-Specific Exclusion Criteria................................................... 56
Table 8
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 82
Table 9
Causal Attribution Guidance ....................................................... 83
LIST OF FIGURES
Figure 1
General Study Design................................................................. 44
Figure 2
Detailed Study Design ................................................................ 47
LIST OF APPENDICES
Appendix 1
Response Evaluation Criteria In Solid Tumors, 
Version 1.1 (RECIST V1.1)....................................................... 108
Appendix 2
Placeholder for Future Arm....................................................... 117
Appendix 3
ECOG Performance Status Scale............................................. 118
Appendix 4
Preexisting Autoimmune Diseases and Immune Deficiencies .. 119
Appendix 5
Anaphylaxis Precautions........................................................... 120
Appendix 6
Risks Associated with Atezolizumab and Guidelines for 
Management of Atezolizumab-Specific Adverse Events........... 121
Appendix 7
Study Details Specific to the Regorafenib Arm (Control) .......... 148
Appendix 8
Placeholder for Future Arm....................................................... 165
Appendix 9
Placeholder for Future Arm....................................................... 166
Appendix 10
Placeholder for Future Arm....................................................... 167
Appendix 11
Study Details Specific to AtezoIdasa Arm.............................. 168
Appendix 12
Study Details Specific to AtezoRegorafenib Arm ................... 218
Appendix 13
Study Details Specific to AtezoRegorafenibAB928 Arm....... 261
Appendix 14
Study Details Specific to AtezoLOAd703 Arm....................... 314
Appendix 15
Schedules of Activities for Screening....................................... 366


CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
11/Protocol CO39612, Version 11
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE Ib/II, OPEN-LABEL, MULTICENTER, 
RANDOMIZED UMBRELLA STUDY EVALUATING 
THE EFFICACY AND SAFETY OF MULTIPLE 
IMMUNOTHERAPY-BASED TREATMENT 
COMBINATIONS IN PATIENTS WITH METASTATIC
COLORECTAL CANCER (MORPHEUS-CRC)
PROTOCOL NUMBER:
CO39612
VERSION NUMBER:
11
EUDRACT NUMBER:
2017-004566-99
IND NUMBER:
137508
NCT NUMBER:
NCT03555149
TEST PRODUCTS:
Atezolizumab (RO5541267), regorafenib, idasanutlin 
(RO5503781), AB928, LOAd703 (delolimogene 
mupadenorepvec)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by Covance.


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PROTOCOL SYNOPSIS
TITLE:
A PHASE Ib/II, OPEN-LABEL, MULTICENTER, RANDOMIZED 
UMBRELLA STUDY EVALUATING THE EFFICACY AND SAFETY 
OF MULTIPLE IMMUNOTHERAPY-BASED TREATMENT 
COMBINATIONS IN PATIENTS WITH METASTATIC 
COLORECTAL CANCER (MORPHEUS-CRC)
PROTOCOL NUMBER:
CO39612
VERSION NUMBER:
11
EUDRACT NUMBER:
2017-004566-99
IND NUMBER:
137508
NCT NUMBER:
NCT03555149
TEST PRODUCTS:
Atezolizumab (RO5541267), regorafenib, idasanutlin (RO5503781), 
AB928, LOAd703 (delolimogene mupadenorepvec)
PHASE:
Ib/II
INDICATION:
Colorectal cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of immunotherapy-based 
treatment combinations in patients with metastatic colorectal cancer (mCRC).  Specific 
objectives and corresponding endpoints for the study are outlined below for Stage 1 (see 
Table 1) and Stage 2 (see Table 2).
Table 1
Objectives and Corresponding Endpoints for Stage 1
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
immunotherapy-based treatment 
combinations during Stage 1
ORR, defined as the proportion of patients with a complete 
response or partial response on two consecutive occasions 
4 weeks apart during Stage 1, as determined by the 
investigator according to RECIST v1.1
ORR objective response rate; RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1.
Note:  Overall response at a single timepoint will be assessed by the investigator using RECIST v1.1.  


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Table 1
Objectives and Corresponding Endpoints for Stage 1 (cont.)
Secondary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of 
immunotherapy-based treatment 
combinations during Stage 1
PFS after randomization,a defined as the time from 
randomization to the first occurrence of disease progression or 
death from any cause (whichever occurs first) in Stage 1, as 
determined by the investigator according to RECIST v1.1
OS after randomization,a defined as the time from
randomization to death from any cause
OS at specific timepoints (e.g., 6 months)
DOR, defined as the time from the first occurrence of a 
documented objective response during Stage 1 to disease 
progression or death from any cause (whichever occurs first), 
as determined by the investigator according to RECIST v1.1
DCR, defined as the proportion of patients with stable disease 
for 12 weeks or a complete or partial response, as 
determined by the investigator according to RECIST v1.1
Safety Objective
Corresponding Endpoints
To evaluate the safety of 
immunotherapy-based treatment 
combinations during Stage 1
Incidence, nature, and severity of adverse events and 
laboratory abnormalities, with severity determined according to 
NCI CTCAE v4.0
Change from baseline in vital signs and ECG parameters
Change from baseline in targeted clinical laboratory test results
Exploratory Pharmacokinetic 
Objectives
Corresponding Endpoints
To characterize the PK profile of drugs 
that are administered as part of an 
immunotherapy-based treatment 
combination during Stage 1
Plasma or serum concentration of each drug (as appropriate) 
at specified timepoints 
To evaluate potential relationships 
between drug exposure during Stage 1 
and the efficacy and safety of 
immunotherapy-based treatment 
combinations
Relationship between plasma or serum concentration or PK 
parameters for each drug (as appropriate on the basis of 
available data) and efficacy endpoints 
Relationship between plasma or serum concentration or PK 
parameters for each drug (as appropriate on the basis of 
available data) and safety endpoints
Exploratory Immunogenicity Objectives
Corresponding Endpoints
To evaluate the immune response to 
drugs that are administered as part of 
an immunotherapy-based treatment 
combination during Stage 1
For drugs for which ADA formation is measured:  presence of 
ADAs during the study relative to the presence of ADAs at 
baseline
ADA anti-drug antibody; DCR disease control rate; DOR duration of response; NCI CTCAE
v4.0 National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0; 
ORR objective response rate; OS overall survival; PFS progression-free survival; PK pharmacokinetic;
RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1.
Note:  Overall response at a single timepoint will be assessed by the investigator using RECIST v1.1.  
a
For the mandatory serial-biopsy arms, PFS and OS will be determined from the time of treatment 
initiation (rather than time of randomization).


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Table 1
Objectives and Corresponding Endpoints for Stage 1 (cont.)
Exploratory Immunogenicity Objectives 
(cont.)
Corresponding Endpoints
To evaluate potential effects of ADAs 
during Stage 1
For drugs for which ADA formation is measured:  relationship 
between ADA status and efficacy, safety, or PK endpoints
Exploratory Biomarker Objective
Corresponding Endpoint
To identify biomarkers during Stage 1 
that are predictive of response to study 
treatment (i.e., predictive biomarkers), 
are associated with progression to a 
more severe disease state 
(i.e., prognostic biomarkers), are 
associated with resistance to study 
treatment, are associated with 
susceptibility to developing adverse 
events (i.e., safety biomarkers), can 
provide evidence of study treatment 
activity (i.e., pharmacodynamic 
biomarkers), or can increase the 
knowledge and understanding of 
disease biology
Relationship between biomarkers in blood and tumor tissue 
and efficacy, safety, PK, immunogenicity, or other biomarker 
endpoints
ADA anti-drug antibody; PK pharmacokinetic.
Table 2
Objectives and Corresponding Endpoints for Stage 2
Exploratory Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of 
immunotherapy-based treatment 
combinations during Stage 2
ORR, defined as the proportion of patients with a complete 
response or partial response on two consecutive occasions 
4 weeks apart during Stage 2, as determined by the 
investigator according to RECIST v1.1 
PFS after initiation of Stage 2, defined as the time from 
initiation of Stage 2 to the first occurrence of disease 
progression or death from any cause (whichever occurs first), 
as determined by the investigator according to RECIST v1.1 
DOR, defined as the time from the first occurrence of a 
documented objective response during Stage 2 to disease 
progression or death from any cause (whichever occurs first), 
as determined by the investigator according to RECIST v1.1 
DCR, defined as the proportion of patients with stable disease 
for 12 weeks or a complete or partial response, as 
determined by the investigator according to RECIST v1.1 and 
Safety Objective
Corresponding Endpoints
To evaluate the safety of 
immunotherapy-based treatment 
combinations during Stage 2
Incidence, nature, and severity of adverse events and 
laboratory abnormalities, with severity determined according to 
NCI CTCAE v4.0
Change from baseline in vital signs and ECG parameters
Change from baseline in targeted clinical laboratory test results
DCR disease control rate; DOR duration of response; NCI CTCAE v4.0 National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0; ORR objective response rate; 
PFS progression-free survival; PK pharmacokinetic; RECIST v1.1 Response Evaluation Criteria in Solid 
Tumors, Version 1.1.
Note:  Overall response at a single timepoint will be assessed by the investigator using RECIST v1.1.  


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Table 2
Objectives and Corresponding Endpoints for Stage 2 (cont.)
Exploratory Pharmacokinetic 
Objective
Corresponding Endpoints
To characterize the PK profile of drugs 
that are administered as part of an 
immunotherapy-based treatment 
combination during Stage 2
Plasma or serum concentration of each drug (as appropriate) 
at specified timepoints 
Exploratory Pharmacokinetic Objective
Corresponding Endpoints
To evaluate potential relationships 
between drug exposure during Stage 2 
and the efficacy and safety of 
immunotherapy-based treatment 
combinations
Relationship between plasma or serum concentration or PK 
parameters for each drug (as appropriate on the basis of 
available data) and efficacy endpoints 
Relationship between plasma or serum concentration or PK 
parameters for each drug (as appropriate on the basis of 
available data) and safety endpoints
Exploratory Immunogenicity Objective
Corresponding Endpoints
To evaluate the immune response to 
drugs that are administered as part of 
an immunotherapy-based treatment 
combination during Stage 2
For drugs for which ADA formation is measured:  presence of 
ADAs during the study relative to the presence of ADAs at 
baseline
To evaluate potential effects of ADAs 
during Stage 2
For drugs for which ADA formation is measured:  relationship 
between ADA status and efficacy, safety, or PK, endpoints
Exploratory Biomarker Objective
Corresponding Endpoint
To identify biomarkers during Stage 2 
that are predictive of response to study 
treatment (i.e., predictive biomarkers), 
are associated with progression to a 
more severe disease state 
(i.e., prognostic biomarkers), are 
associated with resistance to study 
treatment, are associated with 
susceptibility to developing adverse 
events (i.e., safety biomarkers), can 
provide evidence of study treatment 
activity (i.e., pharmacodynamic 
biomarkers), or can increase the 
knowledge and understanding of 
disease biology
Relationship between biomarkers in blood and tumor tissue 
and efficacy, safety, PK, immunogenicity, or other biomarker 
endpoints
ADA anti-drug antibody; PK pharmacokinetic.
STUDY DESIGN
DESCRIPTION OF STUDY
Overview of Study Design
This is a Phase Ib/II, open-label, multicenter, randomized, umbrella study in patients with mCRC.  
The study is designed with the flexibility to open new treatment arms as new treatments 
become available, close existing treatment arms that demonstrate minimal clinical activity or 
unacceptable toxicity, or modify the patient population (e.g., with regard to prior anti-cancer 
treatment or biomarker status).  This study will enroll patients with mCRC who became 
refractory to first- and second-line standard therapies for mCRC. Eligible patients will initially be 
assigned to one of several treatment arms (Stage 1; see below).  Patients who experience 
disease progression, loss of clinical benefit, or unacceptable toxicity during Stage 1 may be 
eligible to continue treatment with a different treatment regimen (Stage 2; see below).




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Patients in the regorafenib control arm will continue to receive treatment until unacceptable 
toxicity or disease progression per Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1).  Patients in the experimental arms will be treated until unacceptable toxicity or 
loss of clinical benefit defined as (1) confirmed disease progression in the tumor assessment 
following the finding of radiographic progression per RECIST v1.1 or (2) lack of continued 
benefit as determined by the investigator after an integrated assessment of radiographic and 
biochemical data, local biopsy results (if available), and clinical status (e.g., symptomatic 
deterioration such as pain secondary to disease).  Because of the possibility of an initial 
increase in tumor burden caused by immune-cell infiltration in the setting of a T-cell response 
(termed pseudoprogression) with cancer immunotherapies (CITs; such as atezolizumab), 
radiographic progression per RECIST v1.1 may not be indicative of true disease progression.  
After the first tumor assessment meeting the criteria for disease progression per RECIST v1.1, 
patients receiving treatment with a CIT drug will be permitted to continue study treatment if they 
meet all of the following criteria:

Evidence of clinical benefit, as determined by the investigator following a review of all 
available data

Absence of symptoms and signs (including laboratory values, such as new or worsening 
hypercalcemia) indicating unequivocal progression of disease

Absence of decline in Eastern Cooperative Oncology Group (ECOG) Performance Status 
that can be attributed to disease progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions
Safety Evaluation Phase
To account for potential overlapping toxicities in the Atezo Idasa, Atezo Regorafenib, 
Atezo Regorafenib AB928, and Atezo LOAd703 arms, enrollment within each arm will be 
suspended after approximately 6 patients have been enrolled to allow for a safety evaluation.  
The safety evaluation will be based on safety data from a minimum of 6 patients who have 
received at least one dose of treatment (i.e., one dose of each agent for a given combination) 
and completed safety follow-up assessments of at least one full treatment cycle.  If a 
combination is determined to be sufficiently safe, enrollment will be resumed in that arm.
Mandatory Serial-Biopsy Arms
If an experimental combination demonstrates clinical activity during the preliminary phase, the 
Sponsor may decide to test that same combination in a mandatory serial-biopsy arm at the time 
that arm is open for expansion.  This arm will consist of patients at participating sites who are 
willing to undergo an on-treatment biopsy.
The opening of mandatory serial-biopsy arms is contingent upon the review and approval of the 
protocol and the mandatory serial biopsy portion of the Informed Consent Form by each site's 
IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for mandatory serial biopsies, these arms will not be opened at that site.
The objective of the mandatory serial-biopsy arms is to analyze serial tissue samples (including 
pretreatment, on-treatment, and post-progression samples) in an effort to better understand 
potential biological changes that occur during treatment with CIT combinations (including 
immune escape), provide evidence of pharmacodynamic effects, or confirm hypothesized 
mechanisms of action.  Biomarkers may include those that inform stromal and immune biology.
Patients entering Stage 1 who are determined by the investigator to be eligible for serial 
biopsies may be enrolled in a mandatory serial-biopsy arm rather than undergo random 
assignment to other arms that are open for enrollment.  If more than one mandatory biopsy arm 
is open, patients will be assigned to one of the available arms by the Sponsor.  
Approximately 15 patients with serial biopsy samples will be enrolled in each mandatory 
serial-biopsy arm.  However, the number of patients will be reduced if optional on-treatment 
biopsies have been collected (and determined to be evaluable) from consenting patients treated 
with that same CIT combination during the preliminary phase, to limit on-treatment biopsy 
collection to a total of approximately 15 patients per CIT combination.  


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Patients will undergo the same assessments as other patients receiving the same treatment 
combination but will have an additional mandatory on-treatment biopsy 4 weeks (7 days)after 
initiation of CIT-combination treatment (if deemed clinically feasible by the investigator). 
To be eligible for a mandatory serial-biopsy arm, a patient should have at least two accessible 
tumors that are amenable to excisional, punch, or core-needle biopsy (a minimum of three 
cores, 18-gauge needle or larger [16-gauge needle preferred]) without unacceptable risk of a 
major procedural complication.  If it is planned that more than one biopsy will be obtained from a 
single lesion, the lesion should be large enough to permit successive biopsies 1 cm apart.
Patients enrolled in a mandatory serial-biopsy arm for whom three evaluable tissue samples 
cannot be obtained may continue to receive study treatment as scheduled. 
Stage 2
During Stage 1, patients who experience disease progression per RECIST v1.1, loss of clinical 
benefit defined as (1) confirmed disease progression or (2) lack of continued benefit as 
determined by the investigator (as described above), or unacceptable toxicity may be eligible to 
receive a different treatment combination during Stage 2, provided a Stage 2 treatment is 
available for enrollment and they meet the eligibility criteria of that treatment regimen.  A 
maximum of 40 patients will be enrolled in each of the Stage 2 treatment regimens as outlined 
in Table 4. 
Stage 2 treatment must begin within 3 months after a patient has experienced disease 
progression per RECIST v1.1 (regorafenib control arm), loss of clinical benefit (experimental 
arms), or unacceptable toxicity and will continue until unacceptable toxicity or loss of clinical 
benefit defined as (1) confirmed disease progression or (2) lack of continued benefit as 
determined by the investigator.  It is recommended that patients begin Stage 2 treatment as 
soon as possible.
Table 4
Stage 2 Treatment Regimens
Study Treatment 
No Stage 2 treatment currently available
The Sponsor may decide to hold or discontinue enrollment in Stage 2 on the basis of a review 
of safety data, preliminary efficacy data, and supportive information (e.g., biomarker research 
data), as appropriate.
Assessments and Monitoring
All patients will be closely monitored for adverse events throughout the study, and adverse 
events will be graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 4.0 (NCI CTCAE v4.0).
Patients will undergo tumor assessments every 6 weeks (starting on Day 1 of Cycle 1) for the 
first 48 weeks and then every 6 or 12 weeks thereafter.  Response will be assessed by the 
investigator using RECIST v1.1.  If clinical activity is demonstrated in an experimental arm, the 
Sponsor may request that tumor assessment scans for that arm and the corresponding control 
arm be submitted for evaluation by an independent reading facility.
Baseline tumor tissue samples will be collected 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, provided that the tissue was obtained from a biopsy performed 
within 6 months prior to enrollment and that the patient has not received any anti-cancer therapy 
since the time of the biopsy.  Tumor tissue will also be collected from patients who discontinue 
Stage 1 because of unacceptable toxicity, disease progression per RECIST v1.1 (regorafenib 
control arm), or loss of clinical benefit defined as (1) confirmed disease progression or (2) lack 
of continued benefit as determined by the investigator (experimental arms) if deemed clinically 
feasible by the investigator.  For patients enrolled in a mandatory serial-biopsy arm at 
participating sites, an additional tumor tissue sample will be collected during treatment (if 
clinically feasible).  These samples, as well as blood samples collected during the study, will be 
utilized for biomarker research.


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To characterize the pharmacokinetic (PK) properties and/or immunogenicity of atezolizumab 
and other therapeutic agents, blood samples will be obtained at various timepoints before and 
during study treatment administration.  
On the basis of a review of real-time safety data and available PK data, treatment regimens 
may be modified by the Sponsor as deemed appropriate.
Internal Monitoring Committee
An Internal Monitoring Committee (IMC) will monitor patient safety throughout the study.  The 
IMC will include representatives from Clinical Science, Safety Science, and Biostatistics.  In 
addition to the ongoing assessment of the incidence, nature, and severity of adverse events, 
serious adverse events, deaths, and laboratory abnormalities performed by the investigator and 
the Medical Monitor, the IMC will review all necessary cumulative data at regular intervals 
during the study.  At the time of each review, the IMC will make appropriate recommendations 
(e.g., the study should continue as planned, enrollment in a specific arm should be discontinued, 
a treatment regimen should be modified, the protocol should be amended, enrollment should be 
held pending further safety evaluations).  Decisions will be made in consideration of the totality 
of the available data.  Ad-hoc meetings may be called in addition to scheduled meetings, as 
necessary, to provide recommendations on management of any new safety issues.  Specific 
operational details such as the committee's composition, frequency and timing of meetings, and 
members' roles and responsibilities will be detailed in an IMC Charter.
Scientific Oversight Committee
A Scientific Oversight Committee (SOC) will act as a consultative body to the Sponsor, 
providing external expert opinions on the safety data collected during the study.  This committee 
will consist of an external group of at least three oncology experts in CIT who will advise the 
Sponsor on the interpretation of study data.  For this purpose, the SOC will evaluate aggregate 
safety data on a periodic basis, approximately every 6 months from the time the first patient is 
enrolled in the study.  Members will follow a charter that outlines their roles and responsibilities.  
Data being evaluated by the SOC will include demographic, adverse event, serious adverse 
event, and relevant laboratory data.  The SOC may review efficacy data if safety concerns 
necessitate benefitrisk assessments.  The Sponsor will retain all decision-making authority for 
this study.
NUMBER OF PATIENTS
Approximately 111382 patients will be enrolled in the study.
TARGET POPULATION
Inclusion Criteria
Patients must meet all of the criteria outlined in Sections 1 and 2 to qualify for Stage 1.  
Patients must meet all of the criteria outlined in Sections 2 and 3 to qualify for Stage 2.
Section 1:  Inclusion Criteria for Stage 1
Patients must meet all of the following criteria to qualify for Stage 1:

Age 18 years at the time of signing Informed Consent Form

ECOG Performance Status of 0 or 1 

Life expectancy 3 months, as determined by the investigator

Histologically confirmed adenocarcinoma originating from the colon or rectum

Metastatic disease (Stage IV American Joint Committee on Cancer, Version 7) not 
amenable to local treatment

Disease progression during or following not more than two separate lines of treatment for 
mCRC that consisted of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing 
chemotherapy in combination with a biologic agent (i.e., bevacizumab, ramucirumab, 
aflibercept, cetuximab, panitumumab) but not other agents
For patients who had disease recurrence within 6 months of completing adjuvant 
chemotherapy, the adjuvant regimen can be considered as one line of treatment for 
metastatic disease.


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The re-introduction of an initially successful induction regimen will not be counted as one 
additional line of treatment.
Patients who have received first-line induction therapy with FOFOXIRI plus a biologic 
agent followed by maintenance therapy must have had documented disease progression 
no less than 3 months after the completion of the first-line induction therapy.

Availability of a representative tumor specimen that is suitable for determination of 
programmed death-ligand 1 (PD-L1) and/or additional biomarker status by means of central 
testing 
Baseline tumor tissue samples will be collected 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, provided that the tissue was obtained from a 
biopsy performed within 6 months prior to enrollment and that the patient has not 
received any anti-cancer therapy since the time of the biopsy.  
A formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block 
(preferred) or 10-16 slides (16 slides preferred) containing unstained, freshly cut, serial 
sections must be submitted along with an associated pathology report.  
Section 2:  Inclusion Criteria for Stage 1 and Stage 2
Patients must meet all of the following criteria to qualify for Stage 1 and to qualify for Stage 2:

Signed Informed Consent Form

Ability to comply with the study protocol, in the investigator’s judgment

Measurable disease (at least one target lesion) according to RECIST v1.1 
Previously irradiated lesions can be considered as measurable disease only 
if progressive disease has been unequivocally documented at that site since radiation.

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 (1500/L) without granulocyte colony-stimulating factor support
-
WBC count 2.5 109/L (2500/L)
-
Lymphocyte count 0.5 109/L (500/L)
-
Platelet count 100 109/L (100,000/L) without transfusion
-
Hemoglobin 90 g/L (9.0 g/dL)
Patients must not have been transfused within 2 weeks prior to screening to meet 
this criterion.
-
AST, ALT, and alkaline phosphatase (ALP) 2.5 upper limit of normal (ULN), with the 
following exceptions:
Patients with documented liver metastases:  AST and ALT 5 ULN
Patients with documented liver or bone metastases:  ALP 5 ULN
-
Bilirubin 1.5 ULN, with the following exception: 
Patients with known Gilbert syndrome:  bilirubin level 3 ULN 
-
Albumin 25 g/L (2.5 g/dL)
-
Creatinine 1.5 ULN 
-
For patients not receiving therapeutic anticoagulation:  INR or aPTT 1.5 ULN

For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen during the 
14 days prior to initiation of study treatment

Negative HIV test at screening
Patients without a prior positive HIV test result will undergo an HIV test at screening, 
unless not permitted per local regulations

Negative hepatitis B surface antigen (HBsAg) test at screening

Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb 
test followed by a negative hepatitis B virus (HBV) DNA test at screening


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The HBV DNA test will be performed only for patients who have a positive total HBcAb 
test.

Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test 
followed by a negative HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive HCV antibody 
test.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures as outlined for each specific 
treatment arm 

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as outlined for 
each specific treatment arm 
Section 3:  Inclusion Criteria for Stage 2
Patients must meet all of the following criteria to qualify for Stage 2: 

ECOG Performance Status of 02 

Patients in the control arm:  ability to initiate Stage 2 treatment within 3 months after 
experiencing unacceptable toxicity or disease progression per RECIST v1.1 while receiving 
Stage 1 treatment

Patients in an experimental arm during Stage 1:  ability to initiate Stage 2 treatment within 
3 months after experiencing unacceptable toxicity not related to atezolizumab or loss of 
clinical benefit defined as (1) confirmed disease progression or (2) lack of continued benefit 
as determined by the investigator while receiving Stage 1 treatment

Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage 1 (if 
deemed clinically feasible by the investigator)
Exclusion Criteria
Patients will be excluded from enrollment during Stage 1 and Stage 2 if they meet any of the 
applicable criteria outlined in subsequent sections, as summarized by treatment arm in Table 5.  
If a patient is eligible only for the control arm, the patient will not be enrolled in the study.  Event 
grades in the exclusion criteria are based on NCI CTCAE v4.0.
Table 5
Arm-Specific Exclusion Criteria
Stage
Treatment Arm
Applicable Exclusion Criteria
1
Regorafenib
Sections 1 and 2 
Atezo Idasa
Sections 1, 2, and 3
Atezo Regorafenib
Sections 1 and 2 
Atezo Regorafenib AB928
Sections 1, 2, and 4
AtezoLOAd703
Sections 1, 2, and 5
2
Not currently available
Not applicable
Atezo atezolizumab; Idasa idasanutlin; LOAd Lokon oncolytic adenovirus.
Section 1:  Exclusion Criteria for Stage 1
Patients who meet any of the following criteria will be excluded from Stage 1:

High microsatellite instability (MSI-H) tumor
Patients with unknown microsatellite instability (MSI) status will be required to undergo 
testing at a local laboratory and provide results at screening; genomic testing using 
polymerase chain reaction (PCR) or sequencing, or immunohistochemistry (IHC) 
techniques are allowed.

Presence of BRAFV600E mutation
Patients with unknown BRAF status will be required to undergo testing at a local 
laboratory and provide results at screening.


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
Prior treatment with any of the protocol-specified study treatments, with the following 
exception:
Patients who received bevacizumab for treatment of CRC are eligible for the study. 

Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies 
including anti-cytotoxic T lymphocyteassociated protein 4 (antiCTLA-4), anti-programmed 
death-1 (antiPD-1), and antiPD-L1 therapeutic antibodies

Biologic treatment (e.g., bevacizumab) within 2 weeks prior to initiation of study treatment, 
or other systemic treatment for colorectal cancer (CRC) within 2 weeks or 5 half-lives of the 
drug (whichever is shorter) prior to initiation of study treatment

Treatment with investigational therapy within 28 days prior to initiation of study treatment 

Eligibility only for the control arm
Section 2:  Exclusion Criteria for Stage 1 and Stage 2
Patients who meet any of the following criteria will be excluded from Stage 1 and from Stage 2:

Prior allogeneic stem cell or solid organ transplantation

Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to the 
initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 
necrosis factor-agents) within 2 weeks prior to initiation of study treatment, or anticipation 
of need for systemic immunosuppressant medication during study treatment, with the 
following exceptions:
Patients who received acute, low-dose, systemic immunosuppressant medications or a 
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study.
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for 
orthostatic hypotension or adrenal insufficiency are eligible for the study.

Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, 
or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months 
after the last dose of atezolizumab

Current treatment with anti-viral therapy for HBV

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently)
Use of an indwelling catheter (e.g., PleurX) is allowed.

Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry.
Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) 
amenable to palliative radiotherapy should be treated prior to enrollment.  Patients should 
be recovered from the effects of radiation.  There is no required minimum recovery 
period.
Asymptomatic metastatic lesions that would likely cause functional deficits or intractable 
pain with further growth (e.g., epidural metastasis that is not presently associated with 
spinal cord compression) should be considered for loco-regional therapy if appropriate 
prior to enrollment.

Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, 
calcium 12 mg/dL, or corrected serum calcium ULN)


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
Symptomatic, untreated, or actively progressing CNS metastases 
Patients with a history of treated CNS metastases are eligible, provided that all of the 
following criteria are met:
-
Measurable disease, per RECIST v1.1, must be present outside the CNS.
-
The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.
-
Metastases are limited to the cerebellum or the supratentorial region (i.e., no 
metastases to the midbrain, pons, medulla, or spinal cord).
-
There is no evidence of interim progression between completion of CNS-directed 
therapy and the screening brain scan.
-
The patient has not received stereotactic radiotherapy within 7 days prior to initiation 
of study treatment or whole-brain radiotherapy within 14 days prior to initiation of 
study treatment.
-
The patient has no ongoing requirement for corticosteroids as therapy for CNS 
disease.  Anti-convulsant therapy at a stable dose is permitted.
Asymptomatic patients with CNS metastases newly detected at screening are 
eligible for the study after receiving radiotherapy or surgery, with no need to repeat 
the screening brain scan.

History of leptomeningeal disease

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, antiphospholipid 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 a stable insulin regimen are 
eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the 
study provided all of following conditions are met:
-
Rash must cover 10% of body surface area.
-
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids.
-
There is no occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 
12 months.

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

History of malignancy other than CRC within 2 years prior to screening, with the exception 
of malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival 
[OS] rate 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma 
skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine 
cancer

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, 
or any active infection that, in the opinion of the investigator, could impact patient safety

Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment


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Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study.

Significant cardiovascular disease (such as New York Heart Association Class II or greater 
cardiac disease or cerebrovascular accident) within 3 months prior to initiation of study 
treatment, unstable angina or new onset angina within 3 months prior to initiation of study 
treatment, recent myocardial infarction within 6 months prior to initiation of study treatment, 
or unstable arrhythmia 

Grade 3 hemorrhage or bleeding event within 28 days prior to initiation of study treatment

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
Placement of central venous access catheter (e.g., port or similar) is not considered a 
major surgical procedure and is therefore permitted.

Adverse events from prior anti-cancer therapy that have not improved to Grade 1 or better, 
with the exception of alopecia of any grade and Grade 2 peripheral neuropathy

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

History of severe allergic reactions to chimeric or humanized antibodies or fusion proteins

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or 
any component of the atezolizumab formulation

Known allergy or hypersensitivity to any of the study drugs or their excipients

Patients entering Stage 2:  inability to tolerate atezolizumab during Stage 1

Pregnancy or breastfeeding, or intention of becoming 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.

Inability to swallow medications 

Malabsorption condition that would alter the absorption of orally administered medications

Evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e., 
in the absence of therapeutic anticoagulation)

Urine dipstick 2protein or 3.5 g of protein in a 24-hour urine collection
Patients discovered to have 2proteinuria on dipstick urinalysis at screening should 
undergo a 24-hour urine collection and must demonstrate 3.5 g of protein in 24 hours to 
be eligible.
Section 3:  Additional Exclusion Criteria for Idasanutlin-Containing Arm during Stage 1
Patients who meet any of the following criteria will be excluded from the idasanutlin-containing 
arm during Stage 1: 

Prior treatment with an MDM2 antagonist

TP53 mutation as determined centrally through use of a blood-based NGS ctDNA assay

Hypersensitivity to idasanutlin active substance or any of the excipients

Inability to interrupt treatment with moderate to strong CYP2C8 inducers and inhibitors 
(including gemfibrozil, which is also an inhibitor of UGT1A3), CYP2C8 substrates, strong 
CYP3A4 inducers or OATP1B1/3 substrates
These agents must be discontinued 14 days prior to the start of study treatment.

History of clinically significant liver cirrhosis (e.g., Child-Pugh class B and C)

Inadequate renal function assessed by either serum creatinine outside local laboratory 
reference ranges OR creatinine clearance (by Cockcroft Gault formula) 50 mL/min


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
Treatment with oral or parenteral anticoagulants/anti-platelet agents (e.g., warfarin, chronic 
daily treatment with aspirin [325 mg/day], clopidogrel, dabigatran, apixaban, rivaroxaban) 
within 7 days (or 5 half-lives) prior to treatment start
Treatment with, or switch to low molecular weight heparin (LMWH) or unfractionated 
heparin (UFH) is allowed, according to local practice.
Patients may receive anticoagulant flushes for maintenance of indwelling catheters.

Unstable seizure disorders

Active GI conditions, including, but not limited to, uncontrolled inflammatory bowel disease 
(e.g., Crohn’s disease, diverticulosis-associated colitis)

History of symptomatic clostridium difficile infection that required treatment within 1 month 
prior to dosing
Upon clinical response to C. difficile treatment, the stool consistency and frequency must 
have returned to pretreatment levels.
Section 4:  Additional Exclusion Criteria for AB928-Containing Arms during Stage 1
Patients who meet any of the following criteria will be excluded from the AB928-containing arm 
during Stage 1: 

Prior treatment with an agent targeting the adenosine pathway

Treatment with strong inhibitors of breast cancer resistance protein (BCRP) 
(e.g., cyclosporin A, eltrombopag) or BCRP substrates with a narrow therapeutic window, 
administered orally (e.g., prazosin, rosuvastatin), and within 4 weeks or 5 half-lives of the 
drug (whichever is longer) prior to initiation of study treatment

Treatment with strong inhibitors of P-glycoprotein (P-gp) (e.g., itraconazole, quinidine, 
verapamil, dronedarone, ranolazine) or P-gp substrates with a narrow therapeutic window, 
administered orally (e.g., digoxin), and within 4 weeks or 5 half-lives of the drug (whichever 
is longer) prior to initiation of study treatment

Treatment with known strong UDP-glucuronosyltransferases (UGTs) of UGT1A1, 1A4, 1A9 
and 2B4 inhibitors (e.g., atazanavir) within 4 weeks or 5 half-lives of the drug (whichever is 
longer) prior to the initiation of study treatment.

Treatment with known sensitive substrates of BSEP_within 4 weeks or 5 half-lives of the 
drug (whichever is longer) prior to the initiation of study treatment.

Treatment with known sensitive substrates of OCT2 within 4 weeks or 5 half-lives of the 
drug (whichever is longer) prior to the initiation of study treatment.

Treatment with known sensitive substrates of MATE-1 within 4 weeks or 5 half-lives of the 
drug (whichever is longer) prior to the initiation of study treatment.

Treatment with strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, 
phenobarbital, and St. John’s Wort) and strong CYP3A4 inhibitors (e.g., clarithromycin, 
grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole)
within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study 
treatment
Section 5:  Additional Exclusion Criteria for LOAd703-Containing Arm during Stage 1
Patients who meet any of the following criteria will be excluded from the LOAd703-containing 
arm during Stage 1:

Prior treatment with an adenovirus-based gene therapy 

Prior treatment with LOAd703 or any other oncolytic virus

Prior treatment with adenovirus-based vaccines (e.g., ChAdOx1 nCoV-19, Ad26.COV2.S)
up to 6 months prior to initiation of study treatment, anticipation of need for such a vaccine 
during LOAd703 treatment, or up to 6 months after the last dose of LOAd703

Absence of available lesion that is both  measurable according to RECIST v1.1 and  
injectable (as assessed by the investigator, refer to Section A14–4.1.2.1 for further 
guidance)


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The injected lesion should not be the only measurable lesion

Known hereditary bleeding diathesis or significant acquired coagulopathy at risk of bleeding 
(e.g., hemophilia, von Willebrand disease, cancer-associated diffuse intravascular 
coagulation) when only deep lesions are available for injection

For procedures with moderate or significant risk of bleeding (deep lesions and/or organs), 
use of therapeutic doses of anticoagulants prior to the initiation of study treatment 
Long-acting agents such as aspirin or clopidogrel should be discussed on a case-by-case 
basis with the Sponsor and may need to be discontinued before the start of study 
treatment.
Patients on preventive doses of LMWH or direct oral anticoagulant (DOAC) may be 
eligible if treatment can be suspended 24 hours (for LMWH) or 48 hours (for DOAC) prior 
to intratumoral injection and resumed 24 hours after the injection.
END OF STUDY
The end of this study is defined as the date when the last patient completes the last visit in both 
stages, including survival follow-up visits conducted by telephone or on-site visit.
LENGTH OF STUDY
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 35 years.
INVESTIGATIONAL MEDICINAL PRODUCTS
The investigational medicinal products (IMPs) for this study are atezolizumab, regorafenib, 
idasanutlin, AB928, and LOAd703.  
TEST PRODUCTS (INVESTIGATIONAL DRUGS)
Atezolizumab plus Idasanutlin (Stage 1)
Idasanutlin is planned to be administered orally at a dose of 200 mg QD 5d Q4W.  However, to 
account for potential toxicities, special caution will be taken by starting idasanutlin at a lower 
dose of 150 mg QD5d during Cycle 1 and continuing idasanutlin at the 200-mg dose in all 
subsequent cycles in (at a minimum) the first 5 patients.  If this regimen is determined to be safe 
and well tolerated, all subsequent patients will receive 200 mg QD5 Q4W in combination with 
atezolizumab during all cycles.  Patients enrolled in the AtezoIdasa arm will receive treatment 
until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an 
integrated assessment of radiographic and biochemical data, local biopsy results (if available), 
and clinical status (e.g., symptomatic deterioration such as pain secondary to disease).  It is 
recommended that treatment be initiated no later than 7 days after randomization.  Treatment 
with Atezo Idasa when idasanutlin is administered at 150 mg or at 200 mg is described in 
Table 6 and 7, respectively.  
Table 6
Initial Treatment Regimen for AtezoIdasa Arm
Cycle Length
Dose, Route, and Regimen
(drugs listed in order of administration)
28 days

Idasanutlin 150 mg orally once daily on Days 15 of each cycle a

Atezolizumab 840 mg IV on Days 1 and 15
Atezo Idasa atezolizumab plus idasanutlin.
a
For details regarding intra-patient dose increase and dose increase after the safety evaluation 
phase, refer to Section A114.1.2.2.


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Table 7
Treatment Regimen for AtezoIdasa Arm after Dose Increase
Cycle Length
Dose, Route, and Regimen
(drugs listed in order of administration)
28 days

Idasanutlin 200 mg orally once daily on Days 15 of each cycle

Atezolizumab 840 mg IV on Days 1 and 15
Atezo Idasa atezolizumab plus idasanutlin.
Atezolizumab plus Regorafenib (Stage 1)
Patients in the Atezo Regorafenib arm will receive treatment as outlined in Table 8 until 
unacceptable toxicity or loss of clinical benefit defined as (1) confirmed disease progression or 
(2) lack of continued benefit as determined by the investigator, after an integrated assessment 
of radiographic and biochemical data, local biopsy results (if available), and clinical status 
(e.g., symptomatic deterioration such as pain secondary to disease).  Treatment must be 
initiated no later than 7 days after treatment assignment.
Table 8
Treatment Regimen for AtezoRegorafenib Arm
Cycle Length
Dose, Route, and Regimen
(drugs listed in order of administration)
28 days

Atezolizumab 840 mg IV on Days 1 and 15 of each cycle

Regorafenib 120 mg by mouth once daily on Days 121 a
Atezoatezolizumab.
a
Regorafenib should be initiated at 80 mg, allowing sufficient time to monitor drug-related toxicities 
before considering dose escalation to 120 mg.  At least 7 days off regorafenib are required prior to 
starting a new treatment cycle.
Atezolizumab plus Regorafenib plus AB928 (Stage 1)
Patients in the Atezo RegorafenibAB928 arm will receive treatment as outlined in Table 9
until unacceptable toxicity or loss of clinical benefit defined as (1) confirmed disease 
progression or (2) lack of continued benefit as determined by the investigator, after an 
integrated assessment of radiographic and biochemical data, local biopsy results (if available), 
and clinical status (e.g., symptomatic deterioration such as pain secondary to disease).  
Treatment must be initiated no later than 7 days after treatment assignment.
Table 9
Treatment Regimen for AtezoRegorafenibAB928 Arm
Cycle Length
Dose, Route, and Regimen
(drugs listed in order of administration)
28 days

AB928 150 mg by mouth once daily on Days 128 of each cycle

Atezolizumab 840 mg IV on Days 1 and 15 of each cycle 

Regorafenib 120 mg by mouth once daily on Days 121 of each cycle a
Atezo atezolizumab; IVintravenous.
a
Regorafenib should be initiated at 80 mg, allowing sufficient time to monitor drug-related toxicities 
before considering dose escalation to 120 mg.  At least 7 days off regorafenib are required prior to 
starting a new treatment cycle.
Atezolizumab plus LOAd703 (Stage 1)
It is recommended that treatment be initiated no later than 7 days after randomization.


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Table 10
Treatment Regimen for Atezo LOAd703 Arm
Cycle Length
Dose, Route, and Regimen
(drugs listed in order of administration)
21 days

Atezolizumab 1200 mg IV on Day 1 of each cycle a

LOAd703 11011 VP or 51011 VP b intratumoral injection on Day 1 of each 
cycle c
a
Atezolizumab will be administered preferably prior to LOAd703 injection.  If LOAd703 cannot be 
administered the day of atezolizumab infusion, LOAd703 can be given on another day during the 
treatment week, after prior consultation with the Medical Monitor.  If atezolizumab is administered 
after LOAd703, it should not be administered until the LOAd703 observation period has ended. 
b
Initially, approximatively 3 to 6 patients will be treated at the dose of 11011 VP. If this dose is 
determined to be safe and well tolerated in these first 36 patients, the dose may be increased to 
51011 VP in the next enrolled patients according to the considerations described in the protocol.
c
After the initial six injections of LOAd703 (Cyles 16), there is an option to continue treatment with 
LOAd703 for an additional 6 administrations (Cycles 712) for a maximum total number of 12 
injections for patients who are deriving clinical benefit as determined by the investigator.  In the 
absence of confirmed PD, atezolizumab treatment can continue after LOAd703 treatment has ended 
or has been discontinued for reasons other than toxicity, provided the patient is tolerating 
atezolizumab and is receiving clinical benefit in the opinion of the investigator.  The Medical Monitor 
is available to advise as needed.
Control Arm
Patients in the regorafenib (control) arm will receive treatment as outlined in Table 11 until
unacceptable toxicity or disease progression per RECIST v1.1.  Treatment must be initiated no 
later than 7 days after treatment assignment.
Table 11
Treatment Regimen for Regorafenib Arm
Cycle Length
Dose, Route, and Regimen
28 days
Regorafenib 160 mg by mouth once daily on Days 121
Dose escalation to 160 mg during Cycle 1 per institutional guidelines, e.g., from 
80 mg in the first week followed by weekly dose increases to 120 mg in the 
second and 160 in the third week, is allowed.
NON-INVESTIGATIONAL MEDICINAL PRODUCTS
For patients in the Atezo Idasa arm, all patients should receive the premedications outlined in 
Table 12 to mitigate the risk of idasanutlin-related GI toxicities.
Table 12
Premedication for Idasanutlin
Premedication/Indication
Timepoint
Administration
5-HT3 receptor antagonist:  
To reduce the incidence and 
severity of nausea and vomiting 
Day 1, 3060 minutes prior to first 
administration of study medication 
(for long-acting anti-emetics, such 
as palonosetron); otherwise prior to 
each study medication 
administration (Days 15, for short 
acting anti-emetics, such as 
ondansetron or granisetron) a
Palonosetron IV 0.25 mg or PO 
0.5 mg, or 
granisetron transdermal system, 
or
oral ondansetron or granisetron b 
according to prescribing 
information
PO by mouth
a
Premedication to be repeated for every cycle.
b
Palonosetron is the recommended option because of its efficacy against delayed nausea and lack of QT 
interval–prolonging effects.


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STATISTICAL METHODS
PRIMARY ANALYSIS
The primary efficacy endpoint is objective response rate (ORR) during Stage 1, as defined in 
Table 1.  Patients with missing or no response assessments will be classified 
as non-responders.
ORR, defined as the proportion of patients with a complete or partial response, will be 
calculated for each arm, along with 95% CIs (ClopperPearson exact method).  The difference 
in ORR between the experimental arms and the corresponding control arm will also be 
calculated, along with 95% CIs, using normal approximation of the binomial distribution.
DETERMINATION OF SAMPLE SIZE  
This study is not designed to make explicit power and type I error considerations for a 
hypothesis test.  Instead, this study is designed to obtain preliminary efficacy, safety, and PK 
data on immunotherapy-based treatment combinations when administered to patients with 
mCRC who experienced disease progression during or following two lines of treatment for 
mCRC that consisted of fluoropyrimidine-, oxaliplatin-, or irinotecan-containing chemotherapy in 
combination with a biologic agent (e.g., bevacizumab, cetuximab), given in combination as two 
separate lines of therapy (in either order).
Approximately 111382 patients will be randomly allocated to the control and experimental 
arms during the study.
Approximately 15 patients with serial-biopsy samples will be enrolled in each mandatory 
serial-biopsy arm.  However, the number of patients may be reduced if optional on-treatment 
biopsies have been collected (and determined to be evaluable) from consenting patients treated 
with that same CIT combination during the preliminary phase, to limit on-treatment biopsy 
collection to approximately 15 patients per CIT combination within each cohort.  
With approximately 15 patients with serial biopsies in each arm, an 80% two-sided CI for a 
30% increase in CD8T cells in the center of the tumor would range from 22.8% to 37.2%, 
assuming a standard deviation of 0.20 for the difference in CD8T cells between paired 
samples (i.e., baseline vs. on-treatment samples, baseline vs. post-progression samples, or 
on-treatment vs. post-progression samples).
INTERIM ANALYSES
It is anticipated that at least one interim analysis will be conducted over the course of the study, 
with the earliest interim analysis taking place when at least one experimental arm has 
completed enrollment in the preliminary phase and patients have been followed for a minimum 
of 6 weeks.  A posterior probability will be used to guide further enrollment of 25 additional 
patients in the experimental arm.  Enrollment may be expanded if the posterior probability of 
demonstrating a given improvement in ORR compared with the control arm is greater than a 
prespecified threshold.  The current considerations are an improvement in ORR of 10% 
compared with the control arm and a posterior probability of 70%.  
An improvement of at least 10% in ORR as compared with control is considered clinically 
meaningful, and a posterior probability of 70% provides reasonable confidence that the 
difference will continue to be observed at the final analysis after completion of the expansion 
phase.  If an improvement of at least 10% is not observed in a given arm, enrollment will either 
be stopped for futility or paused for further evaluation.  The Sponsor may make a decision to 
expand enrollment in an arm based on the totality of available data including, but not limited to, 
duration of the observed responses, PFS, and potentially early OS data.  Safety and biomarker 
data (available at the time of making this decision) will also be taken into consideration from the 
perspective of an adequate benefitrisk assessment.  
The interim analyses will be performed and interpreted by Sponsor study team personnel.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody, also known as anti-therapeutic antibody
Ad5/35
Adenovirus serotype 5 with a fiber (shaft and knob) from 
serotype 35
Atezo
Atezolizumab
CAPOX
capecitabine and oxaliplatin
CEA
carcinoembryonic antigen
CIN
chromosomal instability
CIT
cancer immunotherapy
COVID-19
coronavirus disease 2019
CRC
colorectal cancer
CT
computed tomography (scan)
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T lymphocyteassociated protein 4
DCR
disease control rate
DOR
duration of response
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
FDA
U.S. Food and Drug Administration
FOLFIRI
folinic acid, fluorouracil, and irinotecan
FOLFOX
folinic acid, fluorouracil, and oxaliplatin
FOLFOXIRI
folinic acid, fluorouracil, oxaliplatin, and irinotecan
FFPE
formalin-fixed, paraffin-embedded
GI
gastrointestinal
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HLH
hemophagocytic lymphohistiocytosis
HR
hazard ratio
ICH
International Council for Harmonisation
Idasa
idasanutlin
IFN
interferon
IHC
immunohistochemistry
IMC
Internal Monitoring Committee


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Abbreviation
Definition
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IV
intravenous
IxRS
interactive voice or web-based response system
LMWH
low molecular weight heparin
LOAd
Lokon oncolytic adenovirus
mCRC
metastatic colorectal cancer
mOS
median overall survival
MAS
macrophage activation syndrome
MRI
magnetic resonance imaging
MSI
microsatellite instability
MSI-H
microsatellite instabilityhigh
MSS
microsatellite-stable
NCCN
National Cancer Comprehensive Network
NCI
National Cancer Institute
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
PCR
polymerase chain reaction
PD-1
programmed death-1
PD-L1
programmed death-ligand 1
PBMC
peripheral blood mononuclear cell
PFS
progression-free survival
P-gp
P-glycoprotein
PK
Pharmacokinetic
RBR
Research Biosample Repository
RECIST v1.1
Response Evaluation Criteria in Solid Tumors, Version 1.1
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SEER
Surveillance, Epidemiology and End Results
SITC
Society for Immunotherapy for Cancer
SOC
Scientific Oversight Committee
T3
triiodothyronine
T4
thyroxine
TAS-102
trifluridine/tipiracil
TMZ
trimerized
UFH
unfractionated heparin
ULN
upper limit of normal


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Abbreviation
Definition
VEGF
vascular endothelial growth factor
WES
whole exome sequencing
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON COLORECTAL CANCER
Globally, colorectal cancer (CRC) is the third most commonly diagnosed cancer in males 
and second in females. CRC is also the fourth leading cause of cancer mortality in 
males and third in females (Torre et al. 2016). The estimated incidence of new cases in 
2012 in developed countries was 736,900, and mortality was 333,200, with the highest 
incidence rates in North America, Europe, and Australia/New Zealand (Torre et al. 2016).
Mortality from CRC decreased by 35% from 1990 to 2007 (Siegel et al. 2011) and is 
currently down by about 50% from peak mortality rates (Siegel et al. 2016). Despite the 
observed improvements in the overall CRC mortality rate, a retrospective cohort study of 
the Surveillance, Epidemiology and End Results (SEER) CRC registry found that the 
incidence of CRC in patients younger than 50 years has been increasing; the authors 
estimate the incidence rates for colon and rectal cancers will increase by 90% and 124%, 
respectively, for patients 20 to 34 years by 2030 (Bailey et al. 2015).
In the United States, about 40% of CRC patients are diagnosed with early-stage disease, 
with another 40% diagnosed with regional disease, and 20% diagnosed with distant 
metastasis. Five-year survival rates are 90%, 71%, and 14%, respectively, with most of 
these patients dying from metastatic disease (Alberts and Wagman 2008; Kennecke et 
al. 2014; American Cancer Society 2017). Without treatment, the median survival for 
patients with metastatic CRC (mCRC) is less than 1 year (Liu et al. 2003). Surgical 
resection of metastases can improve outcomes. The 5-year survival rates of the small 
fraction of patients eligible for resection of metastatic lesions are around 27%41% 
(Mandalà et al. 2007; Zaydfudim et al. 2015). In the vast majority of mCRC patients, 
systemic cytotoxic chemotherapy is the mainstay of treatment and median overall 
survival (mOS) is only around 30 months. 
Mechanistically, CRC develops either sporadically (85%), as part of a hereditary cancer 
syndrome (less than 10%), or in the context of inflammatory bowel disease. With regard 
to the molecular pathogenesis, two distinct mechanisms that underlie the development 
of CRC have been identified based on microsatellite instability (MSI) and chromosomal 
instability (CIN) (Gervaz et al. 2002; Haydon and Jass 2002; Jass et al. 2002; Gervaz 
et al. 2004). MSI involves the failure of the nucleotide mismatch recognition and repair 
system (Aaltonen et al. 1993; Ionov et al. 1993). High microsatellite instability (MSI-H)
status is observed in approximately 10%15% of all sporadic CRC (Söreide et al. 2006)
and in about 5% of patients with mCRC. In contrast, CIN is characterized by changes in 
the numbers of chromosomes or profound structural changes of chromosomes and 
accompanies the development of CRC from dysplastic adenoma in conjunction with 
somatic mutations in APC, KRAS, and TP53 oncogenes (Vogelstein et al. 1989).


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1.2
TREATMENT FOR METASTATIC COLORECTAL CANCER
The current management of mCRC involves various active drugs that are used either in 
combination or as single agents: 5-fluorouracil/leucovorin, capecitabine, irinotecan, 
oxaliplatin, bevacizumab, cetuximab, panitumumab, ziv-aflibercept, regorafenib, and 
trifluridine/tipiracil. The putative mechanisms of action of these agents are varied and 
include the interference with DNA replication and inhibition of activities of vascular 
endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). Current 
first- and second-line therapies for mCRC include a variety of different oxaliplatin- and 
irinotecan-based chemotherapy regimens, for example, folinic acid, fluorouracil, and 
oxaliplatin (FOLFOX) and folinic acid, fluorouracil, and irinotecan (FOLFIRI), which have 
similar activity, but different toxicity profiles. Patients with mCRC in the first-line setting 
are typically treated with a cytotoxic doublet such as FOLFOX, capecitabine and 
oxaliplatin (CAPOX), or FOLFIRI or, possibly, in very select cases, the cytotoxic triplet 
folinic acid, fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI). Improved outcomes 
have been demonstrated when combining chemotherapy with cetuximab and 
panitumumab targeting the EGFR pathway or with bevacizumab, ramucirumab, and 
ziv-aflibercept targeting the VEGF pathway. In patients in whom the initial 
chemotherapy regimen failed (i.e., in the second-line setting), the chemotherapy 
backbone is then changed; patients who received FOLFIRI up front will then receive 
FOLFOX and vice versa (Benson et al. 2017).
Once patients have exhausted first- and second-line treatment options, their survival is 
typically less than 6 months. More recently, regorafenib (Stivarga) and 
trifluridine/tipiracil (TAS-102 [LONSURF]) have been approved in these previously 
treated chemotherapy-refractory mCRC patients. Regorafenib is a multikinase inhibitor 
that was approved following a randomized, double-blind, placebo-controlled trial in which
heavily pretreated mCRC patients showed a survival benefit over best supportive care
(mOS 6.4 months for the regorafenib group versus 5.0 months for the placebo group; 
hazard ratio [HR]0.77; 95% CI: 0.64, 0.94; p0.0102). The most common adverse 
events, of all grades observed were hand-foot syndrome (47% of patients), fatigue
(47%), diarrhea (34%), hypertension (29%), voice changes (28%), oral mucositis (28%) 
and rash/desquamation (26%) (Grothey et al. 2013). TAS-102 is an orally administered 
combination of a thymidine−based nucleic acid analogue, trifluridine, and a thymidine 
phosphorylase inhibitor, tipiracil hydrochloride. It was approved by the U.S. Food and 
Drug Administration (FDA) and European Medicines Agency based on a randomized, 
double-blind, placebo-controlled trial demonstrating a survival benefit for TAS-102 over
best supportive care (mOS 7.1 months in the TAS-102 group versus 5.3 months in the 
placebo group; HR0.68; 95 % CI: 0.58, 0.81; p0.001). The most frequently observed 
adverse events were neutropenia (38% of patients) and leukopenia (21%) (Mayer et al. 
2015). Even with the approvals of these two agents, a high unmet need remains in this 
patient population for more efficacious treatment options with better safety profiles.


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1.3
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
Cancer immunotherapy (CIT) has demonstrated significant survival benefit, observed 
across multiple advanced malignancies.  Currently, the prevailing CIT approach is to 
circumvent immune evasion mechanisms and reinvigorate anti-tumor responses by 
targeting T-cell inhibitory factors, such as programmed death-ligand 1/programmed 
death-1 (PD-L1/PD-1).  While these targets have resulted in remarkable clinical 
therapeutic success for various cancer indications, research indicates that a series of 
stepwise events is necessary for the generation of a continuous anti-tumor immune 
response (Chen and Mellman 2013).  Each event is critical for an effective response, 
and each is also susceptible to several tumor immune-evasion mechanisms.  Thus, the 
need to identify and circumvent the various factors that account for the absence of, or 
escape from, an effective anti-cancer immune response will be critical for propagating 
cancer immunity and advancing the field of CIT, most likely through combined targeted 
therapy regimens.
In CRC, single-agent immune checkpoint inhibitors have been shown to have clinical 
benefit in patients with tumors assessed as having MSI-H status but not with 
microsatellite-stable (MSS) tumors (Le et al. 2015). The superior efficacy of checkpoint 
inhibitors in MSI-H CRC has been postulated to be due to a higher number of 
neo-antigens compared with MSS tumors. The higher number of somatic mutations is 
thought to increase the immunogenicity of the tumor resulting in increased recruitment of 
immune effector and antigen presenting cells (Llosa et al. 2015; Zhang et al. 2015). 
Consistently, the MSI-H cancers have increased CD8+ T cells and PD-L1 expression in 
the tumor, which may explain why they are responsive to checkpoint inhibitors (Smedt 
et al. 2015).
While the 4%8% of CRC patients with MSI-H tumors show clinical benefit from CIT, the 
remaining CRC patients do not. This appears to also be the case when checkpoint 
inhibitors, like the anti-PD-1 agent pembrolizumab, are combined with a standard 
doublet of cytotoxics like FOLFOX (Shahda et al. 2017).  Thus, there is a significant 
unmet medical need for the development of combination treatments that will bring the 
benefit of cancer immunotherapies with their often long-lasting responses to patients 
with MSS mCRC.
This randomized Phase Ib/II umbrella study is designed to accelerate the development 
of CIT combinations by identifying early signals and establishing proof-of-concept clinical 
data in patients with MSS mCRC. The study is designed with the flexibility to open new 
treatment arms as new treatment combinations become available and close existing 
treatment arms that demonstrate minimal clinical activity or unacceptable toxicity.  
Enrollment of multiple experimental arms within a single study, rather than one or two 
experimental arms within multiple studies, will result in an overall reduction in the 
number of patients receiving control-arm treatment.  More importantly, this study will 
assess the importance of simultaneously targeting multiple mechanisms of immune 


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escape through immune-cell priming and activation, tumor infiltration, and/or recognition 
of tumor cells for elimination. To improve the confidence of clinical signal detection in 
the experimental arms, this study will include a control arm. Moreover, patients who 
experience disease progression with the initial treatment regimen (Stage 1) may be 
eligible to continue treatment with a different treatment regimen (Stage 2), which may
advance the scientific understanding of immune escape mechanisms in patients who fail 
to respond to, or experience disease progression during, treatment with a CIT or 
chemotherapy regimen.
The target and proposed mechanism-of-action classification for each experimental
investigational medicinal product (IMP) is summarized in Table 1.  The control and 
experimental treatment regimens are described in Sections 3.1.1 and 3.1.2 (see Table 4
and Table 6).  Background information and a rationale for each treatment combination, 
including a benefitrisk assessment for experimental agents, are provided in the 
respective appendix for that treatment arm, as outlined in Table 4 and Table 6.
Table 1
Target and Proposed Mechanism-of-Action Classification for 
Experimental Investigational Medicinal Products
Experimental
IMP
Target
Proposed Mechanism-of-Action Classification
Atezolizumab
PD-L1
Immune checkpoint inhibitor
Regorafenib
Tyrosine kinase
Multiple kinase inhibitor
Idasanutlin
MDM2
Inhibits p53-MDM2 binding, thus activating p53, which,
within the myeloid compartment, promotes the
differentiation of cross-presenting cells, and, in tumor 
cells, promotes a senescence-driven innate immune 
response a
AB928
A2aR/A2bR
Dual adenosine receptor antagonist, reverses 
immunosuppressive effects caused by high 
concentrations of adenosine within the tumor 
microenvironment 
LOAd703
CD40; 4-1BB
Oncolytic adenovirus (Ad5/35) with increased cell 
binding and infectivity of cells expressing CD46; 
oncolysis of tumor cells with de-regulated RB-pathway; 
Expression of transgenic TMZ-CD40L and 4-1BBL 
under the control of CMV promoter in infected tumor and 
stroma cells which leads to activation of myeloid cells, 
T cells, and NK cells. b
A2aRadenosine 2a receptor; A2bRadenosine 2b receptor; Ad5/35adenovirus serotype 5 
with a fiber (shaft and knob) from serotype 35; CMVCytomegalovirus; IMPinvestigational 
medicinal product; LOAdLokon oncolytic adenovirus; MDM2murine double minute 2; 
NKnatural killer; PD-L1programmed deathligand 1.
a Tovar et al. 2006; Xue et al. 2007; Ianello et al. 2013; Guo et al. 2017; Sharma et al. 2018
b Eriksson et al. 2017.


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1.4
COVID-19 BENEFITRISK ASSESSMENT
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are considered a more vulnerable population, 
with the potential for more severe clinical outcomes from severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infection.  However, it is unclear whether or 
how systemic cancer therapies such as chemotherapy, targeted therapy, or 
immunotherapy impact the incidence or severity of SARS-CoV-2 infection.
A possible consequence of immune checkpoint inhibition may be the modulation of the 
host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses (Wykes and Lewin 2018).  In nonclinical models, 
PD-1/PD-L1 blockade appears to be associated with serious exacerbation of 
inflammation in the setting of acute (as opposed to chronic) viral infection with
lymphocytic choriomeningitis virus (Clone 13) (Frebel et al. 2012). However, there are 
insufficient and inconsistent clinical data to assess if outcome from SARS-CoV-2 
infection is altered by CIT.
Severe SARS-CoV-2 infection appears to be associated with a cytokine-release 
syndrome (CRS) involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and 
interferon (IFN)-(Merad and Martin 2020).  While it is not known, there may be a 
potential for an increased risk of an enhanced inflammatory response if a patient 
develops acute SARS-CoV-2 infection while receiving immune checkpoint inhibitor 
therapies (e.g., atezolizumab).  At this time, there is insufficient evidence for causal 
association between immune checkpoint inhibitor therapies and an increased risk of 
severe outcomes from SARS-CoV-2 infection.
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with immune checkpoint inhibitor therapies and 
clinical and radiologic features for SARS-CoV-2related interstitial pneumonia.  Thus, 
investigators should use their clinical judgment when evaluating and managing patients 
with pulmonary symptoms.
There are limited data concerning the possible interactions between CIT treatment and 
COVID-19 vaccination, and it is recognized that human immune responses are highly 
regulated and that immune-modifying therapies may positively or negatively impact the 
efficacy and safety of COVID-19 vaccination (Society for Immunotherapy of Cancer 
[SITC] 2020).
Per recommendations of the National Comprehensive Cancer Network® (NCCN®) 
COVID-19 Vaccination Advisory Committee, COVID-19 vaccination is recommended for 
all patients with cancer receiving active therapy (including immune checkpoint inhibitors), 
with the understanding that there are limited safety and efficacy data in such patients 
(NCCN 2021).  Given the lack of clinical data, currently no recommendations can be 
made regarding the optimal sequence of COVID-19 vaccination in patients who are 


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receiving CIT (SITC 2020).  For patients enrolling in this study and receiving CIT, a 
decision to administer the vaccine to a patient should be made on an individual basis by 
the investigator in consultation with the patient.
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving CIT to receive COVID-19 vaccination 
include the following:  the risk of SARS-CoV-2 infection and potential benefit from the 
vaccine, the general condition of the patient and potential complications associated with 
SARS-CoV-2 infection, underlying disease, and the severity of COVID-19 outbreak in a 
given area or region.  
SITC and NCCN recommendations along with institutional guidelines should be used by 
the investigator when deciding on administering COVID-19 vaccines.  When 
administered, COVID-19 vaccines must be given in accordance with the approved or 
authorized vaccine label.  Receipt of the COVID-19 vaccine is considered a 
concomitant medication and should be documented as such (see respective appendix 
for that treatment arm [Appendix 7 through Appendix 14]).


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2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of 
immunotherapy-based treatment combinations in patients with metastatic CRC.  Specific 
objectives and corresponding endpoints for the study are outlined below for Stage 1 
(see Table 2) and Stage 2 (see Table 3).
Table 2
Objectives and Corresponding Endpoints for Stage 1
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
immunotherapy-based treatment 
combinations during Stage 1
ORR, defined as the proportion of patients with a 
complete response or partial response on two 
consecutive occasions 4 weeks apart during 
Stage 1, as determined by the investigator according 
to RECIST v1.1
Secondary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of 
immunotherapy-based treatment 
combinations during Stage 1
PFS after randomization,a defined as the time from 
randomization to the first occurrence of disease 
progression or death from any cause (whichever 
occurs first) in Stage 1, as determined by the 
investigator according to RECIST v1.1
OS after randomization,a defined as the time from 
randomization to death from any cause
OS at specific timepoints (e.g., 6 months)
DOR, defined as the time from the first occurrence of 
a documented objective response during Stage 1 to 
disease progression or death from any cause 
(whichever occurs first), as determined by the 
investigator according to RECIST v1.1
DCR, defined as the proportion of patients with stable 
disease for 12 weeks or a complete or partial 
response, as determined by the investigator according 
to RECIST v1.1
DCRdisease control rate; DORduration of response; ORRobjective response rate; 
OSoverall survival; PFSprogression-free survival; PKpharmacokinetic; RECIST 
v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1. 
Note:  Overall response at a single timepoint will be assessed by the investigator using RECIST 
v1.1 (see Appendix 1).  
a For the mandatory serial-biopsy arms, PFS and OS will be determined from the time of 
treatment initiation (rather than time of randomization).


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Table 2
Objectives and Corresponding Endpoints for Stage 1 (cont.)
Safety Objective
Corresponding Endpoints
To evaluate the safety of 
immunotherapy-based treatment 
combinations during Stage 1
Incidence, nature, and severity of adverse events 
and laboratory abnormalities, with severity 
determined according to NCI CTCAE v4.0
Change from baseline in vital signs and ECG 
parameters
Change from baseline in targeted clinical laboratory 
test results
Exploratory Pharmacokinetic 
Objectives
Corresponding Endpoints
To characterize the PK profile of drugs 
that are administered as part of an 
immunotherapy-based treatment 
combination during Stage 1
Plasma or serum concentration of each drug (as 
appropriate) at specified timepoints 
To evaluate potential relationships 
between drug exposure during Stage 1 
and the efficacy and safety of 
immunotherapy-based treatment 
combinations
Relationship between plasma or serum concentration 
or PK parameters for each drug (as appropriate on 
the basis of available data) and efficacy endpoints 
Relationship between plasma or serum concentration 
or PK parameters for each drug (as appropriate on 
the basis of available data) and safety endpoints
Exploratory Immunogenicity 
Objectives
Corresponding Endpoints
To evaluate the immune response to 
drugs that are administered as part of 
an immunotherapy-based treatment 
combination during Stage 1
For drugs for which ADA formation is measured:  
presence of ADAs during the study relative to the 
presence of ADAs at baseline
To evaluate potential effects of ADAs 
during Stage 1
For drugs for which ADA formation is measured:  
relationship between ADA status and efficacy, safety, 
or PK endpoints
Exploratory Biomarker Objective
Corresponding Endpoint
To identify biomarkers during Stage 1 
that are predictive of response to study 
treatment (i.e., predictive biomarkers), 
are associated with progression to a 
more severe disease state 
(i.e., prognostic biomarkers), are 
associated with resistance to study 
treatment, are associated with 
susceptibility to developing adverse 
events (i.e., safety biomarkers), can 
provide evidence of study treatment
activity (i.e., pharmacodynamic 
biomarkers), or can increase the 
knowledge and understanding of 
disease biology
Relationship between biomarkers in blood and tumor 
tissue (listed in Section 4.5.7) and efficacy, safety, 
PK, immunogenicity, or other biomarker endpoints
ADAanti-drug antibody; NCI CTCAE v4.0National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.0; PKpharmacokinetic. 


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Table 3
Objectives and Corresponding Endpoints for Stage 2
Exploratory Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of 
immunotherapy-based treatment 
combinations during Stage 2
ORR, defined as the proportion of patients with a complete 
response or partial response on two consecutive 
occasions 4 weeks apart during Stage 2, as determined 
by the investigator according to RECIST v1.1
PFS after initiation of Stage 2, defined as the time from 
initiation of Stage 2 to the first occurrence of disease 
progression or death from any cause (whichever occurs 
first), as determined by the investigator according to 
RECIST v1.1
DOR, defined as the time from the first occurrence of a 
documented objective response during Stage 2 to disease 
progression or death from any cause (whichever occurs 
first), as determined by the investigator according to 
RECIST v1.1
DCR, defined as the proportion of patients with stable 
disease for 12 weeks or a complete or partial response, 
as determined by the investigator according to 
RECIST v1.1
Safety Objective
Corresponding Endpoints
To evaluate the safety of 
immunotherapy-based treatment 
combinations during Stage 2
Incidence, nature, and severity of adverse events and 
laboratory abnormalities, with severity determined 
according to NCI CTCAE v4.0
Change from baseline in vital signs and ECG parameters
Change from baseline in targeted clinical laboratory test 
results
DCRdisease control rate; DORduration of response; NCI CTCAE v4.0National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 4.0; ORRobjective 
response rate; OSoverall survival; PFSprogression-free survival; PKpharmacokinetic;
RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1. 
Note:  Overall response at a single timepoint will be assessed by the investigator using RECIST 
v1.1 (see Appendix 1).  


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Table 3
Objectives and Corresponding Endpoints for Stage 2 (cont.)
Exploratory Pharmacokinetic 
Objectives
Corresponding Endpoints
To characterize the PK profile of 
drugs that are administered as 
part of an immunotherapy-based 
treatment combination during 
Stage 2
Plasma or serum concentration of each drug (as 
appropriate) at specified timepoints 
To evaluate potential relationships 
between drug exposure during 
Stage 2 and the efficacy and 
safety of immunotherapy-based 
treatment combinations
Relationship between plasma or serum concentration or 
PK parameters for each drug (as appropriate on the 
basis of available data) and efficacy endpoints 
Relationship between plasma or serum concentration or 
PK parameters for each drug (as appropriate on the 
basis of available data) and safety endpoints
Exploratory Immunogenicity 
Objectives
Corresponding Endpoints
To evaluate the immune response 
to drugs that are administered as 
part of an immunotherapy-based 
treatment combination during 
Stage 2
For drugs for which ADA formation is measured:  
presence of ADAs during the study relative to the 
presence of ADAs at baseline
To evaluate potential effects of 
ADAs during Stage 2
For drugs for which ADA formation is measured:  
relationship between ADA status and efficacy, safety, or 
PK, endpoints
Exploratory Biomarker Objective
Corresponding Endpoint
To identify biomarkers during 
Stage 2 that are predictive of 
response to study treatment
(i.e., predictive biomarkers), are 
associated with progression to a 
more severe disease state 
(i.e., prognostic biomarkers), are 
associated with resistance to study 
treatment, are associated with 
susceptibility to developing 
adverse events (i.e., safety 
biomarkers), can provide evidence 
of study treatment activity (i.e., 
pharmacodynamic biomarkers), or 
can increase the knowledge and 
understanding of disease biology
Relationship between biomarkers in blood and tumor 
tissue (listed in Section 4.5.7) and efficacy, safety, PK, 
immunogenicity, or other biomarker endpoints
ADAanti-drug antibody; PKpharmacokinetic. 


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase Ib/II, open-label, multicenter, randomized, umbrella study in patients with 
mCRC.  The study is designed with the flexibility to open new treatment arms as new 
treatments become available, close existing treatment arms that demonstrate minimal 
clinical activity or unacceptable toxicity, or modify the patient population (e.g., with 
regard to prior anti-cancer treatment or biomarker status).  This study will enroll patients 
with mCRC who became refractory to first- and second-line standard therapies for 
mCRC. Eligible patients will initially be assigned to one of several treatment arms 
(Stage 1; see Section 3.1.1). Patients who experience disease progression, loss of 
clinical benefit, or unacceptable toxicity during Stage 1 may be eligible to continue 
treatment with a different treatment regimen (Stage 2; see Section 3.1.2).




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3.1.1
Stage 1
During Stage 1, patients will be randomly assigned to the control arm (regorafenib) or
an experimental arm consisting of atezolizumab in combination with idasanutlin 
(AtezoIdasa) or regorafenib (AtezoRegorafenib) or regorafenib and AB928 
(AtezoRegorafenibAB928) or LOAd703 (AtezoLOAd703) (see Figure 2). Details 
on the treatment regimens for Stage 1 are provided in Appendix 7 through Appendix 14, 
as specified in Table 4. Table 5 lists Stage 1 treatment arms for which enrollment and 
patient follow-up has been completed.
Approximately 111382 patients will be enrolled during Stage 1.  Enrollment within 
the experimental arms will take place in two phases:  a preliminary phase followed 
by an expansion phase.  Approximately 15 patients will be enrolled in the AtezoIdasa, 
AtezoRegorafenib, AtezoRegorafenibAB928, and AtezoLOAd703 arms during 
the preliminary phase.  If clinical activity is observed in an experimental arm during the 
preliminary phase, approximately 25 additional patients may be enrolled in that arm 
during the expansion phase.  The Sponsor may decide to delay or suspend enrollment 
within a given treatment arm. Randomization will be suspended in some arms after 
enrollment of approximately 6 patients to allow for a safety evaluation (see 
Section 3.1.1.1 for details).  The Sponsor may also decide to open enrollment in 
separate mandatory serial-biopsy arms to enable patients at participating sites who are 
willing to undergo serial biopsies to receive treatment with an experimental combination 
that has qualified for the expansion phase (see Section 3.1.1.2 for details).  
Experimental arms with insufficient clinical activity or unacceptable toxicity will not 
undergo expansion.  Additional patients may be enrolled to ensure balance among 
treatment arms with respect to demographic and baseline characteristics, including 
potential predictive biomarkers, to enable further subgroup analyses.  New experimental 
arms may be added during the study by amending the protocol.
Patients will be randomly assigned to treatment arms, with the exception of the 
mandatory serial-biopsy arms, and the randomization ratio will depend on the number of 
experimental arms that are available (e.g., if an arm is added or enrollment in an arm is 
suspended, pending analysis of results from the preliminary phase), with the stipulation 
that the likelihood of being allocated to the control arm will be no more than 35%.  
Randomization will take into account arm-specific exclusion criteria.  Patients will be 
ineligible for a specific arm if they meet any of the exclusion criteria outlined for that arm 
(see Section 4.1.2).  Details on treatment assignment and randomization are provided in 
Section 4.2.




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Figure 2
Detailed Study Design
Atezoatezolizumab; CRCcolorectal cancer; ECEthics Committee; Idasaidasanutlin; IRBInstitutional Review Board; Isaisatuximab; 
LOAdLokon adenovirus; PDprogressive disease; Rrandomization; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; 
MSSmicrosatellite-stable.
a
Refractory to standard therapies is defined as the progression on not more than two prior lines of treatment (see Section 4.1.1.1).
b
Patients who experience disease progression per RECIST v1.1, loss of clinical benefit defined as (1) confirmed disease progression or (2) lack 
of continued benefit as determined by the investigator (for details, see Section 3.1.1), or unacceptable toxicity during Stage 1 may be eligible to 
receive a different treatment during Stage 2, provided a Stage 2 treatment is available for enrolment and they meet the eligibility criteria.  Details 
are provided in the respective appendix for each treatment arm (see Appendix 7 through Appendix 14).
c
At the time of implementation of protocol Version 8, the AtezoIdasa arm had been closed for further enrollment.
d
The Sponsor may open enrollment in separate mandatory serial-biopsy arms to enable patients at participating sites who are willing to undergo 
serial biopsies to receive treatment with an experimental combination that has demonstrated clinical activity during the preliminary phase. If a 
site has not been granted IRB/EC approval for mandatory serial biopsies, these arms will not be opened at that site (see Section 3.1.1.2).


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Table 5
Treatment Arms with Completed Enrollment and Patient 
Follow-Up
Stage 
Arm Name
Treatment
Number of 
Patients Enrolled
Protocol Version 
Describing Arm
1
AtezoIsa
atezolizumab, isatuximab
15
19
1
AtezoSeliBev
atezolizumab, selicrelumab, and 
bevacizumab
6
19
1
Atezo Imprime
Bev
atezolizumab, Imprime PGG, and 
bevacizumab
15
110
Patients in the regorafenib control arm will continue to receive treatment until
unacceptable toxicity or disease progression per Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST v1.1; see Appendix 1).  Patients in the experimental arms 
will be treated until unacceptable toxicity or loss of clinical benefit defined as (1) 
confirmed disease progression in the tumor assessment following the finding of 
radiographic progression per RECIST v1.1 or (2) lack of continued benefit as determined 
by the investigator after an integrated assessment of radiographic and biochemical data, 
local biopsy results (if available), and clinical status (e.g., symptomatic deterioration such 
as pain secondary to disease).  Because of the possibility of an initial increase in tumor 
burden caused by immune-cell infiltration in the setting of a T-cell response (termed 
pseudoprogression) with CITs (such as atezolizumab), radiographic progression per 
RECIST v1.1 may not be indicative of true disease progression.  After the first tumor 
assessment meeting the criteria for disease progression per RECIST v1.1, patients
receiving treatment with a CIT drug will be permitted to continue study treatment if they 
meet all of the following criteria:

Evidence of clinical benefit, as determined by the investigator following a review of all 
available data

Absence of symptoms and signs (including laboratory values, such as new or 
worsening hypercalcemia) indicating unequivocal progression of disease

Absence of decline in Eastern Cooperative Oncology Group (ECOG) Performance 
Status that can be attributed to disease progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions
3.1.1.1
Safety Evaluation Phase 
To account for potential overlapping toxicities in the AtezoIdasa, AtezoRegorafenib, 
AtezoRegorafenibAB928, and AtezoLOAd703 arms, enrollment within each arm
will be suspended after approximately 6 patients have been enrolled to allow for a safety 
evaluation. The safety evaluation will be based on safety data from a minimum of 6 
patients who have received at least one dose of treatment (i.e., one dose of each agent 
for a given combination) and completed safety follow-up assessments of at least one full


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treatment cycle.  If a combination is determined to be sufficiently safe, enrollment will be 
resumed in that arm.
3.1.1.2
Mandatory Serial-Biopsy Arms 
If an experimental combination demonstrates clinical activity during the preliminary 
phase, the Sponsor may decide to test that same combination in a mandatory 
serial-biopsy arm at the time that arm is open for expansion. This arm will consist of 
patients at participating sites who are willing to undergo an on-treatment biopsy.
Opening of mandatory serial-biopsy arms is contingent upon the review and approval of 
the protocol and the mandatory serial biopsy portion of the Informed Consent Form by 
each site's IRB/EC and, if applicable, an appropriate regulatory body. If a site has not 
been granted approval for mandatory serial biopsies, these arms will not be opened at 
that site.
The objective of the mandatory serial-biopsy arms is to analyze serial tissue samples
(including pretreatment, on-treatment, and post-progression samples) in an effort to
better understand potential biological changes that occur during treatment with CIT 
combinations (including immune escape), provide evidence of pharmacodynamic 
effects, or confirm hypothesized mechanisms of action.  Biomarkers may include those 
that inform stromal and immune biology (Turley et al. 2015).
Patients entering Stage 1 who are determined by the investigator to be eligible for serial 
biopsies may be enrolled in a mandatory serial-biopsy arm rather than undergo random 
assignment to other arms that are open for enrollment.  If more than one mandatory 
biopsy arm is open, patients will be assigned to one of the available arms by 
the Sponsor.  
Approximately 15 patients with serial-biopsy samples will be enrolled in each mandatory 
serial-biopsy arm.  However, the number of patients will be reduced if optional 
on-treatment biopsies have been collected (and determined to be evaluable) from 
consenting patients treated with that same CIT combination during the preliminary 
phase, to limit on-treatment biopsy collection to a total of approximately 15 patients per 
CIT combination.  
Patients will undergo the same assessments as other patients receiving the same 
treatment combination but will have an additional mandatory on-treatment biopsy 
4 weeks (7 days) after initiation of CIT-combination treatment (if deemed clinically 
feasible by the investigator).  Details about the timing of biopsy sample collection are 
provided in the schedule of activities for each arm (see Appendix 7 through
Appendix 14).
To be eligible for a mandatory serial-biopsy arm, a patient should have at least two 
accessible tumors that are amenable to excisional, punch, or core-needle biopsy 


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(a minimum of three cores, 18-gauge needle or larger [16-gauge needle preferred]) 
without unacceptable risk of a major procedural complication.  If it is planned that more 
than one biopsy will be obtained from a single lesion, the lesion should be large enough 
to permit successive biopsies 1 cm apart.
Patients enrolled in a mandatory serial-biopsy arm for whom three evaluable tissue
samples cannot be obtained may continue to receive study treatment as scheduled. 
3.1.2
Stage 2
During Stage 1, patients who experience disease progression per RECIST v1.1, loss of 
clinical benefit defined as (1) confirmed disease progression or (2) lack of continued 
benefit as determined by the investigator (for details, see Section 3.1.1), or unacceptable 
toxicity may be eligible to receive a different treatment combination during Stage 2, 
provided a Stage 2 treatment is available for enrollment and they meet the eligibility 
criteria of that treatment regimen.  Details are provided in the respective appendices for 
each treatment arm (see Appendix 7 through Appendix 14). A maximum of 40 patients 
will be enrolled in each of the Stage 2 treatment regimens.
Stage 2 treatment must begin within 3 months after a patient has experienced disease 
progression per RECIST v1.1 (regorafenib control arm), loss of clinical benefit 
(experimental arms), or unacceptable toxicity and will continue until unacceptable toxicity 
or loss of clinical benefit defined as (1) confirmed disease progression or (2) lack of 
continued benefit as determined by the investigator.  It is recommended that patients 
begin Stage 2 treatment as soon as possible.
Table 6
Stage 2 Treatment Regimens
Study Treatment
Appendix
No Stage 2 treatment currently available

The Sponsor may decide to hold or discontinue enrollment in Stage 2 on the basis of a 
review of safety data, preliminary efficacy data, and supportive information 
(e.g., biomarker research data), as appropriate.
3.1.3
Assessments and Monitoring
All patients will be closely monitored for adverse events throughout the study, and 
adverse events will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0).
Patients will undergo tumor assessments every 6 weeks (starting on Day 1 of Cycle 1) 
for the first 48 weeks and then every 6 or 12 weeks thereafter (see Section 4.5.6 and 
Appendix 7 through Appendix 14 for details).  Response will be assessed by the 
investigator using RECIST v1.1 (see Appendix 1).  If clinical activity is demonstrated in 
an experimental arm, the Sponsor may request that tumor assessment scans for that 


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arm and the corresponding control arm be submitted for evaluation by an independent 
reading facility.
Baseline tumor tissue samples will be collected 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, provided that the tissue was obtained from a 
biopsy performed within 6 months prior to enrollment and that the patient has not 
received any anti-cancer therapy since the time of the biopsy. Tumor tissue will also be 
collected from patients who discontinue Stage 1 because of unacceptable toxicity, 
disease progression per RECIST v1.1 (regorafenib control arm), or loss of clinical benefit,
defined as (1) confirmed disease progression or (2) lack of continued benefit as 
determined by the investigator (experimental arms) if deemed clinically feasible by the 
investigator.  For patients enrolled in a mandatory serial-biopsy arm at participating sites, 
an additional tumor tissue sample will be collected during treatment (if clinically feasible).  
These samples, as well as blood samples collected during the study, will be utilized for 
biomarker research (see rationale for biomarker assessments in Section 3.3.3 and 
details on tissue sample collection in Section 4.5.7).
To characterize the pharmacokinetic (PK) properties and/or immunogenicity of 
atezolizumab and other therapeutic agents, blood samples will be obtained at various 
timepoints before and during study treatment administration.  
On the basis of a review of real-time safety data and available PK data, treatment 
regimens may be modified by the Sponsor as deemed appropriate.
The schedule of activities for each treatment arm is presented in Appendix 7 through
Appendix 14.
3.1.4
Internal Monitoring Committee
An Internal Monitoring Committee (IMC) will monitor patient safety throughout the study.  
The IMC will include representatives from Clinical Science, Safety Science, and 
Biostatistics.  In addition to the ongoing assessment of the incidence, nature, and 
severity of adverse events, serious adverse events, deaths, and laboratory abnormalities 
performed by the investigator and the Medical Monitor, the IMC will review all necessary 
cumulative data at regular intervals during the study.  At the time of each review, the 
IMC will make appropriate recommendations (e.g., the study should continue as planned, 
enrollment in a specific arm should be discontinued, a treatment regimen should be 
modified, the protocol should be amended, enrollment should be held pending further 
safety evaluations).  Decisions will be made in consideration of the totality of the 
available data.  Ad-hoc meetings may be called in addition to scheduled meetings, as 
necessary, to provide recommendations on management of any new safety issues.  
Specific operational details such as the committee's composition, frequency and timing 
of meetings, and members' roles and responsibilities will be detailed in an IMC Charter.


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3.1.5
Scientific Oversight Committee
A Scientific Oversight Committee (SOC) will act as a consultative body to the Sponsor, 
providing external expert opinions on the safety data collected during the study. This 
committee will consist of an external group of at least three oncology experts in CIT who 
will advise the Sponsor on the interpretation of study data. For this purpose, the SOC 
will evaluate aggregate safety data on a periodic basis, approximately every 6 months 
from the time the first patient is enrolled in the study. Members will follow a charter that 
outlines their roles and responsibilities. Data being evaluated by the SOC will include 
demographic, adverse event, serious adverse event, and relevant laboratory data. The 
SOC may review efficacy data if safety concerns necessitate benefitrisk assessments. 
The Sponsor will retain all decision-making authority for this study.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient completes the last visit
in both stages, including survival follow-up visits conducted by telephone or on-site visit.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 35 years.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Patient Population
Although the combination of chemotherapy agents and biologics has provided an
improvement of the clinical outcomes in patients with mCRC over recent years, 
treatment beyond the second line remains challenging.  A significant unmet medical 
need exists in this patient population for more efficacious and better tolerated treatments. 
The study will enroll patients with mCRC who became refractory to first- and second-
line standard therapies for mCRC.  While the efficacy of single-agent checkpoint 
inhibitors in CRC has been limited to the small percentage of patients with MSI-H tumors,
no appreciable efficacy has been observed in patients with MSS tumors, hence the need 
to explore combination therapies. The design of this umbrella trial is expected to allow
for rapid signal detection in a defined patient population. This study will exclude patients 
with MSI-H mCRC tumors and will focus on patients with a high unmet need in second-
and third-line therapy.
3.3.2
Rationale for Immunotherapy-Based Treatment beyond Initial 
Radiographic Progression
In studies of immunotherapeutic agents, complete response, partial response, 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
immune-cell infiltration in the setting of a T-cell response has been termed 
pseudoprogression (Hales et al. 2010).  In Study PCD4989g, evidence of tumor growth 
followed by a response was observed in several tumor types.  In addition, in some 


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responding patients with radiographic evidence of progression, biopsies of new lesions 
or areas of new growth in existing lesions revealed immune cells and no viable cancer 
cells.  Because of the potential for a response after pseudoprogression, this study will 
allow patients randomly allocated to immunotherapy-based treatment arms to continue 
combination treatment after apparent radiographic progression per RECIST v1.1, 
provided the benefitrisk ratio is judged to be favorable by the investigator (see criteria 
in Section 3.1.1). Patients should be discontinued for unacceptable toxicity or loss of 
clinical benefit defined as (1) confirmed disease progression or (2) lack of continued 
benefit as determined by the investigator after an integrated assessment of radiographic 
and biochemical data, local biopsy results (if available), and clinical status (see 
Section 3.1.1 for details).
3.3.3
Rationale for Biomarker Assessments
Blood samples for biomarker assessments will be collected at baseline and during the 
study.  Changes in biomarkers in blood may provide evidence of biologic activity of the 
specific treatment combinations. Correlations between surrogate biomarkers in blood 
(such as tumor burden markers, cytokines, chemokines, immune cell subpopulations, 
gene expression, and circulating tumor DNA) and drug dose and efficacy and safety 
endpoints may allow for the development of a blood-based biomarker to help define 
future treatments and predict which patients are more likely to benefit from specific 
treatment combinations.  
Baseline tumor tissue samples will be collected from all patients, preferably by means of 
a biopsy performed at study entry.  Tumor tissue will also be collected for patients who 
discontinue Stage 1 because of unacceptable toxicity, disease progression per 
RECIST v1.1, or loss of clinical benefit defined as (1) confirmed disease progression or 
(2) lack of continued benefit as determined by the investigator (see Section 3.1.1 for 
details) (if deemed clinically feasible by the investigator), to enable analysis of tumor 
tissue biomarkers related to resistance, disease progression, and clinical benefit of study 
treatments.  Tumor samples will be evaluated for biomarkers such as tumor-infiltrating 
immune cells, PD-L1, CD8, and expression of targets specific to each drug combination.  
Evaluation of the tumor microenvironment in response to treatment within each arm, 
including changes in the number and functional status of tumor-infiltrating immune cells,
could provide validation of the postulated mechanism of action and confirmation that an 
appropriate dose and exposure for the specific treatment combination have been 
achieved.  
Tumor tissue and blood samples may be analyzed through use of next-generation 
sequencing (NGS) methods, such as whole exome sequencing (WES), to identify 
somatic mutations that are predictive of response to study drug, are associated with 
progression to a more severe disease state, are associated with acquired resistance to 
study drug, are associated with susceptibility to developing adverse events, or can 
increase the knowledge and understanding of disease biology.


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4.
MATERIALS AND METHODS
4.1
PATIENTS
4.1.1
Inclusion Criteria
Patients must meet all of the criteria outlined in Sections 4.1.1.1 and 4.1.1.2 to qualify 
for Stage 1.  Patients must meet all of the criteria outlined in Sections 4.1.1.2 and 4.1.1.3
to qualify for Stage 2.
4.1.1.1
Inclusion Criteria for Stage 1 
Patients must meet all of the following criteria to qualify for Stage 1:

Age 18 years at the time of signing Informed Consent Form

ECOG Performance Status of 0 or 1 (see Appendix 3)

Life expectancy 3 months, as determined by the investigator

Histologically confirmed adenocarcinoma originating from the colon or rectum

Metastatic disease (Stage IV American Joint Committee on Cancer, Version 7) not 
amenable to local treatment

Disease progression during or following not more than two separate lines of 
treatment for mCRC that consisted of fluoropyrimidine-, oxaliplatin-, and 
irinotecan-containing chemotherapy in combination with a biologic agent 
(i.e., bevacizumab, ramucirumab, aflibercept, cetuximab, panitumumab) but not other 
agents
For patients who had disease recurrence within 6 months of completing 
adjuvant chemotherapy, the adjuvant regimen can be considered as one line 
of treatment for metastatic disease.
The re-introduction of an initially successful induction regimen will not be 
counted as one additional line of treatment.
Patients who have received first-line induction therapy with FOFOXIRI plus a 
biologic agent followed by maintenance therapy must have had documented 
disease progression no less than 3 months after the completion of the first-line 
induction therapy.

Availability of a representative tumor specimen that is suitable for determination of 
PD-L1 and/or additional biomarker status by means of central testing 
Baseline tumor tissue samples will be collected 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, provided that the 
tissue was obtained from a biopsy performed within 6 months prior to 
enrollment and that the patient has not received any anti-cancer therapy since 
the time of the biopsy. 
A formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block 
(preferred) or 1016 slides (16 slides preferred) containing unstained, freshly 
cut, serial sections must be submitted along with an associated pathology 


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report.  Refer to Section 4.5.7 for additional information on tumor specimens 
collected at screening. 
4.1.1.2
Inclusion Criteria for Stage 1 and Stage 2 
Patients must meet all of the following criteria to qualify for Stages 1 and 2:

Signed Informed Consent Form

Ability to comply with the study protocol, in the investigator’s judgment

Measurable disease (at least one target lesion) according to RECIST v1.1 
Previously irradiated lesions can be considered as measurable disease only 
if progressive disease has been unequivocally documented at that site 
since radiation.

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 (1500/L) without granulocyte colony-stimulating factor 
support
–
WBC count 2.5109/L (2500/L)
–
Lymphocyte count 0.5109/L (500/L)
–
Platelet count 100109/L (100,000/L) without transfusion
–
Hemoglobin 90 g/L (9.0 g/dL)
Patients must not have been transfused within 2 weeks prior to screening 
to meet this criterion.
–
AST, ALT, and alkaline phosphatase (ALP) 2.5 upper limit of normal (ULN), 
with the following exceptions:
Patients with documented liver metastases:  AST and ALT 5ULN
Patients with documented liver or bone metastases:  ALP 5ULN
–
Bilirubin 1.5ULN, with the following exception: 
Patients with known Gilbert syndrome:  bilirubin level 3ULN 
–
Albumin 25 g/L (2.5 g/dL)
–
Creatinine 1.5ULN 
–
For patients not receiving therapeutic anticoagulation:  INR or aPTT 1.5 ULN

For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen
during the 14 days prior to initiation of study treatment

Negative HIV test at screening
Patients without a prior positive HIV test result will undergo an HIV test at 
screening, unless not permitted per local regulations.

Negative hepatitis B surface antigen (HBsAg) test at screening

Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total 
HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening


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The HBV DNA test will be performed only for patients who have a positive total 
HBcAb test.

Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody 
test followed by a negative HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures as outlined for each 
specific treatment arm in Appendix 7 through Appendix 14

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
outlined for each specific treatment arm in Appendix 7 through Appendix 14
4.1.1.3
Inclusion Criteria for Stage 2
Patients must meet all of the following criteria to qualify for Stage 2: 

ECOG Performance Status of 02 (see Appendix 3)

Patients in the control arm:  ability to initiate Stage 2 treatment within 3 months after 
experiencing unacceptable toxicity or disease progression per RECIST v1.1 while 
receiving Stage 1 treatment

Patients in an experimental arm during Stage 1:  ability to initiate Stage 2 treatment 
within 3 months after experiencing unacceptable toxicity not related to atezolizumab
or loss of clinical benefit defined as (1) confirmed disease progression or (2) lack of 
continued benefit as determined by the investigator (see Section 3.1.1 for details) 
while receiving Stage 1 treatment

Availability of a tumor specimen from a biopsy performed upon discontinuation of 
Stage 1 (if deemed clinically feasible by the investigator)
4.1.2
Exclusion Criteria
Patients will be excluded from enrollment during Stage 1 and Stage 2 if they meet any of 
the applicable criteria outlined in subsequent sections, as summarized by treatment arm 
in Table 7.  If a patient is eligible only for the control arm, the patient will not be enrolled 
in the study.  Event grades in the exclusion criteria are based on NCI CTCAE v4.0.
Table 7
Arm-Specific Exclusion Criteria
Stage
Treatment Arm
Applicable Exclusion Criteria
1
Regorafenib
Sections 4.1.2.1 and 4.1.2.2
AtezoIdasa
Sections 4.1.2.1, 4.1.2.2, and 4.1.2.3
AtezoRegorafenib
Sections 4.1.2.1 and 4.1.2.2
AtezoRegorafenibAB928
Sections 4.1.2.1, 4.1.2.2, and 4.1.2.4
AtezoLOAd703
Sections 4.1.2.1, 4.1.2.2, and 4.1.2.5
2
Not currently available
Not applicable


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Atezoatezolizumab; Idasa=Idasanutlin; LOAdLokon oncolytic adenovirus.
4.1.2.1
Exclusion Criteria for Stage 1 
Patients who meet any of the following criteria will be excluded from Stage 1:

High microsatellite instability (MSI-H) tumor
Patients with unknown MSI status will be required to undergo testing at a local 
laboratory and provide results at screening; genomic testing using polymerase 
chain reaction (PCR) or sequencing, or immunohistochemistry (IHC) techniques 
are allowed.

Presence of BRAFV600E mutation
Patients with unknown BRAF status will be required to undergo testing at a 
local laboratory and provide results at screening.

Prior treatment with any of the protocol-specified study treatments, with the following 
exception:
Patients who received bevacizumab for treatment of CRC are eligible for the 
study.

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

Biologic treatment (e.g., bevacizumab) within 2 weeks prior to initiation of study 
treatment, or other systemic treatment for CRC within 2 weeks or 5 half-lives of the 
drug (whichever is shorter) prior to initiation of study treatment

Treatment with investigational therapy within 28 days prior to initiation of study
treatment 

Eligibility only for the control arm
4.1.2.2
Exclusion Criteria for Stage 1 and Stage 2
Patients who meet any of the following criteria will be excluded from Stage 1 and from 
Stage 2:

Prior allogeneic stem cell or solid organ transplantation

Treatment with systemic immunostimulatory agents (including, but not limited to, IFN
and IL-2) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to the 
initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-tumor necrosis factor-agents) within 2 weeks prior to initiation of study 
treatment, or anticipation of need for systemic immunosuppressant medication 
during study treatment, with the following exceptions:
Patients who received acute, low-dose, systemic immunosuppressant 
medications or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study.


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Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible 
for the study.

Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment 
or within 5 months after the last dose of atezolizumab

Current treatment with anti-viral therapy for HBV

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently)
Use of an indwelling catheter (e.g., PleurX) is allowed.

Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry.
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the effects of radiation.  There is 
no required minimum recovery period.
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not 
presently associated with spinal cord compression) should be considered for 
loco-regional therapy if appropriate prior to enrollment.

Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L,
calcium 12 mg/dL, or corrected serum calcium ULN)

Symptomatic, untreated, or actively progressing CNS metastases 
Patients with a history of treated CNS metastases are eligible, provided that all 
of the following criteria are met:
–
Measurable disease, per RECIST v1.1, must be present outside the CNS.
–
The patient has no history of intracranial hemorrhage or spinal cord 
hemorrhage.
–
Metastases are limited to the cerebellum or the supratentorial region 
(i.e., no metastases to the midbrain, pons, medulla, or spinal cord).
–
There is no evidence of interim progression between completion of 
CNS-directed therapy and the screening brain scan.
–
The patient has not received stereotactic radiotherapy within 7 days prior 
to initiation of study treatment or whole-brain radiotherapy within 14 days 
prior to initiation of study treatment.
–
The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease.  Anti-convulsant therapy at a stable dose is permitted.


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Asymptomatic patients with CNS metastases newly detected at screening are 
eligible for the study after receiving radiotherapy or surgery, with no need to 
repeat the screening brain scan.

History of leptomeningeal disease

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, antiphospholipid 
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix 4 for a more comprehensive list of 
autoimmune diseases and immune deficiencies), with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on a stable insulin 
regimen are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met:
–
Rash must cover 10% of body surface area.
–
Disease is well controlled at baseline and requires only low-potency topical
corticosteroids.
–
There is no occurrence of acute exacerbations of the underlying condition 
requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, or high-potency or oral 
corticosteroids within the previous 12 months.

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

History of malignancy other than CRC within 2 years prior to screening, with the 
exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year 
overall survival [OS] rate 90%), such as adequately treated carcinoma in situ of the 
cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in 
situ, or Stage I uterine cancer

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, or any active infection that, in the opinion of the investigator, could 
impact patient safety


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
Treatment with therapeutic oral or intravenous (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.

Significant cardiovascular disease (such as New York Heart Association Class II or 
greater cardiac disease or cerebrovascular accident) within 3 months prior to 
initiation of study treatment, unstable angina or new onset angina within 3 months
prior to initiation of study treatment, recent myocardial infarction within 6 months prior 
to initiation of study treatment, or unstable arrhythmia

Grade 3 hemorrhage or bleeding event within 28 days prior to initiation of study 
treatment

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
Placement of central venous access catheter (e.g., port or similar) is not 
considered a major surgical procedure and is therefore permitted.

Adverse events from prior anti-cancer therapy that have not improved to Grade 1 or 
better, with the exception of alopecia of any grade and Grade 2 peripheral 
neuropathy

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

History of severe allergic reactions to chimeric or humanized antibodies or fusion 
proteins

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation

Known allergy or hypersensitivity to any of the study drugs or their excipients

Patients entering Stage 2:  inability to tolerate atezolizumab during Stage 1

Pregnancy or breastfeeding, or intention of becoming 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.

Inability to swallow medications 

Malabsorption condition that would alter the absorption of orally administered 
medications

Evidence of inherited bleeding diathesis or significant coagulopathy at risk of 
bleeding (i.e., in the absence of therapeutic anticoagulation)


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
Urine dipstick 2protein or 3.5 g of protein in a 24-hour urine collection
Patients discovered to have 2proteinuria on dipstick urinalysis at screening 
should undergo a 24-hour urine collection and must demonstrate 3.5 g of 
protein in 24 hours to be eligible.
4.1.2.3
Additional Exclusion Criteria for Idasanutlin-Containing Arm 
during Stage 1
Patients who meet any of the following criteria will be excluded from the 
idasanutlin-containing arm during Stage 1: 

Prior treatment with an MDM2 antagonist

TP53 mutation as determined centrally through use of a blood-based NGS ctDNA 
assay

Hypersensitivity to idasanutlin active substance or any of the excipients

Inability to interrupt treatment with moderate to strong CYP2C8 inducers and 
inhibitors (including gemfibrozil, which is also an inhibitor of UGT1A3), CYP2C8
substrates, strong CYP3A4 inducers or OATP1B1/3 substrates (see Tables 68 in 
Appendix 11 for more details)
These agents must be discontinued 14 days prior to the start of study treatment.

History of clinically significant liver cirrhosis (e.g., Child-Pugh class B and C)

Inadequate renal function assessed by either serum creatinine outside local 
laboratory reference ranges OR creatinine clearance (by Cockcroft Gault formula) 
50 mL/min

Treatment with oral or parenteral anticoagulants/anti-platelet agents (e.g., warfarin, 
chronic daily treatment with aspirin [325 mg/day], clopidogrel, dabigatran, 
apixaban, rivaroxaban) within 7 days (or 5 half-lives) prior to treatment start
Treatment with, or switch to low molecular weight heparin (LMWH) or 
unfractionated heparin (UFH) is allowed, according to local practice. 
Patients may receive anticoagulant flushes for maintenance of indwelling
catheters.

Unstable seizure disorders

Active GI conditions, including, but not limited to, uncontrolled inflammatory bowel 
disease (e.g., Crohn’s disease, diverticulosis-associated colitis)

History of symptomatic clostridium difficile infection that required treatment within 
1 month prior to dosing
Upon clinical response to C. difficile treatment, the stool consistency and 
frequency must have returned to pretreatment levels.
4.1.2.4
Additional Exclusion Criteria for AB928-Containing Arm during 
Stage 1
Patients who meet any of the following criteria will be excluded from the 
AB928-containing arm during Stage 1: 


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
Prior treatment with an agent targeting the adenosine pathway

Treatment with strong inhibitors of breast cancer resistance protein (BCRP)
(e.g., cyclosporin A, eltrombopag) or BCRP substrates with a narrow therapeutic 
window, administered orally (e.g., prazosin, rosuvastatin), and within 4 weeks or 
5 half-lives of the drug (whichever is longer) prior to initiation of study treatment

Treatment with strong inhibitors of P-glycoprotein (P-gp) (e.g., itraconazole, 
quinidine, verapamil, dronedarone, ranolazine) or P-gp substrates with a narrow 
therapeutic window, administered orally (e.g., digoxin), and within 4 weeks or 5 
half-lives of the drug (whichever is longer), prior to initiation of study treatment

Treatment with known strong UDP-glucuronosyltransferases (UGTs) of UGT1A1, 
1A4, 1A9 and 2B4 inhibitors (e.g., atazanavir) within 4 weeks or 5 half-lives of the 
drug (whichever is longer) prior to the initiation of study treatment.

Treatment with known sensitive substrates of BSEP within 4 weeks or 5 half-lives of 
the drug (whichever is longer) prior to the initiation of study treatment.

Treatment with known sensitive substrates of OCT2 within 4 weeks or 5 half-lives of 
the drug (whichever is longer) prior to the initiation of study treatment.

Treatment with known sensitive substrates of MATE-1 within 4 weeks or 5 half-lives
of the drug (whichever is longer) prior to the initiation of study treatment.

Treatment with strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, 
phenobarbital, and St. John’s Wort) and strong CYP3A4 inhibitors (e.g., 
clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, 
telithromycin, and voriconazole) within 4 weeks or 5 half-lives of the drug (whichever 
is longer) prior to initiation of study treatment
4.1.2.5
Additional Exclusion Criteria for LOAd703-Containing Arm 
during Stage 1
Patients who meet any of the following criteria will be excluded from the 
LOAd703-containing arm during Stage 1:

Prior treatment with an adenovirus-based gene therapy 

Prior treatment with LOAd703 or any other oncolytic virus

Prior treatment with adenovirus-based vaccines (e.g., ChAdOx1 nCoV-19, 
Ad26.COV2.S) up to 6 months prior to initiation of study treatment, anticipation of 
need for such a vaccine during LOAd703 treatment or up to 6 months after the last 
dose of LOAd703

Absence of available lesion that is both  measurable according to RECIST v1.1  and  
injectable  (as assessed by the investigator, refer to Section A14–4.1.2.1 for further 
guidance)
The injected lesion should not be the only measurable lesion

Known hereditary bleeding diathesis or significant acquired coagulopathy at risk of 
bleeding (e.g., hemophilia, von Willebrand disease, cancer-associated diffuse 
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
For procedures with moderate or significant risk of bleeding (deep lesions and/or 
organs), use of therapeutic doses of anticoagulants prior to the initiation of study 
treatment 
Long-acting agents such as aspirin or clopidogrel should be discussed on a 
case-by-case basis with the Sponsor and may need to be discontinued before 
the start of study treatment.
Patients on preventive doses of LMWH or direct oral anticoagulant (DOAC) 
may be eligible if treatment can be suspended 24 hours (for LMWH) or 48 
hours (for DOAC) prior to intratumoral injection and resumed 24 hours after the 
injection.
4.2
METHOD OF TREATMENT ASSIGNMENT
This is a randomized, open-label study.  After initial written informed consent has been 
obtained, prescreen testing (if applicable; see Section 4.5.2) has been completed, all 
screening procedures and assessments have been completed, and eligibility has been 
established for a patient, the study site will obtain the patient’s identification number and 
Stage 1 treatment assignment from the interactive voice or web-based response system 
(IxRS).  Patients who enroll in Stage 2 will be assigned to treatment per investigator’s 
choice if more than one treatment option is available and will retain the same patient 
identification number that was assigned in Stage 1.
For Stage 1, this study will employ a permuted-block randomization method with 
dynamically changing randomization ratios to account for fluctuation in the number of 
treatment arms that are open for enrollment over the course of the study. The 
randomization ratio will depend on the number of experimental arms that are open for 
enrollment (e.g., if an arm is added or enrollment in an arm is suspended pending 
analysis of results from the preliminary phase), with the stipulation that the likelihood of 
being allocated to control arm is no more than 35%. The randomization ratios may be 
altered to increase enrollment into a given experimental arm. 
Randomization will take into account general exclusion criteria and arm-specific 
exclusion criteria as outlined in Sections 4.1.1 and 4.1.2.  For example, the 
AtezoRegorafenib arm will be removed as an option for patients who are ineligible for 
that arm.  If a patient is only eligible for the control arm, the patient will not be enrolled in 
the study.  If the Atezo + Idasa arm is open, the Sponsor may decide to limit 
randomization to the Atezo + Idasa arm and the regorafenib arm for patients who have a 
TP53 wild-type status and are eligible for this arm. 
If more than one mandatory serial-biopsy arm is open for enrollment at a time, eligible 
patients at participating sites will be assigned to one of the available arms by the 
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Patients who do not receive at least one dose of each drug for their assigned treatment 
regimen will not be included in the efficacy analyses.  Additional patients may be 
enrolled in Stage 1 to reach the target number of treated patients planned for analysis.
4.3
STUDY TREATMENT 
Details on the therapeutic agents for each treatment arm are provided in the respective 
appendix for that treatment arm, as outlined in Table 4 and Table 6.
4.3.1
Investigational Medicinal Product Accountability
The IMPs for this study are atezolizumab, regorafenib, idasanutlin, AB928, and 
LOAd703.
All IMPs required for completion of this study will be provided by the Sponsor where 
required by local health authority regulations.  The study site will acknowledge receipt of 
IMPs supplied by the Sponsor to confirm the shipment condition and content.  Any 
damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site’s method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on a Drug Inventory Log.
4.3.2
Post-Trial Access to Study Treatment
Currently, the Sponsor does not have any plans to provide study treatments or 
interventions to patients who have completed the study.  The Sponsor may evaluate 
whether to continue providing study treatments in accordance with the Roche Global 
Policy on Continued Access to Investigational Medicinal Product, available at the 
following web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY AND PROHIBITED FOOD
Details on concomitant therapy, prohibited food, and additional restrictions for each 
treatment arm are provided in the respective appendix for that treatment arm (see 
Appendix 7 through Appendix 14).
4.5
STUDY ASSESSMENTS 
A schedule of activities to be performed during the study is provided for each treatment 
arm in Appendix 7 through Appendix 14.  All activities must be performed and 


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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 
infusion; dosing will occur only if the clinical assessment and local laboratory test values 
are acceptable.
4.5.1
Informed Consent Forms and Screening
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including prescreen testing [if applicable; see 
Section 4.5.2] and screening evaluations).  Informed Consent Forms for enrolled 
patients and for patients who are not subsequently enrolled will be maintained at the 
study site.
Written informed consent must also be obtained from patients before performing 
screening evaluations and study-related procedures for Stage 2.
Screening evaluations for Stage 1 and Stage 2 are to be performed within 28 days prior 
to initiation of study treatment (Day 1).  All screening evaluations must be completed and 
reviewed to confirm that patients meet all eligibility criteria before enrollment.  
Patients who fail their first screening for study eligibility (Stage 1 or Stage 2) may qualify 
for two re-screening opportunities (for a total of three screenings per patient) at the 
investigator’s discretion.  Patients must re-sign the consent form prior to re-screening.  
Results of standard-of-care tests or examinations performed prior to obtaining informed 
consent and within a specified time prior to Day 1 (see the schedule of activities for each 
arm in Appendix 7 through Appendix 14) may be used; such tests do not need to be 
repeated for screening or re-screening.
4.5.2
Prescreen Testing for TP53 Mutation Status for AtezoIdasa 
Arm
If additional experimental treatment arms are open for enrollment, patients will proceed 
directly into screening after written consent for screening has been obtained (see 
Section 4.5.1). In addition, the option for prescreening for TP53 mutation status may be 
available.  By signing the prescreening consent form, patients may specifically allow for 
the collection and genetic testing of a fresh blood sample. Only if prescreening shows 
that there are no TP53 alterations and the AtezoIdasa arm is the only experimental 
arm open, patients may proceed to the 28-day screening period provided prior written 
consent for the screening of the study has been obtained (see Section 4.5.1).
4.5.3
Medical History, Molecular Profile, Concomitant Medication,
and Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking 
history, and use of alcohol and drugs of abuse, will be recorded at baseline.  The 
molecular profile of the patient’s cancer, if available, will be recorded at screening and 


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updated whenever information becomes available during the study. In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within a specified 
time prior to initiation of study treatment will be recorded (as outlined for each arm in 
Appendix 7 through Appendix 14).  At the time of each follow-up physical examination, 
an interval medical history should be obtained and any changes in medications and 
allergies should be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.4
Physical Examinations
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, GI, genitourinary, and 
neurologic systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions electronic Case Report Form (eCRF).
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated.  
During visits when a patient will undergo a tumor assessment, the physical 
examination should include an evaluation of the presence and degree of enlarged lymph 
nodes, hepatomegaly, and splenomegaly. Changes from baseline abnormalities should 
be recorded in patient notes.  New or worsened clinically significant abnormalities should 
be recorded as adverse events on the Adverse Event eCRF.
4.5.5
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, pulse oximetry, and 
temperature.
Vital signs should be measured at specified timepoints, as outlined for each arm in the 
schedules of activities (see Appendix 7 through Appendix 14), and as clinically indicated.
4.5.6
Tumor and Response Evaluations
Patients will undergo tumor assessments at baseline, every 6 weeks (1 week) for the 
first 48 weeks following initiation of combination treatment, and every 12 weeks 
(2 weeks) thereafter, regardless of dose delays, until radiographic disease progression 
according to RECIST v1.1, except in the case of patients in atezolizumab-containing 
arms who continue treatment after radiographic disease progression; such patients will 
undergo tumor assessments every 6 weeks (1 week) until loss of clinical benefit
defined as (1) confirmed disease progression or (2) lack of continued benefit as 
determined by the investigator (see Section 3.1.1 for details). Thus, tumor assessments 
are to continue according to schedule in patients who discontinue treatment for reasons 


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other than disease progression or loss of clinical benefit, even if they start new,
nonprotocol-specified anti-cancer therapy.  At the investigator’s discretion, tumor 
assessments may be repeated at any time if progressive disease is suspected.
Baseline tumor assessments for Stage 2 must be performed within 28 days prior to 
initiation of Stage 2 treatment (i.e., Day 1 of Cycle 1).  For patients eligible for Stage 2, 
tumor assessments performed prior to or at the time of unacceptable toxicity, disease 
progression per RECIST v1.1, or loss of clinical benefit during Stage 1 may serve as 
baseline assessments for Stage 2, provided the tumor assessments are performed 
within 28 days prior to initiation of Stage 2 treatment.
All measurable and/or evaluable lesions should be assessed and documented at 
screening (in both Stage 1 and Stage 2).  Brain metastases treated with radiotherapy or 
surgery will not be considered measurable or evaluable but will be documented at 
screening as a site of metastatic disease.  Tumor assessments performed as standard 
of care prior to obtaining informed consent and within 28 days prior to initiation of study 
treatment do not have to be repeated at screening.  
Screening assessments must include CT scans (with IV contrast; with or without oral 
contrast) or magnetic resonance imaging (MRI) scans (with IV contrast) of the chest, 
abdomen, pelvis, and head.  A spiral CT scan of the chest may be obtained but is not a 
requirement.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast 
allergy or impaired renal clearance), a non-contrast CT scan of the chest may be 
performed and MRI scans of the abdomen, pelvis, and head should be performed.  
A CT scan with contrast or MRI scan with contrast of the head must be done at 
screening to evaluate CNS metastasis in all patients (MRI scan must be performed if 
contrast is contraindicated).  Bone scans and CT scans of the neck should also be 
performed if clinically indicated.  At the investigator’s discretion, other methods 
of assessment of measurable disease as per RECIST v1.1 may be used.
If a CT scan for tumor assessment is performed in a positron emission tomography/CT 
scanner, the CT acquisition must be consistent with the standards for a full-contrast 
diagnostic CT scan.
All measurable and/or evaluable lesions identified at baseline should be re-assessed at 
subsequent tumor evaluations according to the schedule described above.  Brain 
metastases identified at baseline that have been treated with radiotherapy or surgery will 
not be considered measurable or evaluable unless there is suspected disease 
progression in the brain (i.e., the patient becomes symptomatic).  Thus subsequent head 
scans are not required unless clinically indicated.  The same radiographic procedures 
used to assess disease sites at screening should be used for subsequent tumor 
assessments (e.g., the same contrast protocol for CT scans). To facilitate evaluation of 
post-progression tumor changes while treatment is ongoing, tumor assessments must 
be continued after disease progression per RECIST v1.1 for patients who receive 


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treatment beyond progression.  This includes continued measurement of target lesions, 
evaluation of non-target lesions (including monitoring for further worsening of any 
non-target lesions that have shown unequivocal progression), and evaluation of any 
newly identified lesions (including measurements, if lesions are measurable) at all 
subsequent assessments.
Overall response at a given timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1).  Assessments should be performed by the same 
evaluator, if possible, to ensure internal consistency across visits. Available results must 
be reviewed by the investigator before further dose administration.
4.5.7
Laboratory, Biomarker, and Other Biologic Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other 
cells)

Chemistry panel (serum or plasma):  sodium, potassium, magnesium, chloride, 
bicarbonate or carbon dioxide (as per standard of care for the region), glucose, BUN 
or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, 
ALT, and AST in all arms and CPK, lipase, and amylase in specified arms

Coagulation:  INR and aPTT

Thyroid function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) (or 
total T3 for sites where free T3 is not performed), and free thyroxine (also known as 
T4)

Ferritin (performed for specified arms only; details provided in schedules of activities)

HIV serology, unless not permitted per local regulations

HBV serology:  HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb 
test is positive) HBV DNA
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection.

HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection.

C-reactive protein

Lactate dehydrogenase 

Carcinoembryonic antigen (CEA)

Pregnancy test


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All women of childbearing potential will have a serum pregnancy test at Stage 1 
screening.  Urine or serum pregnancy tests will be performed at specified 
subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by 
a serum pregnancy test.
A woman is considered to be of childbearing potential if she is 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).

Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); dipstick 
permitted 
For patients in a bevacizumab- or regorafenib-containing arm, if urinary protein 
is 2on dipstick, then a 24-hour urine collection is required to check the total 
urinary protein.  If there is an explanation for the positive dipstick result (e.g., 
menses), it should be recorded and there is no need to perform further 
laboratory assessments.

For patients with unknown status:  MSI/MSS and BRAF status through testing
performed on tumor tissue collected at baseline
Samples for the following laboratory test will be sent to a central laboratory for analysis: 

Blood sample for blood-based NGS ctDNA assay performed by Foundation 
Medicine
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis:

Archival or fresh tumor tissue sample collected at baseline for determination of 
PD-L1 expression and for exploratory research on biomarkers
Baseline tumor tissue samples from the primary lesion or a metastatic lesion 
will be collected 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, provided that the tissue was obtained from a 
biopsy performed within 6 months prior to enrollment and that the patient has 
not received any anti-cancer therapy since the time of the biopsy.  
A representative FFPE tumor specimen in a paraffin block (preferred) or 
1016 slides (16 slides preferred) containing unstained, freshly cut, serial 
sections must be submitted along with an associated pathology report.  
Tumor tissue should be of good quality based on total and viable tumor content.  
Samples must contain a minimum of 50 viable tumor cells that preserve cellular 
context and tissue architecture regardless of needle gauge or retrieval method.  
Samples collected via resection, core-needle biopsy (at least three cores, 
embedded in a single paraffin block), or excisional, incisional, punch, or forceps 
biopsy are acceptable.  Fine-needle aspiration (defined as samples that do not 
preserve tissue architecture and yield cell suspension and/or smears), brushing, 
cell pellets from pleural effusion, and lavage samples are not acceptable.  


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Tumor tissue from bone metastases that have been decalcified is not 
acceptable.
Remaining archival tumor tissue blocks will be returned to the site upon request 
or 18 months after final closure of the study database, whichever occurs first.  

Serum sample for analysis of autoantibodies:  anti-nuclear antibody, 
antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and 
perinuclear anti-neutrophil cytoplasmic antibody in all arms 
The serum autoantibody sample collected at screening will be analyzed only if a 
patient experiences a suspected immune-related adverse event and the serum 
autoantibody results are positive during the treatment period.  

Plasma or serum samples for PK analysis (see Appendix 7 through Appendix 14)

Plasma or serum samples for immunogenicity analysis (see Appendix 7 through
Appendix 14)

Plasma, serum, and peripheral blood mononuclear cell (PBMC) samples for 
exploratory research on biomarkers (see Appendix 7 through Appendix 14)

Serum and urine samples, oral and rectal swabs for LOAd703 shedding analysis 
(see Appendix 14, Table 9) 

Mandatory serial-biopsy arms at participating sites:  tumor tissue sample collected 
4 weeks (7 days) after initiation of Stage 1 treatment (if deemed clinically feasible 
by the investigator) for exploratory research on biomarkers 
Patient should have at least two accessible tumors that are amenable to 
excisional, punch, or core-needle biopsy (a minimum of three cores, 18-gauge 
needle or larger [16-gauge needle preferred]) without unacceptable risk of a 
major procedural complication.  If it is planned that more than one biopsy will be 
obtained from a single lesion, the lesion should be large enough to permit 
successive biopsies 1 cm apart.

Tumor tissue sample collected during Stage 1, at the time of unacceptable toxicity, 
disease progression per RECIST v1.1, or loss of clinical benefit defined as 
(1) confirmed disease progression or (2) lack of continued benefit as determined by 
the investigator (see Section 3.1.1 for details) (if deemed clinically feasible by the 
investigator) for exploratory research on biomarkers
Biopsies should be performed within 40 days after determination of 
unacceptable toxicity, disease progression, or loss of clinical benefit, or prior to 
the next anti-cancer therapy, whichever is sooner.  Samples collected via
resection, core-needle biopsy (at least three cores preferred), or excisional, 
incisional, punch, or forceps biopsy are preferred.
Exploratory biomarker research may include, but will not be limited to, analysis of genes 
or gene signatures associated with tumor immunobiology, PD-L1, cytokines associated 
with T-cell activation, T-cell receptor repertoire, CEA, or density, localization, and 
activation status of immune cells and their subsets.  Research may involve extraction of 
DNA, cell-free DNA, or RNA; analysis of mutations, single nucleotide polymorphisms, 


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and other genomic variants; and genomic profiling through use of NGS of a 
comprehensive panel of genes.  DNA extracted from blood may be compared with DNA 
extracted from tissue to identify somatic variants by distinguishing germline variants 
from somatic variants.  NGS methods may include whole genome sequencing (WGS) or 
WES of tissue and blood samples, but WGS or WES of blood samples will be performed 
only at participating sites (see Section 4.5.9).
NGS may be performed by Foundation Medicine.  If performed by Foundation Medicine, 
the investigator can obtain results from these analyses in the form of an NGS report, 
which is available upon request directly from Foundation Medicine.  If allowed by local 
laws, 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.  Results may 
not be available for samples that do not meet testing criteria.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.11), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Serum or plasma, and shedding samples collected for PK analysis, immunogenicity 
analysis, or LOAd703 shedding analysis may be needed for additional 
immunogenicity characterization and PK and immunogenicity assay development 
and validation; therefore, these samples will be destroyed no later than 5 years after 
the final Clinical Study Report has been completed.

Plasma, serum, PBMC, 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, with the exception of the samples that undergo WES, which will be stored 
until they are no longer needed or until they are exhausted.  However, the storage 
period for the WES samples will be in accordance with the Institutional Review Board 
or Ethics Committee (IRB/EC)-approved Informed Consent Form and applicable laws 
(e.g., health authority requirements).
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.


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Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from Foundation 
Medicine).  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
4.5.8
Electrocardiograms
An ECG will be performed at screening and as outlined for each arm in the schedules of 
activities (see Appendix 7 through Appendix 14). ECGs for each patient should be 
obtained from the same machine wherever possible.  Lead placement should be as 
consistent as possible.  It is recommended that patients be resting in a supine position 
for at least 10 minutes prior to ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF.
4.5.9
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites)
At participating sites, blood samples will be collected for DNA extraction to enable 
WGS or WES to identify variants that are predictive of response to study drug, are 
associated with progression to a more severe disease state, are associated with acquired 
resistance to study drug, are associated with susceptibility to developing adverse events, 
can lead to improved adverse event monitoring or investigation, or can increase the 
knowledge and understanding of disease biology and drug safety.  Research may include 
exploration of germline variants.  The samples may be sent to one or more laboratories 
for analysis.
Collection and submission of blood samples for WGS or WES is contingent upon the 
review and approval of the exploratory research by each site's IRB/EC and, if applicable, 
an appropriate regulatory body.  If a site has not been granted approval for WGS or 
WES, this section of the protocol (Section 4.5.9) will not be applicable at that site.
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which patients are more likely to respond to a drug or 
develop adverse events.  Data will be analyzed in the context of this study but may also 
be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.


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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Blood samples collected for WGS or WES are to be stored until they are no longer 
needed or until they are exhausted.  However, the storage period will be in accordance 
with the IRB/ECapproved Informed Consent Form and applicable laws (e.g., health 
authority requirements).
Data generated from blood samples collected for WGS or WES will be analyzed in 
aggregate rather than on an individual patient basis.  Thus, there will be no 
identification and reporting of incidental findings to investigators or patients.
If permitted by local law, a patient may request access to uninterpreted WGS or WES 
data derived from analysis of his or her blood sample.  If a patient wishes to access these 
data, the investigator must inform the Sponsor, using the following email address:  
global.return-genomics-results@roche.com.  The Sponsor will provide available data to 
the investigator in the form of a raw genomic sequencing data file, but will not provide 
any interpretation of the data.  The investigator should not include the data file in the 
patient's medical record.  Samples may be stored and analyzed in the future, and some 
samples may never be analyzed.  Thus, data may not be available at the time of the 
request or may never be available.
The aggregate results of any conducted research will be available in accordance with the 
effective Sponsor policy on study data publication.
4.5.10
Optional Tumor Biopsies
Consenting patients will undergo optional tumor biopsies 4 weeks (7 days) after 
treatment initiation, or as otherwise indicated in the schedules of activities, and may 
undergo additional on-treatment biopsies at any other time at the investigator’s 
discretion (if deemed clinically feasible by the investigator).  Samples collected via
resection, core-needle biopsy (at least three cores preferred), or excisional, incisional, 
punch, or forceps biopsy are preferred.  For sampling procedures, storage conditions, 
and shipment instructions, see the laboratory manual.  
The Informed Consent Form will contain a separate section that addresses optional 
biopsies.  A separate, specific signature will be required to document a patient's 
agreement to undergo optional biopsies.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the Optional Biopsy 
Sample Informed Consent eCRF.
Samples may be used for exploratory biomarker research as described in Section 4.5.7.  
Refer to Section 4.5.7 for details on sample storage, use of samples after patient 


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withdrawal, confidentiality standards for data, and availability of data from biomarker 
analyses.
4.5.11
Optional Samples for Research Biosample Repository
4.5.11.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.11.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB/EC and, if applicable, an appropriate regulatory body.  
If a site has not been granted approval for RBR sampling, this section of the protocol 
(Section 4.5.11) will not be applicable at that site.
4.5.11.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to CIT or diseases:

Blood samples collected on Day 1 of Cycle 1 during Stage 1 and Stage 2

Leftover blood, serum, plasma, PBMC, and tumor tissue samples (with the exception 
of leftover tissue from archival FFPE blocks, which will be returned to sites) and any 
derivatives thereof (e.g., DNA, RNA, proteins, peptides) collected during Stage 1 or 
Stage 2 of the study, including leftover tissue samples from additional tumor biopsies 
or medically indicated procedures (e.g., bronchoscopy, 
esophagogastroduodenoscopy, colonoscopy) performed at the investigator's 
discretion 


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The above samples may be sent to one or more laboratories for analysis of germline or
somatic mutations via WGS, NGS, or other genomic analysis methods. 
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.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.11.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.11.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 


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time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.11.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR at any time for any reason. After withdrawal of consent, any 
remaining samples will be destroyed or will no longer be linked to the patient.  However, 
if RBR specimens have been tested prior to withdrawal of consent, results from those 
tests will remain as part of the overall research data. If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and, if the trial is ongoing, must enter the date of withdrawal on the 
RBR Research Sample Withdrawal of Informed Consent eCRF.  
If a patient wishes to withdraw consent to the testing of his or her RBR samples after 
closure of the site, the investigator must inform the Sponsor by emailing the study 
number and patient number to the following email address: 
global_rcr-withdrawal@roche.com 
A patient's withdrawal from this study does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from this study.
4.5.11.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.


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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:

Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient’s potential response to therapy and severity of the event

Any medical condition that may jeopardize the patient’s safety if he or she continues 
study treatment

Investigator or Sponsor determines it is in the best interest of the patient

Use of another non-protocol anti-cancer therapy

Pregnancy

Experimental arms:  loss of clinical benefit defined as (1) confirmed disease 
progression or (2) lack of continued benefit as by the investigator after an integrated 
assessment of radiographic and biochemical data, local biopsy results (if available), 
and clinical status (e.g., symptomatic deterioration such as pain secondary to 
disease) (see Section 3.1.1 for details)

Regorafenib control arm:  radiographic disease progression per RECIST v1.1
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.
Patients will return to the clinic for a treatment discontinuation visit 30 days after the 
last dose of study treatment.  The visit at which response assessment shows 
progressive disease or loss of clinical benefit may be used as the treatment 
discontinuation visit.  Patients who discontinue study treatment for any reason other than 
progressive disease or loss of clinical benefit will continue to undergo tumor response 
assessments as outlined in the schedule of activities provided for each arm in
Appendix 7 through Appendix 14.
After treatment discontinuation, information on survival follow-up and new anti-cancer 
therapy will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 months until death (unless the patient withdraws consent or the 
Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this 
request must be documented in the source documents and signed by the investigator.  If 
the patient withdraws from study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status only.  For an 
experimental arm in which all patients discontinued treatment and passed the safety 
follow-up window, as well as approximately 80% of patients discontinued the study, the 
Sponsor may conclude the arm (the remaining ~20% of patients will be discontinued 
from the study).


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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:

Withdrawal of consent

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.
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
5.1
SAFETY PLAN
A safety plan for each treatment arm, including a summary of risks and management 
guidelines for patients who experience specific adverse events, is provided in the 
respective appendix for that treatment arm (see Appendix 7 through Appendix 14).
Patients with active infection are excluded from study participation.  In the setting of a 
pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to 


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and during study participation should be considered according to local or institutional 
guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology).
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 and 
5.3.5.10 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.


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
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event results 
in substantial disruption of the patient’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study treatment

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
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 each 
treatment arm are listed in the respective appendix for that treatment arm (see 
Appendix 7 through Appendix 14).
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.


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After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study treatment, all adverse events will be reported until 30 days after 
the last dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first, and serious adverse events and adverse events of special 
interest will continue to be reported until 135 days (180 days for patients in the 
AtezoLOAd703 arm; see Section A14-5.1) after the last dose of study treatment or 
until initiation of new systemic anti-cancer therapy, whichever occurs first.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 8 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 8
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 
adverse event is considered to be related to study treatment, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also 
Table 9):

Temporal relationship of event onset to the initiation of study treatment

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment (as applicable)

Known association of the event with study treatment or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
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Table 9
Causal Attribution Guidance
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than study treatment
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment).
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 or Injection-Site Reactions and Cytokine
Release Syndrome
There may be significant overlap in signs and symptoms of infusion-related reactions 
(IRRs) and CRS.  While IRRs occur during or within 24 hours after treatment 
administration, time to onset of CRS may vary.  Differential diagnosis should be 
applied, particularly for late-onset CRS (occurring more than 24 hours after treatment 
administration), to rule out other etiologies such as delayed hypersensitivity reactions, 
sepsis or infections, hemophagocytic lymphohistiocytosis, tumor lysis syndrome, early 
disease progression, or other manifestations of systemic inflammation.
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion or injection should be captured 
on the Adverse Event eCRF as a diagnosis (e.g., "infusion-related reaction," 
"injection-site reaction," or "cytokine release syndrome").  Avoid ambiguous terms 
such as "systemic reaction."  Cases of late-onset CRS should be reported as "cytokine 
release syndrome" on the Adverse Event eCRF.  Associated signs and symptoms should 
be recorded on the dedicated Infusion-Related or Injection-Site Reaction eCRF or 
Cytokine Release Syndrome eCRF.  If a patient experiences both a local and systemic 
reaction to a single administration of study treatment, each reaction should be recorded 
separately on the Adverse Event eCRF, with associated signs and symptoms also 


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recorded separately on the dedicated Infusion-Related or Injection Reaction eCRF or 
Cytokine Release Syndrome eCRF.
In recognition of the challenges in clinically distinguishing between IRRs and CRS, 
consolidated guidelines for medical management of IRRs and CRS are provided in
Appendix 6.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related or injection reactions (see 
Section 5.3.5.1), a diagnosis (if known) should be recorded on the Adverse Event eCRF 
rather than individual signs and symptoms (e.g., record only liver failure or hepatitis 
rather than jaundice, asterixis, and elevated transaminases).  However, if a constellation 
of signs and/or symptoms cannot be medically characterized as a single diagnosis or 
syndrome at the time of reporting, each individual event should be recorded on the 
Adverse Event eCRF.  If a diagnosis is subsequently established, all previously reported 
adverse events based on signs and symptoms should be nullified and replaced by one 
adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
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 


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recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., 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).


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5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 baseline value in combination with total 
bilirubin 2 ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3 baseline value in combination with clinical 
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 mCRC should be recorded on the Death 
Attributed to Progressive Disease eCRF.  All other deaths that occur during the adverse 


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event reporting period, regardless of relationship to study treatment, must be recorded 
on the Adverse Event eCRF and immediately reported to the Sponsor (see 
Section 5.4.2).
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Metastatic Colorectal 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.  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.  


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An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study treatment
administration or performance of an efficacy measurement for the study)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The patient has not experienced an adverse event.

Hospitalization due solely to progression of the underlying cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
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.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
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(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For the IMPs 
studied in this trial (see Section 4.3.1), adverse events associated with special situations 
should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes.
In addition, all special situations associated with the IMPs studied in this trial (see 
Section 4.3.1) regardless of whether they result in an adverse event, should be recorded 
on the Adverse Event eCRF as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box.


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
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.
As an example, an accidental overdose that resulted in a headache would require 
two entries on the Adverse Event eCRF, one entry to report the accidental overdose and 
one entry to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
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.


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5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Primary Medical Monitor/
Roche Medical Responsible:
, M.D., Ph.D.
Email:
Mobile Telephone No.:
Backup Medical Monitor:
Email:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Adverse Event/Special Situations Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.
5.4.2.2
Events That Occur after Study Treatment Initiation
After initiation of study treatment, all adverse events will be reported until 30 days after 
the last dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first, and serious adverse events and adverse events of special 
interest will continue to be reported until 135 days (180 days for patients in the 
AtezoLOAd703 arm; see Section A14-5.1) after the last dose of study treatment or 
until initiation of new systemic anti-cancer therapy, whichever occurs first.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 


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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 135 days (180 days for 
patients in the AtezoLOAd703 arm; see Section A14-5.1) after the last dose of study 
treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
Reporting requirements for pregnancies are described for each treatment arm in the 
respective appendix for that treatment arm (see Appendix 7 through Appendix 14).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study treatment or trial-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 135 days [180 days for 
patients in the AtezoLOAd703 arm; see Section A14-5.1] after the last dose of study 
treatment or until initiation of new, systemic anti-cancer therapy, whichever occurs first), 
all deaths, regardless of cause, should be reported through use of the Long-Term 
Survival Follow-Up eCRF.  
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study treatment, the event should be reported through 
use of the Adverse Event eCRF.  However, if the EDC system is not available, the 


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investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Atezolizumab Investigator's Brochure

Idasanutlin Investigator’s Brochure

AB928 Investigator’s Brochure

LOAd703 Investigator’s Brochure

Summary of Product Characteristics for regorafenib
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The final study analysis will be based on patient data collected through study 
discontinuation.  If not otherwise specified, efficacy analyses will be based on the 
efficacy-evaluable population, defined as all patients who receive at least one dose of 
each drug for their assigned treatment regimen. Other analyses will be based on the 
safety-evaluable population, defined as all patients who receive any amount of study 
treatment, if not otherwise specified.
The analysis results will be summarized by the treatment that patients actually received, 
as well as by stage (Stage 1 or Stage 2). Data will be described and summarized as 
warranted by sample size.  Continuous variables will be summarized through use of 
means, standard deviations, medians, and minimum and maximum values.  Categorical 
variables will be summarized through use of counts and percentages.  Listings will be 
used in place of tables in the event of small sample sizes.


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New baseline values will be established for the Stage 2 efficacy and safety analyses.  
For evaluation of tumor response, new baseline tumor assessments will be established 
as described in Section 4.5.6.  For other endpoints (e.g., change from baseline in vital 
signs or laboratory test results), the last non-missing value prior to the patient's first dose 
during Stage 2 will serve as the new baseline.  
6.1
DETERMINATION OF SAMPLE SIZE
This study is not designed to make explicit power and type I error considerations for a 
hypothesis test. Instead, this study is designed to obtain preliminary efficacy, safety, 
and PK data on immunotherapy-based treatment combinations when administered to
patients with mCRC who experienced disease progression during or following two lines 
of treatment for mCRC that consisted of fluoropyrimidine-, oxaliplatin-, or 
irinotecan-containing chemotherapy in combination with a biologic agent 
(e.g., bevacizumab, cetuximab), given in combination as two separate lines of therapy 
(in either order).
Approximately 111382 patients will be randomly allocated to the control and 
experimental arms during the study.
Approximately 15 patients with serial biopsy samples will be enrolled in each mandatory 
serial-biopsy arm.  However, the number of patients may be reduced if optional 
on-treatment biopsies have been collected (and determined to be evaluable) from 
consenting patients treated with that same CIT combination during the preliminary 
phase, to limit on-treatment biopsy collection to approximately 15 patients per CIT 
combination within each cohort.  
With approximately 15 patients with serial biopsies in each arm, an 80% two-sided CI for 
a 30% increase in CD8T cells in the center of the tumor would range from 22.8% to
37.2%, assuming a standard deviation of 0.20 for the difference in CD8T cells between 
paired samples (i.e., baseline vs. on-treatment samples, baseline vs. post-progression 
samples, or on-treatment vs. post-progression samples).
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment will be summarized by region, country, and investigator by treatment arm
within the two stages.  Patient disposition will be summarized by treatment arm within 
each stage.  Major protocol deviations, including major deviations with regard to the 
inclusion and exclusion criteria, will be summarized by treatment arm within each stage.
For safety-evaluable patients, study drug administration data will be tabulated or listed 
by treatment arm within each stage, and any dose modifications will be flagged.  Means 
and standard deviations will be used to summarize the total dose and dose intensity for 
each study drug.  Reasons for discontinuation of study drugs will also be tabulated.  


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6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, race/ethnicity, weight, 
malignancy duration, metastatic disease site, primary tumor sidedness, and baseline 
ECOG Performance Status) will be summarized overall and by treatment arm within 
each stage.
6.4
EFFICACY ANALYSES
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is ORR during Stage 1, as defined in Section 2
(see Table 2).  Patients with missing or no response assessments will be classified 
as non-responders.
ORR, defined as the proportion of patients with a complete or partial response, will be 
calculated for each arm, along with 95% CIs (ClopperPearson exact method). The 
difference in ORR between the experimental arms and the corresponding control arm 
will also be calculated, along with 95% CIs, using normal approximation of the binomial 
distribution.
6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are progression-free survival (PFS), OS, OS at 
specific timepoints (e.g., 6 months), duration of response (DOR), and disease control
rate (DCR) during Stage 1, as defined in Section 2 (see Table 2).  PFS, DOR, and DCR
are determined by the investigator according to RECIST v1.1.  
DOR will be derived for efficacy-evaluable patients with a complete or partial response.
For patients who do not have documented disease progression or death in a study stage, 
PFS and DOR will be censored at the day of the last tumor assessment.
Patients who are still alive at the time of OS analysis will be censored at the last date 
they were known to be alive.
The Kaplan-Meier method will be used to estimate the median for PFS, OS, and DOR,
with 95% CIs constructed through use of the Brookmeyer and Crowley method. OS rate 
at specific timepoints will also be estimated through use of the Kaplan-Meier method,
with 95% CIs calculated on the basis of the Greenwood estimate for the variance.
DCR, defined as the proportion of patients with stable disease for 12 weeks, a partial 
response, or a complete response, will be calculated for each treatment arm, with 95%
CIs estimated through use of the Clopper-Pearson exact method. 


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6.4.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are ORR, PFS, DOR, and DCR during Stage 2, as 
determined by the investigator according to RECIST v1.1 (see Table 3).
Objective response, PFS, DOR, and DCR will be analyzed through use of the same 
methods described in Sections 6.4.1 and 6.4.2.  DOR will be derived for 
efficacy-evaluable patients with a complete or partial response.
6.5
SAFETY ANALYSES
Verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities thesaurus terms, and adverse event severity will be graded according to 
NCI CTCAE v4.0.
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in vital signs and ECGs, and exposure to study drugs.  Exposure to 
combination treatment and length of safety follow-up will be summarized by treatment 
arm within each stage.
Treatment-emergent adverse events occurring after initiation of treatment will be 
summarized.  For each patient, the maximum reported severity of each adverse event
will be used in the summaries by severity grade.  All treatment-emergent adverse events, 
serious adverse events, adverse events leading to withdrawal of study treatment, 
Grade 3 adverse events, deaths, and causes of death will be listed and summarized by 
mapped term, appropriate thesaurus level, and NCI CTCAE severity grade. 
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse 
oximetry, and temperature), and ECG data will be displayed by time, with grades
identified where appropriate.  Additionally, a shift table of selected laboratory tests will be 
used to summarize the baseline and maximum postbaseline severity grade.  Changes in 
vital signs and ECGs will be summarized. 
6.6
PHARMACOKINETIC ANALYSES
Sparse samples will be collected for PK analyses of atezolizumab (patients who receive 
at least one dose of atezolizumab) and drugs given in combination with atezolizumab
(patients who receive at least one dose of the drug).  Serum or plasma concentrations of 
the various study drugs will be reported as individual values and summarized (mean, 
standard deviation, coefficient of variation, median, range, geometric mean, and 
geometric mean coefficient of variation) by treatment arm and by cycle and day when 
appropriate and as data allow.  Individual and median serum or plasma concentrations 
of the various study drugs will be plotted by treatment arm and cycle and day.  PK data
for combination drugs may be compared with available historical data from internal and 
published previous studies.  Atezolizumab concentration data may be pooled with data 
from other studies using an established population PK model to derive PK parameters 
such as clearance, volume of distribution, and area under the curve.


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6.7
IMMUNOGENICITY ANALYSES
Immunogenicity will be assessed for atezolizumab and other study treatments as 
appropriate (refer to arm-specific appendices for details).  The immunogenicity analyses 
will include all patients with at least one anti-drug antibody (ADA) assessment.  Patients 
will be grouped according to treatment received or, if no treatment is received prior to 
study discontinuation, according to treatment assigned.
For atezolizumab, the numbers and proportions of ADA-positive patients and 
ADA-negative patients at baseline (baseline prevalence) and after drug administration 
(postbaseline incidence) will be summarized by treatment group.  When determining 
postbaseline incidence, patients are considered to be ADA positive if they are ADA
negative or are missing data at baseline but develop an ADA response following study 
drug exposure (treatment-induced ADA response), or if they are ADA positive at 
baseline and the titer of one or more postbaseline samples is at least 0.60 titer unit 
greater than the titer of the baseline sample (treatment-enhanced ADA response).  
Patients are considered to be ADA negative if they are ADA negative or are missing data 
at baseline and all postbaseline samples are negative, or if they are ADA positive at 
baseline but do not have any postbaseline samples with a titer that is at least 0.60 titer 
unit greater than the titer of the baseline sample (treatment unaffected).
For other study treatments where ADA is tested, positivity will be determined according 
to standard methods established in previous studies of that drug.
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported via descriptive statistics.
6.8
SHEDDING ANALYSES
The presence of LOAd703 viral particles in the oral cavity, feces and urine are evaluated 
at baseline and at different time points during and after LOAd703 treatments to 
understand possible shedding and route. The results will be compared to baseline levels 
and differences will be estimated.
6.9
BIOMARKER ANALYSES
Exploratory biomarker analyses will be performed in an effort to understand the 
association of these biomarkers with response to study drugs, taking into account
efficacy and safety endpoints.
6.10
INTERIM ANALYSES
It is anticipated that at least one interim analysis will be conducted over the course of the 
study, with the earliest interim analysis taking place when at least one experimental arm 
has completed enrollment in the preliminary phase and patients have been followed for a 
minimum of 6 weeks. A posterior probability will be used to guide further enrollment of 
25 additional patients in the experimental arm.  Enrollment may be expanded if the 
posterior probability of demonstrating a given improvement in ORR compared with the 


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control arm is greater than a prespecified threshold.  The current considerations are an 
improvement in ORR of 10% compared with the control arm and a posterior probability 
of 70%.
An improvement of at least 10% in ORR as compared with control is considered 
clinically meaningful, and a posterior probability of 70% provides reasonable confidence 
that the difference will continue to be observed at the final analysis after completion of 
the expansion phase. If an improvement of at least 10% is not observed in a given arm, 
enrollment will either be stopped for futility or paused for further evaluation.  The 
Sponsor may make a decision to expand enrollment in an arm based on the totality of 
available data including, but not limited to, duration of the observed responses, PFS, and 
potentially early OS data.  Safety and biomarker data (available at the time of making 
this decision) will also be taken into consideration from the perspective of an adequate 
benefitrisk assessment.
The interim analyses will be performed and interpreted by Sponsor study team 
personnel.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.


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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format 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 into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.


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7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMPs, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for 15 years after 
completion or discontinuation of the study or for the length of time required by relevant 
national or local health authorities, whichever is longer.  After that period of time, the 
documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a 
U.S. Investigational New Drug (IND) Application will comply with U.S. FDA regulations 
and applicable local, state, and federal laws.  Studies conducted in the European Union 
or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC) and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Forms (and ancillary sample Informed Consent 
Forms such as a Mobile Nursing Informed Consent Form, if applicable) will be provided 
to each site.  If applicable, they will be provided in a certified translation into the local 
language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 


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consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
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 
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).


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In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient, last 
visit).


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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 trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Screening and enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker analyses, and PK analyses), as specified in 
Section 4.5.7.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected.
An IMC and an SOC will be employed to monitor and evaluate patient safety throughout 
the study (see Sections 3.1.4 and 3.1.5).
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses, in clinical trial registries of the U.S. National Institutes of Health and the 


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European Medicines Agency, and in peer-reviewed journals. The Sponsor will comply 
with all requirements for publication of study results.  Study data may be shared with 
others who are not participating in this study, and redacted clinical study reports and 
other summary reports will be provided upon request (see Section 8.4 for more details).  
For more information, refer to the Roche Global Policy on Sharing of Clinical Study 
Information at the following web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Response Evaluation Criteria In Solid Tumors, 
Version 1.1 (RECIST V1.1)
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1), (Eisenhauer et al. 2009) are presented below, with slight modifications 
from the original publication and the addition of explanatory text as needed for clarity.1
TUMOR MEASURABILITY
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression.
Definition of Measurable Lesions
Tumor Lesions
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes
To be considered pathologically enlarged and measurable, a lymph node must be 
15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be 5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters").
                                           
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made.


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Definition of Non-Measurable Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 mm but 15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions:

Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area (e.g., brain metastases) or in 
an area subjected to other loco-regional therapy are usually not considered 
measurable unless there has been demonstrated progression in the lesion.


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


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non-target disease or new lesions on a different modality, since the same lesion may 
appear to have a different size using a new modality.
Endoscopy, Laparoscopy, Ultrasound, Tumor Markers, Cytology, Histology
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
used for objective tumor evaluation.
ASSESSMENT OF TUMOR BURDEN
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.
Identification of Target and Non-Target Lesions
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be considered non-target lesions.  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and should be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis 10 mm 


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


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To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is 5 mm, and in that case "too small to measure" should 
not be ticked.
Measuring Lesions That Split or Coalesce on Treatment
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion.
Evaluation of Non-Target Lesions
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to 10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis 10 mm), this should be captured on the CRF as part of the assessment of 
non-target lesions.
RESPONSE CRITERIA
Criteria for Target Lesions
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below:

Complete response (CR):  Disappearance of all target lesions
Any pathological lymph nodes must have reduction in short axis to 10 mm.

Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR

Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints 
(including baseline) 
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of 5 mm.

Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD


Appendix 1:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
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Criteria for Non-Target Lesions
Definitions of the criteria used to determine the tumor response for the group of 
non-target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedules of activities.

CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or (if applicable) 
maintenance of tumor marker level above the normal limits

PD:  Unequivocal progression of existing non-target lesions
Special Notes on Assessment of Progression of Non-Target Lesions
Patients with Measurable and Non-Measurable Disease
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a 
"new" cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared using the date of the 
initial scan.


Appendix 1:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
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Criteria for Overall Response at a Single Timepoint
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline.
Table 1
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not all evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
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.


Appendix 1:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
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116/Protocol CO39612, Version 11
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
REFERENCES
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):22847.


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Appendix 2
Placeholder for Future Arm
The Modified RECIST v1.1 for Immune-Based Therapeutics (iRECIST) appendix has 
been removed as the Sponsor no longer plans to perform these analyses. Appendix 2 
will serve as a placeholder for a future arm to avoid having to renumber subsequent 
appendices.


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


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Appendix 4
Preexisting Autoimmune Diseases and Immune Deficiencies
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Caution should be used when considering 
atezolizumab for patients who have previously experienced a severe or life-threatening 
skin adverse reaction while receiving another immune-stimulatory anti-cancer agent.  
The Medical Monitor is available to advise on any uncertainty over autoimmune 
exclusions.
Autoimmune Diseases and Immune Deficiencies
Acute disseminated 
encephalomyelitis
Addison disease
Ankylosing spondylitis
Antiphospholipid antibody 
syndrome
Aplastic anemia
Autoimmune hemolytic 
anemia
Autoimmune hepatitis
Autoimmune 
hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune 
thrombocytopenic purpura
Behçet disease
Bullous pemphigoid
Chronic fatigue syndrome
Chronic inflammatory 
demyelinating 
polyneuropathy
Churg-Strauss syndrome
Crohn disease 
Dermatomyositis
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 cholangitis
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 5
Anaphylaxis Precautions
EQUIPMENT NEEDED

Oxygen

Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1.
Stop the study treatment infusion.
2.
Maintain an adequate airway.
3.
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge.
4.
Continue to observe the patient and document observations.


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Appendix 6
Risks Associated with Atezolizumab and Guidelines for 
Management of Atezolizumab-Specific Adverse Events
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology, 
when clinically indicated.
Although most immune-mediated adverse events observed with atezolizumab have 
been mild and self-limiting, such events should be recognized early and treated promptly 
to avoid potential major complications.  Discontinuation of atezolizumab may not have 
an immediate therapeutic effect, and in severe cases, immune-mediated toxicities may 
require acute management with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents. 
The investigator should consider the benefitrisk balance for a given patient prior 
to further administration of atezolizumab.  In patients who have met the criteria for 
permanent discontinuation, resumption of atezolizumab may be considered if the patient 
is deriving benefit and has fully recovered from the immune-mediated event.  The 
decision to re-challenge patients with atezolizumab should be based on investigator’s 
assessment of benefitrisk and documented by the investigator.  The Medical Monitor is 
available to advise as needed.
Guidelines for managing patients who experience selected adverse events are provided 
in the following sections.  Management guidelines are presented by adverse event 
severity based on the National Cancer Institute Common Terminology Criteria for 
Adverse Events.
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 Table 1.


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
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Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis
Event
Management
Pulmonary 
event, Grade 1 
Continue atezolizumab and monitor closely.
Re-evaluate on serial imaging.
Consider patient referral to pulmonary specialist.
For Grade 1 pneumonitis, consider withholding atezolizumab.
Pulmonary 
event, Grade 2
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to pulmonary and infectious disease specialists and consider 
bronchoscopy or BAL.
Initiate treatment with 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 or events with no improvement after 48–72 hours of 
corticosteroids,, treat as a Grade 3 or 4 event.
Pulmonary 
event, Grade 3 
or 4
Permanently discontinue atezolizumab and contact Medical Monitor. c
Bronchoscopy or BAL is recommended.
Initiate treatment with 12 mg/kg/day IV methylprednisolone.
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
BALbronchoscopic alveolar lavage.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The Medical 
Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented 
by the investigator (or an appropriate delegate). The Medical Monitor is available to advise as 
needed.
Hepatic Events
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment.  Management guidelines for hepatic events are provided in Table 2.


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
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Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.
Table 2
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1
Continue atezolizumab.
Monitor LFTs until values resolve to within normal limits. 
Hepatic event, 
Grade 2
All events:
Monitor LFTs more frequently until return to baseline values. 
Events of 5 days’ duration:
Withhold atezolizumab for up to 12 weeks after event onset. a
Initiate treatment with 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
Hepatic event, 
Grade 3 or 4
Permanently discontinue atezolizumab and contact Medical Monitor. c
Consider patient referral to GI specialist for evaluation and liver biopsy to 
establish etiology of hepatic injury. 
Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.
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; LFT liver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator. The Medical 
Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented 
by the investigator (or an appropriate delegate). The Medical Monitor is available to advise as 
needed. 


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
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Gastrointestinal Events
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 3.
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1
Continue atezolizumab.
Initiate symptomatic treatment.
Endoscopy is recommended if symptoms persist for 7 days.
Monitor closely.
Diarrhea or 
colitis, Grade 2
Withhold atezolizumab for up to 12 weeks after event onset. a
Initiate symptomatic treatment.
Patient referral to GI specialist is recommended.
For recurrent events or events that persist 5 days, initiate treatment with 
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
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 based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented by 
the investigator (or an appropriate delegate). The Medical Monitor is available to advise as 
needed. 


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
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Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.)
Diarrhea or 
colitis, Grade 3
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to GI specialist for evaluation and confirmatory biopsy.
Initiate treatment with 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
Diarrhea or 
colitis, Grade 4
Permanently discontinue atezolizumab and contact Medical Monitor. c
Refer patient to GI specialist for evaluation and confirmation biopsy.
Initiate treatment with 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 based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented by 
the investigator (or an appropriate delegate). The Medical Monitor is available to advise as 
needed. 
Endocrine Events
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have
been associated with the administration of atezolizumab.  Management guidelines for 
endocrine events are provided in Table 4.
Patients with unexplained symptoms, such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes, should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., TSH, 
growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 


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magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency.
Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism
Continue atezolizumab.
Initiate treatment with thyroid replacement hormone.
Monitor TSH closely.
Symptomatic 
hypothyroidism
Withhold atezolizumab.
Initiate treatment with thyroid replacement hormone.
Monitor TSH closely.
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.
Consider patient referral to endocrinologist.
TSH 0.1 mU/L:
Follow guidelines for symptomatic hyperthyroidism.
Consider patient referral to endocrinologist.
Symptomatic 
hyperthyroidism
Withhold atezolizumab.
Initiate treatment with anti-thyroid drug such as methimazole or carbimazole 
as needed.
Consider patient referral to endocrinologist.
Resume atezolizumab when symptoms are controlled and thyroid function is 
improving.
Permanently discontinue atezolizumab and contact Medical Monitor for 
life-threatening immune-mediated hyperthyroidism. c
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be based on an 
assessment of benefit-risk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The Medical 
Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefit-risk and documented by 
the investigator (or an appropriate delegate). The Medical Monitor is available to advise as 
needed.


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Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Symptomatic adrenal 
insufficiency, 
Grade 24 
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to endocrinologist.
Perform appropriate imaging.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or equivalent
upon improvement.
If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b
If event does not resolve to Grade 1 or better or patient is not stable on 
replacement therapy while withholding atezolizumab, permanently 
discontinue atezolizumab and contact Medical Monitor. c
Hyperglycemia, 
Grade 1 or 2 
Continue atezolizumab.
Investigate for diabetes.  If patient has Type 1 diabetes, treat as a 
Grade 3 event.  If patient does not have Type 1 diabetes, treat as per 
institutional guidelines.
Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4
Withhold atezolizumab.
Initiate treatment with insulin.
Evaluate for diabetic ketoacidosis and manage as per institutional 
guidelines.
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 based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator. The Medical Monitor is available 
to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented by 
the investigator (or an appropriate delegate). The Medical Monitor is available to advise as 
needed.


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Table 4
Management Guidelines for Endocrine Events (cont.)
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 as clinically needed.
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 as clinically needed.
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 based on an assessment of benefitrisk by 
the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator. The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented by the 
investigator (or an appropriate delegate). The Medical Monitor is available to advise as needed. 


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
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Ocular Events
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.
Table 5
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 
Continue atezolizumab.
Patient referral to ophthalmologist is strongly recommended.
Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.
If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2
Withhold atezolizumab for up to 12 weeks after event onset. a
Patient referral to ophthalmologist is strongly recommended.
Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Ocular event, 
Grade 3 or 4
Permanently discontinue atezolizumab and contact Medical Monitor. c
Refer patient to ophthalmologist.
Initiate treatment with 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 based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The
Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented 
by the investigator (or an appropriate delegate). The Medical Monitor is available to advise as 
needed. 


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
130/Protocol CO39612, Version 11
Immune-Mediated Myocarditis
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab.  Immune-mediated myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not limited to, 
laboratory (e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, 
chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  Myocarditis 
may also be a clinical manifestation of myositis and should be managed accordingly.  
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from 
infection (commonly viral, e.g., in a patient who reports a recent history of 
gastrointestinal [GI] illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6.


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Table 6
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated
myocarditis, Grade 1
Refer patient to cardiologist.
Initiate treatment as per institutional guidelines.
Immune-mediated
myocarditis, Grade 24
Permanently discontinue atezolizumab and contact Medical Monitor. a
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 Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented by 
the investigator (or an appropriate delegate). The Medical Monitor is available to advise as 
needed.
Infusion-Related Reactions and Cytokine-Release Syndrome
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with atezolizumab may receive premedication with antihistamines, 
anti-pyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions.
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of 
its potential for causing agranulocytosis.  
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity.
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 


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with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab.
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 7.
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon-(Merad and Martin 
2020).  If a patient develops suspected CRS during the study, a differential diagnosis 
should include SARS-CoV-2 infection, which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or radiologic 
evaluations per investigator judgment.  If a diagnosis of SARS-CoV-2 infection is 
confirmed, the disease should be managed as per local or institutional guidelines.


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


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


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
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Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
ASTCTAmerican Society for Transplantation and Cellular Therapy; BiPAPbi-level positive 
airway pressure; CARchimeric antigen receptor; CPAPcontinuous positive airway pressure; 
CRScytokine-release syndrome; CTCAECommon Terminology Criteria for Adverse Events; 
eCRFelectronic Case Report Form; HLH=hemophagocytic lymphohistiocytosis; ICUintensive 
care unit; IRR=infusion-related reaction; MAS=macrophage activation syndrome; 
NCCNNational Cancer Comprehensive Network; NCINational Cancer Institute.
Note:  The management guidelines have been adapted from NCCN guidelines for management 
of CAR T-cellrelated toxicities (Version 2.2019).
a Grading system for management guidelines is based on ASTCT consensus grading for CRS.  
NCI CTCAE (version as specified in the protocol) should be used when reporting severity of 
IRRs, CRS, or organ toxicities associated with CRS on the Adverse Event eCRF.  Organ 
toxicities associated with CRS should not influence overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no 
longer required when subsequently determining event severity (grade).  In this case, the grade 
is driven by the presence of hypotension and/or hypoxia.
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional treatment 
may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as oxygen 
delivered at 6 L/min.
e Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the event.  The decision to re-challenge patients with atezolizumab should 
be based on investigator's assessment of benefitrisk and documented by the investigator (or 
an appropriate delegate). The Medical Monitor available to advise as needed.  For subsequent 
infusions, administer oral premedication with antihistamines, anti-pyretics, and/or analgesics, 
and monitor closely for IRRs and/or CRS.  Premedication with corticosteroids and extending 
the infusion time may also be considered after assessing the benefitrisk ratio.
f
Refer to Riegler et al. (2019).


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
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Pancreatic Events
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of atezolizumab.  
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate 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 8.
Table 8
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 based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented 
by the investigator (or an appropriate delegate). The Medical Monitor is available to advise 
as needed. 


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
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Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-mediated
pancreatitis, Grade 2 or 3
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to GI specialist.
Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
Immune-mediated 
pancreatitis, Grade 4
Permanently discontinue atezolizumab and contact Medical 
Monitor. c
Refer patient to GI specialist.
Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.
If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator. The 
Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented 
by the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed. 


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
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138/Protocol CO39612, Version 11
Dermatologic Events
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash were mild in severity and self-limiting, with or without pruritus.  Although 
uncommon, cases of severe cutaneous adverse reactions such as Stevens-Johnson 
syndrome and toxic epidermal necrolysis have also been reported with atezolizumab.  A 
dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy should 
be considered unless contraindicated.  Management guidelines for dermatologic events 
are provided in Table 9.


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
139/Protocol CO39612, Version 11
Table 9
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 
Continue atezolizumab.
Consider treatment with topical corticosteroids and/or other symptomatic 
therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 
Continue atezolizumab.
Consider patient referral to dermatologist for evaluation and, if indicated, 
biopsy.
Initiate treatment with topical corticosteroids.
Consider treatment with higher-potency topical corticosteroids if event does 
not improve.
If unresponsive to topical corticosteroids, consider oral prednisone 
0.5 mg/kg/day.
Dermatologic 
event, Grade 3 
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to dermatologist for evaluation and, if indicated, biopsy.
Initiate 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 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical Monitor. c
Dermatologic 
event, Grade 4
Permanently discontinue atezolizumab and contact Medical Monitor. c
Stevens-
Johnson 
syndrome or 
tumor epidermal 
necrolysis (any 
grade) 
Additional guidance for Stevens-Johnson syndrome or toxic epidermal 
necrolysis:

Withhold atezolizumab for suspected Stevens-Johnson syndrome or toxic 
epidermal necrolysis.

Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist, or urologist as relevant), for evaluation and, if indicated, 
biopsy.

Follow the applicable treatment and management guidelines above.
If Stevens-Johnson syndrome or toxic epidermal necrolysis is confirmed, 
permanently discontinue atezolizumab.
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 based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed. 


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
140/Protocol CO39612, Version 11
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 10.
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-mediated
neuropathy, 
Grade 1
Continue atezolizumab.
Investigate etiology.
Immune-mediated
neuropathy, 
Grade 2 
Withhold atezolizumab for up to 12 weeks after event onset. a
Investigate etiology and refer patient to neurologist.
Initiate treatment as per institutional guidelines.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact Medical 
Monitor. c
Immune-mediated
neuropathy, 
Grade 3 or 4
Permanently discontinue atezolizumab and contact Medical Monitor. c 
Refer patient to neurologist.
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 based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The Medical 
Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented 
by the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed. 


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
141/Protocol CO39612, Version 11
Immune-Mediated Meningoencephalitis
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-mediated meningoencephalitis should be 
suspected in any patient presenting with signs or symptoms suggestive of meningitis or 
encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, motor 
or sensory dysfunction, and altered or depressed level of consciousness.  
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from 
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or 
progression of malignancy, or secondary to a paraneoplastic process.  
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted.
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 11.
Table 11 Management Guidelines for Immune-Mediated
Meningoencephalitis
Event
Management
Immune-mediated
meningoencephalitis, 
all grades
Permanently discontinue atezolizumab and contact Medical Monitor. a
Refer patient to neurologist.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed.
Renal Events
Immune-mediated nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as 


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
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non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment.
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 12.
Table 12 Management Guidelines for Renal Events 
Event
Management
Renal event, 
Grade 1

Continue atezolizumab.

Monitor kidney function, including creatinine and urine protein, 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. c

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 based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The
Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge patients
with atezolizumab should be based on investigator's assessment of benefitrisk and
documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
143/Protocol CO39612, Version 11
Immune-Mediated Myositis
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.  
Patients with possible myositis should be referred to a rheumatologist or neurologist.  
Patients with possible myositis should be monitored for signs of myocarditis.
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13.
Table 13 Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-
mediated
myositis, Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.
Immune-
mediated
myositis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a and contact 
Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If corticosteroids are initiated and event does not improve within 48 hours 
after initiating corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements 
for the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented by 
the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as 
needed. 


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
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144/Protocol CO39612, Version 11
Table 13 Management Guidelines for Immune-Mediated Myositis (cont.)
Immune-
mediated
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a and contact 
Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.  

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely compromised 
(e.g., cardiac or respiratory symptoms, dysphagia, or weakness that severely 
limits mobility); convert to 12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical Monitor. c

For recurrent events, treat as a Grade 4 event.
Immune-
mediated 
myositis, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements 
for the duration of treatment and documented by the investigator. The Medical Monitor is 
available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented by 
the investigator (or an appropriate delegate). The Medical Monitor is available to advise as 
needed. 


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
145/Protocol CO39612, Version 11
Hemophagocytic lymphohistiocytosis and Macrophage Activation 
Syndrome
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), 
which are considered to be potential risks for atezolizumab.
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.  
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014). A patient should be classified as having HLH if five of the 
following eight criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
–
Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants 4 weeks old)
–
Platelet count 100109/L (100,000/L)
–
ANC 1.0109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

Soluble IL-2 receptor (soluble CD25) elevated 2 standard deviations above 
age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count 181109/L (181,000/L)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 14.


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
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146/Protocol CO39612, Version 11
Table 14 Management Guidelines for Suspected Hemophagocytic
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH 
or MAS

Permanently discontinue atezolizumab and contact Medical Monitor.

Consider patient referral to hematologist.

Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines.

Consider initiation of IV corticosteroids, an immunosuppressive agent, 
and/or anti-cytokine therapy.

If event does not respond to treatment within 24 hours, contact 
Medical Monitor and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019).

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
HLHhemophagocytic lymphohistiocytosis; MASmacrophage activation syndrome.
REFERENCES
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024.
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:1906.
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577.
Lee DW, Santomasso BD, Locke FL et al. ASTCT Consensus Grading for Cytokine 
Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. 
Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638.
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resouce on the Internet]. 2014 [updated 29 
October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis.
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 


Appendix 6:  Management of Atezolizumab-Specific Adverse Events
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
147/Protocol CO39612, Version 11
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:4819.
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335.
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642.
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814.


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Appendix 7
Study Details Specific to the Regorafenib Arm (Control)
TABLE OF CONTENTS
A71.
Materials and Methods Specific to Regorafenib Arm
A71.1
Treatment in Regorafenib Arm
A71.1.1
Formulation, Packaging, and Handling
A71.1.2
Dosage, Administration, and Compliance
A71.1.3
Stage 2 Treatment
A71.2
Concomitant Therapy for Regorafenib Arm
A71.3
Contraception Requirements for Regorafenib Arm
A72.
Assessment of Safety for Regorafenib Arm
A72.1
Safety Plan for Regorafenib Arm
A72.1.1
Risks Associated with Regorafenib
A72.1.2
Management of Patients Who Experience Specific 
Adverse Events in Regorafenib Arm
A72.2
Adverse Events of Special Interest for Regorafenib Arm (Immediately 
Reportable to the Sponsor)
A72.3 Reporting Requirements for Pregnancies in Regorafenib Arm
A72.3.1
Pregnancies in Female Patients
A72.3.2
Pregnancies in Female Partners of Male Patients
A72.3.3
Abortions
A72.3.4
Congenital Anomalies/Birth Defects
A73.
Schedule of Activities and Sample Collection for Regorafenib Arm


Appendix 7:  Study Details Specific to Regorafenib Arm (Control)
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149/Protocol CO39612, Version 11
A71.
MATERIALS AND METHODS SPECIFIC TO REGORAFENIB ARM
A71.1 TREATMENT IN REGORAFENIB ARM
A71.1.1
Formulation, Packaging, and Handling
For information on the formulation, packaging, and handling of regorafenib, refer to the
local prescribing information.
A71.1.2
Dosage, Administration, and Compliance
Patients in the regorafenib arm will receive treatment as outlined in Table 1 until 
unacceptable toxicity or disease progression per Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST v1.1). It is recommended that treatment be initiated no 
later than 7 days after randomization.  
Table 1
Treatment Regimen for Regorafenib Arm
Cycle Length
Dose, Route, and Regimen
28 days
Regorafenib 160 mg by mouth once daily on Days 121
Dose escalation to 160 mg during Cycle 1 per institutional guidelines, e.g.,
from 80 mg in the first week followed by weekly dose increases to 120 mg in 
the second and 160 in the third week, is allowed.
Regorafenib will be used in the commercially available formulation.
Patients will receive regorafenib at the approved dose level of 160 mg (four tablets of 
40 mg each) orally once daily on Days 1−21 of a 28-day cycle (see Table 1). This 
4-week period is considered a treatment cycle.
Regorafenib should be taken at the same time each day. The tablets should be 
swallowed whole with water after a light meal that contains 30% fat. An example of a 
light (low-fat) meal would include one portion of cereal (about 30 g), one glass of 
skimmed milk, one slice of toast with jam, one glass of apple juice, and one cup of coffee 
or tea (520 calories, 2 g fat).
Guidelines for regorafenib dose modification and treatment interruption or 
discontinuation because of toxicities are provided in Sections A72.1.2.1 and
A72.1.2.2. Regorafenib treatment may be suspended for reasons other than toxicity 
(e.g., surgical procedures). The acceptable length of treatment interruption must be 
based on an assessment of benefitrisk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator. The Medical Monitor is available to advise as needed.


Appendix 7:  Study Details Specific to Regorafenib Arm (Control)
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150/Protocol CO39612, Version 11
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 5.3.5.12. Adverse events associated with an overdose or incorrect 
administration of any of the study treatments should be recorded on the Adverse Event 
eCRF.  The highest dose of regorafenib studied clinically is 220 mg per day. The most 
frequently observed adverse drug reactions at this dose were dermatologic events, 
dysphonia, diarrhea, mucosal inflammation, dry mouth, decreased appetite, 
hypertension, and fatigue. There is no specific antidote for regorafenib overdose. In the 
event of suspected overdose, interrupt regorafenib, institute supportive care, and 
observe until clinical stabilization.
A71.1.3
Stage 2 Treatment
Patients who experience disease progression per RECIST v1.1 or unacceptable toxicity, 
may be eligible to receive a different treatment combination during Stage 2, provided a 
Stage 2 treatment is available for enrolment and they meet the eligibility criteria of that 
treatment regimen. Stage 2 treatment must begin within 3 months after the patient has 
experienced disease progression.  It is recommended that patients begin Stage 2 
treatment as soon as possible, but no earlier than 2 weeks after the last dose of 
treatment in Stage 1.  
Tumor assessments performed prior to or at the time of disease progression during 
Stage 1 may serve as baseline assessments for Stage 2, provided the tumor 
assessments are performed within 28 days prior to initiation of Stage 2 treatment 
(i.e., Day 1 of Cycle 1).  Stage 2 treatment will continue until unacceptable toxicity or 
loss of clinical benefit as determined by the investigator.
Table 2
Stage 2 Treatment Regimens Available for the Regorafenib Arm
Study Treatment
Appendix
No Stage 2 treatment currently available

A71.2 Concomitant Therapy for Regorafenib Arm
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated study treatment from 
7 days prior to initiation of study treatment to the treatment discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.


Appendix 7:  Study Details Specific to Regorafenib Arm (Control)
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151/Protocol CO39612, Version 11
Regorafenib is metabolized by CYP3A4, therefore concomitant use of strong CYP3A4 
inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) 
and strong inhibitors of CYP3A4 activity (e.g., clarithromycin, grapefruit juice, 
itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole) is to be 
avoided. For more detailed information on permitted, prohibited, or cautionary therapy, 
prohibited foods, and other restrictions (as applicable) for regorafenib, refer to the local 
prescribing information.
Regorafenib is metabolized by UGT1A1, and regorafenib and its metabolites are 
inhibitors of UGT1A1 and UGT1A9.  Therefore, inhibitors of UGT1A1 (e.g., erlotinib, 
nilotinib, pazopanib, lapatinib, sorafenib) and substrates of UGT1A1 (e.g., irinotecan with 
its active metabolite SN-38, raltegravir, bazedoxifene, eltrombopag) and substrates of 
UGT1A9 (e.g., sorafenib, mycophenolic acid) should be used with caution.  Also, 
patients receiving substrates of the BCRP transporter (e.g., methotrexate, fluvastatin, 
atorvastatin) should be monitored for signs and symptoms of increased exposure.
Concomitant therapy intended for the treatment of cancer (including, but not limited to, 
chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal therapy), 
whether health authority approved or experimental, is prohibited for various time periods 
prior to starting study treatment, depending on the agent as per Section 4.1.2.1, and is 
prohibited during study treatment until disease progression is documented and the 
patient has discontinued study treatment. Investigational therapy (other than 
protocol-mandated study treatment) is prohibited within 28 days prior to initiation of study 
treatment and during study treatment.
A71.3 Contraception Requirements for Regorafenib Arm
Contraception requirements for women and men in the regorafenib arm are outlined 
below:

Women of childbearing potential must agree to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 
1% per year during the treatment period and for 2 months after the last dose of 
regorafenib.  Women must refrain from breastfeeding during this same period of 
time.


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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, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, 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.

Men must agree to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agree to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for 
2 months after the last dose of regorafenib to avoid exposing the embryo. Men 
must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
A72.
ASSESSMENT OF SAFETY FOR REGORAFENIB ARM
A72.1 SAFETY PLAN FOR REGORAFENIB ARM
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.  Adverse events will be reported as described in 
Sections 5.25.6 in the protocol body.
A72.1.1
Risks Associated with Regorafenib
The overall safety profile of regorafenib is based on data from more than 4800 treated 
patients in clinical trials including placebo-controlled Phase III data for 636 patients with 
metastatic colorectal cancer, 132 patients with gastrointestinal (GI) stromal tumors, and 
374 patients with hepatocellular carcinoma.  The most serious adverse drug reactions in 
patients receiving regorafenib are severe liver injury, hemorrhage, GI perforation, and 
infection.  The most frequently observed adverse drug reactions (30%) in patients 
receiving regorafenib are pain, hand-foot skin reaction, asthenia/fatigue, diarrhea, 
decreased appetite and food intake, hypertension, and infection.


Appendix 7:  Study Details Specific to Regorafenib Arm (Control)
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Please refer to the regorafenib prescribing information for complete information 
regarding clinical safety.
A72.1.2
Management of Patients Who Experience Specific Adverse 
Events in Regorafenib Arm
A72.1.2.1 Dose Modifications
The dose of regorafenib can be reduced by decrements of 40 mg once a day (one dose 
level) up to two times for management of drug-related toxicities (i.e., from 160 to 120 mg
and then from 120 to 80 mg).  During the allowed dose escalation in Cycle 1 
(Section A71.1.2), the continuation of a dose below 160 mg for more than 1 week for 
the management of drug-related toxicities is also allowed. If further dose reduction is 
indicated after two dose reductions, the patient must discontinue regorafenib.  After dose 
reduction, the dose of regorafenib may be re-escalated at the investigator's discretion, 
provided there are no safety concerns.
A72.1.2.2 Treatment Interruption for Toxicities
Regorafenib treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment (see Table 3).  If regorafenib has been 
withheld for 42 days because of toxicity, the patient should be discontinued from 
regorafenib.
Refer to Section A71.1.2 for information on dose interruptions for reasons other than 
toxicity (e.g., surgical procedures).
A72.1.2.3 Management Guidelines for Adverse Events
Toxicities associated or possibly associated with regorafenib treatment should be 
managed according to standard medical practice. Guidelines for the management of 
patients who experience adverse events are provided in Table 3.  Please refer to the 
regorafenib prescribing information for further guidance.


Appendix 7:  Study Details Specific to Regorafenib Arm (Control)
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Table 3
Guidelines for Management of Patients Who Experience Adverse 
Events in the Regorafenib Arm
Event
Action to Be Taken
Dermatologic toxicity (hand-foot skin reaction/ palmar-plantar erythrodysesthesia)
Dermatologic event, Grade 1
Continue regorafenib at the same dose level.
Immediately institute supportive measures for symptomatic 
relief.
Dermatologic event, Grade 2
First occurrence: Decrease dose by one level and immediately 
institute supportive measures.
If no improvement occurs despite dose reduction, withhold 
regorafenib for a minimum of 7 days until toxicity resolves to 
Grade 1.
A dose re-escalation is permitted at the investigator’s discretion.
If no improvement within 7 days or second occurrence: Withhold 
regorafenib for a minimum of 7 days until toxicity resolves to 
Grade 1.
When restarting treatment, decrease dose by one level.
A dose re-escalation is permitted at the investigator’s discretion.
Third occurrence: Withhold regorafenib for a minimum of 
7 days, until toxicity resolves to Grade 1.
When restarting treatment, decrease dose by one level.
A dose re-escalation is permitted at the investigator’s discretion.
Fourth occurrence: Discontinue regorafenib permanently.
Dermatologic event,
Grade 3 or 4 
First occurrence: Institute supportive measures immediately and 
withhold regorafenib for a minimum of 7 days until toxicity 
resolves to Grade 1.
When restarting treatment, decrease dose by one level.
A dose re-escalation is permitted at the investigator’s discretion.
Second occurrence: Institute supportive measures immediately 
and withhold regorafenib for a minimum of 7 days, until toxicity 
resolves to Grade 1.
When restarting treatment, decrease dose by one level.
Third occurrence: Discontinue regorafenib permanently.
GIgastrointestinal; ULNupper limit of normal.
a Resumption of regorafenib may be considered in patients who are deriving benefit at the 
investigator’s discretion if the potential benefit outweighs the risks.


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Table 3
Guidelines for Management of Patients Who Experience Adverse 
Events in the Regorafenib Arm (cont.)
Event
Action to Be Taken
Elevations in ALT, AST, and/or bilirubin
5 ULN elevations in ALT/AST 
(maximum Grade 2)
Continue regorafenib treatment.
Monitor liver function weekly until transaminases return to 
3 ULN (Grade 1) or baseline.
5 ULN but 20 ULN 
elevations in ALT/AST (Grade 3)
First occurrence: Withhold regorafenib treatment.
Monitor liver function weekly until transaminases return to 
3 ULN (Grade 1) or baseline.
If restarting treatment a, decrease dose by one level and 
monitor liver function weekly for at least 4 weeks.
Re-occurrence: Discontinue regorafenib permanently.
20 ULN (Grade 4) elevations in 
ALT/AST
Discontinue regorafenib permanently.
3 ULN (Grade 2 or higher) with 
concurrent bilirubin 2 ULN 
elevations in ALT/AST
Discontinue regorafenib permanently.
Monitor liver function weekly until resolution or return to 
baseline.
Exception: Patients with Gilbert syndrome who develop 
elevated transaminases should be managed as per the above 
outlined recommendations for the respective observed 
elevation of ALT and/or AST.
Infection
Grade 3 or 4 infections, or 
worsening infection of any grade
Withhold regorafenib treatment.
Resume regorafenib at the same dose following resolution of 
infection.
Hemorrhage 
Grade 3 or 4 hemorrhage
Discontinue regorafenib permanently. a
Monitor INR levels more frequently in patients receiving 
warfarin.
GI perforation or fistula 
Any GI perforation or fistula
Discontinue regorafenib permanently.
GIgastrointestinal; ULNupper limit of normal.
a Resumption of regorafenib may be considered in patients who are deriving benefit at the 
investigator’s discretion if the potential benefit outweighs the risks.


Appendix 7:  Study Details Specific to Regorafenib Arm (Control)
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156/Protocol CO39612, Version 11
Table 3
Guidelines for Management of Patients Who Experience Adverse 
Events in the Regorafenib Arm (cont.)
Event
Action to Be Taken
Hypertension
General guidance
Grade 2 or above, start antihypertensive therapy.
Hypertension, Grade 2 
Withhold regorafenib treatment.
Once blood pressure is 150/100 mmHg, patient may 
continue regorafenib treatment, and consider reducing dose 
by one level at the investigator’s discretion.
Hypertension, Grade 3
If blood pressure is not controlled to 150/100 mmHg with 
medication, discontinue regorafenib.
Hypertension, Grade 4
(includes hypertensive crisis and 
hypertensive encephalopathy)
Discontinue regorafenib permanently. a
Cardiac ischemia and infarction
New or acute onset cardiac 
ischemia or infarction
Withhold regorafenib treatment.
Resume regorafenib only after resolution of acute cardiac 
ischemic events and if the potential benefits outweigh the risks 
of further cardiac ischemia.
Reversible posterior leukoencephalopathy syndrome
Reversible posterior 
leukoencephalopathy syndrome
Discontinue regorafenib permanently.
Wound dehiscence
Wound dehiscence, any grade 
requiring medical or surgical 
therapy
Discontinue regorafenib permanently.
Regorafenib-related toxicities not described above
Grade 1 or Grade 2 (tolerable)
Continue regorafenib treatment at the same dose.
Grade 2 (intolerable) or Grade 3 
First occurrence: Withhold regorafenib until toxicity resolves 
to Grade 1.
When restarting treatment, decrease dose by one level.
Second occurrence: Withhold regorafenib until toxicity 
resolves to Grade 1.
When restarting treatment, decrease dose by one level.
Third occurrence: Consider permanent discontinuation.
Grade 4 
Discontinue regorafenib permanently. a
GIgastrointestinal; ULNupper limit of normal.
a Resumption of regorafenib may be considered in patients who are deriving benefit at the 
investigator’s discretion if the potential benefit outweighs the risks.


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A72.2 ADVERSE EVENTS OF SPECIAL INTEREST FOR REGORAFENIB 
ARM (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 in the protocol body for reporting instructions).  Adverse events of special 
interest for the regorafenib arm are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7 in the protocol body) 

Suspected transmission of an infectious agent by the study treatment, as defined 
below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of study treatment is suspected.
A72.3 REPORTING REQUIREMENTS FOR PREGNANCIES IN 
REGORAFENIB ARM
A72.3.1
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 2 months after the last 
dose of regorafenib.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue regorafenib 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.  


Appendix 7:  Study Details Specific to Regorafenib Arm (Control)
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A72.3.2
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 
2 months after the last dose of regorafenib.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to regorafenib.  
When permitted by the site, the pregnant partner would need to sign an Authorization for 
Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy.  If the authorization has been signed, the investigator should submit a 
Clinical Trial Pregnancy Reporting Form when updated information on the course and 
outcome of the pregnancy becomes available.  An investigator who is contacted by the 
male patient or his pregnant partner may provide information on the risks of the 
pregnancy and the possible effects on the fetus, to support an informed decision in 
cooperation with the investigator and/or obstetrician.
A72.3.3
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 in the protocol body).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
A72.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2 in the protocol body).


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A73.
SCHEDULE OF ACTIVITIES AND SAMPLE COLLECTION FOR REGORAFENIB ARM
Table 4
Schedule of Activities for Regorafenib Arm
Assessment/Procedure
Screening
Days
–28 to –1
Treatment Cycles (28-Day Cycles) a
Stage 2 
Screen. c
or Treat. 
Discon. d
Follow-Up
Every 
3 Months
(7 days)
Cycle 1 b
Cycle 2
Cycles 3
Days 
Days 
Day 1
(3 days)
1
8
(3 d)
15
(3 d)
22
(3 d)
1
(3 d)
8
(3 d)
15
(3 d)
Molecular profile of CRC (if available)
See
Appendix 15
Whenever updated information becomes available
Vital signs e
x f
x f
x f
x f
x f
x f
x
x
Weight 
x g
x g
x g
x
Height
Complete physical examination h
x
Limited physical examination i
x g
x g
x g
ECOG Performance Status
x g
x g
x g
x
ECG j
Perform as clinically indicated g
x k
Hematology l
x m, n
x m
x m
x
Chemistry
x m, n, o
x m, p
x m, o
x m, p
x m, o
x o
Coagulation (INR and aPTT) q
x m, n
x m
x m
x k
TSH, free T3 (or total T3), and free T4 r
x k
Viral serology s
x k
C-reactive protein
x k
Plasma CEA t
x m
x m, t


Appendix 7:  Study Details Specific to Regorafenib Arm (Control)
Table 4
Schedule of Activities for Regorafenib Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
160/Protocol CO39612, Version 11
Assessment/Procedure
Screening
Days
–28 to –1
Treatment Cycles (28-Day Cycles) a
Stage 2 
Screen. c
or Treat. 
Discon. d
Follow-Up
Every 
3 Months
(7 days)
Cycle 1 b
Cycle 2
Cycles 3
Days 
Days 
Day 1
(3 days)
1
8
(3 d)
15
(3 d)
22
(3 d)
1
(3 d)
8
(3 d)
15
(3 d)
LDH
See
Appendix 1
5
x k
Pregnancy test u
x m
x m
x m
x
x u
Urinalysis v
x
x
x
x k
Serum autoantibody sample w
x k
Blood sample for RBR (optional) x
x
Plasma, serum, and PBMC samples 
for biomarkers 
Refer to Table 5 below
Tumor biopsy
x y
Tumor biopsy (optional)
x z
Tumor response assessments
x aa, bb, cc
Concomitant medications dd
x
x
x
x
Adverse events ee
x
x
x
x
x
x
x
x
x ee
x ee
Dispense regorafenib ff, gg
x
x
x
Survival follow-up and anti-cancer 
treatment
x hh
CEAcarcinoembryonic antigen; CRCcolorectal cancer; CTcomputed tomography; ddays; Discon.discontinuation; ECOG Eastern 
Cooperative Oncology Group; eCRF electronic Case Report Form; HBcAbhepatitis B core antibody; HBsAghepatitis B surface antigen; 
HBVhepatitis B virus; HCVhepatitis C virus; LDHlactate dehydrogenase; PBMCperipheral blood mononuclear cell; RBRResearch 
Biosample Repository; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; Screen.screening; T3triiodothyronine; 
T4thyroxine; Treat.treatment; TSHthyroid-stimulating hormone.
Note:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.


Appendix 7:  Study Details Specific to Regorafenib Arm (Control)
Table 4
Schedule of Activities for Regorafenib Arm (cont.)
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161/Protocol CO39612, Version 11
a If a visit is precluded because of a holiday, vacation, or other circumstance, it may occur outside of the specified window. 
b It is recommended that treatment be initiated no later than 7 days after randomization.
c Patients who experience disease progression per RECIST v1.1 or unacceptable toxicity will be given the option of receiving a different treatment 
combination during Stage 2 of the study (as outlined in Section 3.1.2 in the protocol body provided Stage 2 is open for enrollment) and will 
undergo screening assessments to determine eligibility.  Study details specific to the Stage 2 treatment regimens are provided in the appropriate 
appendix.  Written informed consent must be obtained before performing screening evaluations for Stage 2. 
d Patients will return to the clinic for a Stage 2 screening or treatment discontinuation visit not more than 30 days after the last dose of study 
treatment.  The visit at which disease progression is confirmed may be used as the Stage 2 screening or treatment discontinuation visit.  
Treatment discontinuation assessments must be performed for all patients, regardless of whether they enter Stage 2.  Patients who do not enter 
Stage 2 will then undergo follow-up assessments after completing the treatment discontinuation visit.
e Vital signs include respiratory rate, pulse rate, pulse oximetry, 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.
f
Monitor vital signs weekly for the first 6 weeks and then on Day 1 of every cycle thereafter.
g Assessment may be performed within 24 hours prior to dosing during the treatment period.
h Complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  At subsequent visits, record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.
i
Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  Record abnormalities 
observed at baseline on the General Medical History and Baseline Conditions eCRF.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
j
ECG recordings will be obtained during screening and as clinically indicated at other timepoints.  It is recommended that patients be resting in a 
supine position for at least 10 minutes prior to ECG recording.
k Assessments to be performed only for patients undergoing Stage 2 screening.
l
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, and other cells).
m Laboratory tests must be performed within 96 hours prior to dosing during the treatment period.
n If screening laboratory assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated.


Appendix 7:  Study Details Specific to Regorafenib Arm (Control)
Table 4
Schedule of Activities for Regorafenib Arm (cont.)
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o Chemistry panel (serum or plasma) includes sodium, potassium, magnesium, chloride, bicarbonate or carbon dioxide (per standard of care in the 
region), glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, and AST.  Additionally, CPK, 
amylase, and lipase will be performed on Day 1 of each cycle.
p Only liver function (ALP, ALT, AST, and total bilirubin) will be tested on Day 15 of Cycles 1 and 2.  
q Monitoring of INR/aPTT should be performed more frequently if clinically indicated.
r
TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed at screening.
s At Stage 2 screening, patients without a prior positive HIV test result will undergo an HIV test, unless not permitted per local regulations.  
Patients will also be tested for HBsAg, total HBcAb, and HCV antibody. If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient has an HBV infection.  If a patient has a positive HCV antibody 
test at screening, an HCV RNA test must also be performed to determine if the patient has an HCV infection.  
t
CEA will be assessed on Day 1 of Cycle 1 and every 2 cycles thereafter (i.e., Cycles 3, 5, 7, etc.) until disease progression.
u All women of childbearing potential will have a serum pregnancy test at screening.  Urine or serum pregnancy tests will be performed at specified 
subsequent visits and at 3 months and 6 months after treatment discontinuation.  If a urine pregnancy test is positive, it must be confirmed by a 
serum pregnancy test.
v Urinalysis includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted.  Patients with 2+ protein on dipstick urinalysis 
must undergo a 24-hour urine collection and demonstrate 3.5 g of protein in 24 hours.
w Autoantibody analysis includes anti-nuclear antibody, antidouble-stranded DNA, circulating antineutrophil cytoplasmic antibody, and 
perinuclear antineutrophil cytoplasmic antibody.
x Not applicable for a site that has not been granted approval for RBR sampling.  Perform only for patients at participating sites who have provided 
written informed consent to participate.  RBR sample should be collected prior to study treatment.
y Patients will undergo tumor biopsy sample collection at the time of unacceptable toxicity or disease progression per RECIST v1.1, if deemed 
clinically feasible by the investigator.  Biopsies should be performed within 40 days after determination of unacceptable toxicity or disease 
progression, or prior to the next anti-cancer therapy, whichever is sooner.  See Section 4.5.7 in the protocol body for tissue sample requirements.
z Consenting patients will undergo optional tumor biopsy sample collection 4 weeks (7 days) after treatment initiation (if deemed clinically 
feasible) and may undergo additional on-treatment biopsies at any other time at the investigator's discretion.
aa Patients will undergo tumor assessments at baseline, every 6 weeks (1 week) for the first 48 weeks following treatment initiation, and every 
12 weeks (2 weeks) thereafter, regardless of dose delays, until radiographic disease progression according to RECIST v1.1.  Tumor 
assessments are to continue according to schedule in patients who discontinue treatment for reasons other than disease progression, even if 
they start new nonprotocol-specified anti-cancer therapy.


Appendix 7:  Study Details Specific to Regorafenib Arm (Control)
Table 4
Schedule of Activities for Regorafenib Arm (cont.)
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bb All measurable and/or evaluable lesions should be re-assessed at subsequent tumor evaluations according to the schedule described above.  
Brain metastases identified at baseline that have been treated with radiotherapy or surgery will not be considered measurable or evaluable 
unless there is suspected disease progression in the brain (i.e., the patient becomes symptomatic).  Thus, subsequent head CT scans are not 
required unless clinically indicated.  The same radiographic procedures used to assess disease sites at screening should be used for 
subsequent tumor assessments (e.g., the same contrast protocol for CT scans).
cc For patients who undergo screening for Stage 2, tumor assessments performed prior to or at the time of disease progression during Stage 1 may 
serve as baseline assessments for Stage 2, provided the tumor assessments are performed within 28 days prior to initiation of Stage 2 treatment 
(i.e., Day 1 of Cycle 1).
dd Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by a patient in addition to protocol-mandated study treatment from 7 days prior to initiation of study treatment until the treatment 
discontinuation visit.
ee After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of 
special interest will continue to be reported until 135 days after the last dose of study treatment or until initiation of new systemic anti-cancer 
therapy, whichever occurs first.  After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified 
if the investigator becomes aware of any serious adverse event that is believed to be related to prior exposure to study treatment (see 
Section 5.6 in the protocol body).  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the 
event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study treatment or trial-related procedures until a final outcome can be reported.
ff Patients will receive regorafenib at a dose of 160 mg (four tablets) orally once a day on Days 121 of each cycle.  At least 7 days off regorafenib 
are required prior to starting a new treatment cycle.  Dose escalation to 160 mg during Cycle 1 per institutional guidelines is allowed.  
Regorafenib should be taken approximately the same time each day and no later than 12 hours after the scheduled time.  The tablets should be 
swallowed whole with water and a light meal (30% fat).
gg Treatment will continue until unacceptable toxicity or disease progression per RECIST v1.1 (see Section 3.1.1 in the protocol body for details).
hh After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) 
will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months until death (unless the patient 
withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this request must be documented 
in the source documents and signed by the investigator.  If the patient withdraws from study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status only.


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Table 5
Schedule of Biomarker Samples for Patients Treated with 
Regorafenib
Visit
Time
Sample Type
Day 1 of Cycle 1
Prior to study treatment
Biomarkers (plasma, serum, 
PBMC)
Day 1 of Cycle 2
Prior to study treatment
Biomarkers (plasma, serum, 
PBMC)
Day 1 of Cycle 4
Prior to study treatment
Biomarkers (plasma, serum)
Day 1 of Cycle 8
Prior to study treatment
Biomarkers (plasma, serum)
Treatment discontinuation visit 
(30 days after last dose)
At visit
Biomarkers (plasma, serum)
PBMCperipheral blood mononuclear cell.
Note:  No pharmacokinetic samples are being collected for this treatment arm.


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Appendix 8
Placeholder for Future Arm
The atezolizumab plus Imprime PGG plus bevacizumab (Atezo Imprime Bev) arm 
has been removed because enrollment and patient follow-up has been completed for that 
arm, and the content of Appendix 8 (previously entitled “Study Details Specific to the 
Atezo Imprime Bev Arm”) has been deleted.  Appendix 8 will serve as a placeholder 
for a future arm to avoid having to renumber subsequent appendices.


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Appendix 9
Placeholder for Future Arm
The atezolizumab plus isatuximab (AtezoIsa) arm has been removed because 
enrollment and patient follow-up has been completed for that arm, and the content of 
Appendix 9 (previously entitled “Study Details Specific to the AtezoIsa Arm”) has been 
deleted.  Appendix 9 will serve as a placeholder for a future arm to avoid having to 
renumber subsequent appendices.


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Appendix 10
Placeholder for Future Arm
The atezolizumab plus selicrelumab plus bevacizumab (Atezoselibev) arm has been 
removed because enrollment and patient follow-up has been completed for that arm, 
and the content of Appendix 10 (previously entitled “Study Details Specific to 
Atezoselibev Arm”) has been deleted. Appendix 10 will serve as a placeholder for a 
future arm to avoid having to renumber subsequent appendices.


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Appendix 11
Study Details Specific to AtezoIdasa Arm 
TABLE OF CONTENTS
A111.
Background on AtezoIdasa Arm
A111.1 Background on Atezolizumab
A111.2 Background on Idasanutlin
A112.
Rationale for AtezoIdasa Arm
A112.1 The PD-L1 Pathway
A112.2 MDM2 Antagonism
A112.3 Rationale for Combining Idasanutlin with Checkpoint Inhibition
A112.4 BenefitRisk Assessment
A113.
Rationale for Dose and Schedule for AtezoIdasa Arm
A113.1 Rationale for Atezolizumab Dose and Schedule
A113.2 Rationale for Idasanutlin Dose and Schedule
A114.
Materials and Methods Specific to AtezoIdasa Arm
A114.1 Treatment in AtezoIdasa Arm
A114.1.1 Formulation, Packaging, and Handling
A114.1.2 Dosage, Administration, and Compliance
A114.1.3 Stage 2 Treatment
A114.2 Concomitant Therapy for AtezoIdasa Arm
A114.2.1 Permitted Therapy for AtezoIdasa Arm
A114.2.2 Cautionary Therapy for AtezoIdasa Arm
A114.2.3 Prohibited Therapy for AtezoIdasa Arm
A114.3 Contraception Requirements for AtezoIdasa Arm
A115.
Assessment of Safety for AtezoIdasa Arm
A115.1 Safety Plan for AtezoIdasa Arm
A115.1.1 Risks Associated with Atezolizumab
A115.1.2 Risks Associated with Idasanutlin
A115.1.3 Risks Associated with Combination Use of Atezolizumab 
and Idasanutlin
A115.1.4 Management of Patients Who Experience Adverse 
Events in AtezoIdasa Arm
A115.2 Adverse Events of Special Interest for AtezoIdasa Arm (Immediately 
Reportable to the Sponsor)
A115.3 Reporting Requirements for Pregnancies in AtezoIdasa Arm
A115.3.1 Pregnancies in Female Patients
A115.3.2 Pregnancies in Female Partners of Male Patients
A115.3.3 Abortions
A115.3.4 Congenital Anomalies/Birth Defects
A116.
Schedule of Activities and Sample Collection for AtezoIdasa Arm


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A111 BACKGROUND FOR ATEZOIDASA ARM
A111.1
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated antibody 
mediated clearance of activated effector T cells.
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy.
Atezolizumab has been generally well tolerated.  Adverse events with potentially 
immune-mediated causes consistent with an immunotherapeutic agent, including rash, 
influenza like illness, endocrinopathies, hepatitis or transaminitis, pneumonitis, colitis, 
and myasthenia gravis, have been observed (see the Atezolizumab Investigator's 
Brochure for detailed safety results).  To date, these events have been manageable with 
treatment. 
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer, small-cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, 
and melanoma.
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies.
A111.2
BACKGROUND ON IDASANUTLIN
Idasanutlin belongs to a class of small-molecule compounds, termed nutlins, and was 
identified as a potent and selective inhibitor of the p53-murine double minute 2 (MDM2)
interaction (Vassilev et al. 2004) with a median inhibitory concentration [IC50] of 17 nM. 
Idasanutlin binds to the surface of MDM2 in the p53-binding pocket, thus preventing the 
p53-MDM2 protein-protein interaction (Kussie et al. 1996). 
In nonclinical models, exposure of solid tumor cell lines expressing functional p53 to 
idasanutlin resulted in a dose-dependent stabilization and accumulation of p53 protein 
and activation of p53 and its transcriptional targets.  This in turn led to inhibition of 
proliferation and/or apoptosis.  In vivo, idasanutlin, as a single agent, demonstrated 


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anti-tumor activity in an established osteosarcoma xenograft model, increased efficacy 
and survival when given in combination with cytarabine in an acute myeloid leukemia 
(AML) model in immunodeficient mice, and increased efficacy when given in 
combination with obinutuzumab in a non-Hodgkin lymphoma (NHL) model in 
immunodeficient mice.
Idasanutlin has been investigated as a single agent in patients with solid tumors in three 
Phase I Studies:  NP27872 (99 patients), NP28902 (61 patients), and NP29910 
(8 patients) and in a Phase I study in 122 patients with AML (NP28679).  A 
bioequivalence study in patients with solid tumors (Study NP39051) and a single-agent 
Phase I/II study in patients with polycythemia vera (NP39761) are ongoing.  Idasanutlin 
is also currently being investigated in combination with cytarabine in fit patients with 
relapsed or refractory (R/R) AML in a Phase III study (WO29519) and in combination 
with venetoclax in a Phase Ib/II study (GH29914) in unfit patients with R/R AML.  In 
addition, two Phase Ib/II studies are being conducted in combination with obinutuzumab 
or rituximab (Study BH29812) and in combination with obinutuzumab or rituximab and 
venetoclax (Study BH39174) in patients with follicular lymphoma and diffuse large B-cell 
lymphoma. 
The majority of the adverse events recorded for idasanutlin treatment are transient in 
nature and reversible. 
Refer to the Idasanutlin Investigator’s Brochure for details on nonclinical and clinical 
studies.
A112 RATIONALE FOR ATEZO+IDASA ARM
A112.1
THE PD-L1 PATHWAY 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies (Hodi et al. 
2010; Kantoff et al. 2010; Chen et al. 2012).
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that downregulates immune responses through binding 
to its two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor expressed on T cells 
following T-cell activation, and expression is sustained in states of chronic stimulation 
(Blank et al. 2005; Keir et al. 2008).  B7-1 is a molecule expressed on antigen presenting 
cells and activated T cells.  Binding of PD-L1 to PD-1 and B7-1 inhibits T-cell 
proliferation and activation, cytokine production, and cytolytic activity, leading to the 
functional inactivation or exhaustion of T cells (Butte et al. 2007; Yang et al. 2011).  


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Overexpression 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 pathway represents an attractive strategy for restoring tumor 
specific T-cell immunity.
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed standard of care therapies.  Objective 
responses have been observed across a broad range of malignancies, including NSCLC, 
urothelial carcinoma, renal cell carcinoma, melanoma, CRC, head and neck cancer, 
gastric cancer, breast cancer, and sarcoma (see the Atezolizumab Investigator's 
Brochure for detailed efficacy results).  
Early clinical data had shown encouraging results with the antiPD-1 checkpoint inhibitor 
pembrolizumab as a single agent in patients with mCRC assessed as having high 
microsatellite instability (MSI-H) status but not with microsatellite stable (MSS) status 
(Le et al. 2015).  These data resulted in the May 2017 approval of pembrolizumab in 
adult and pediatric patients with tumors characterized as MSI-H or deficient for mismatch 
repair genes based on objective response rate (ORR) and durability of the response.  
ORR was similar irrespective of whether patients were diagnosed with CRC (36%) or a 
different cancer type (46% across the 14 other MSI-H cancer types).  Similar response 
rates were observed in patients with second line or later mCRC enrolled in a Phase Ia 
study investigating atezolizumab as single agent (Roche Study PCD4989g) and a Phase 
Ib study investigating the combination of atezolizumab plus bevacizumab (Roche Study 
GP28328, Arm A).  In Study PCD4989g, there was 1 responder reported in 14 patients 
with MSS status per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 
v1.1).  In the 10 patients with MSI-H status enrolled in Study GP28328, the investigator 
assessed confirmed ORR per RECIST v1.1 was 40% (95% CI: 12.2, 73.8), with all 4 
responders having partial responses.  No objective responses were seen in the 14 
patients with MSS tumors.
A112.2
MDM2 ANTAGONISM
MDM2 was identified as a major negative regulator of the tumor suppressor p53.  p53 is 
a transcription factor whose best understood function is the ability to arrest or eliminate 
cells in response to DNA damage or other cellular stresses (e.g., dysregulated 
oncogenes) that can promote malignant transformation. In response to cellular stress,
p53 regulates the expression of cell cycle and survival genes, the end result of which is 
either transient cell cycle arrest, senescence, or apoptosis, depending on the nature and 
the severity of the stress, the cell type and genetic context (Kastenhuber and 
Lowe 2017). 
While TP53 is the most frequently mutated gene in human cancer, around 50% of 
cancers retain wild-type p53 (Kastenhuber and Lowe 2017), including approximately 22% 


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of CRC tumors (based on an unpublished TP53 mutation analysis in the IMblaze 370 
trial). In these tumors, amplification of the MDM2 gene or overexpression of the MDM2 
protein was frequently found (Wade et al. 2013), and the interaction between MDM2 and 
p53 is considered to be the primary mechanism for inhibition of the p53 function (Wade
et al. 2013). 
MDM2 inhibits p53 activity by interfering with p53 transactivation function and targeting it 
for degradation by the ubiquitin-proteasome system (Shangary and Wang. 2008). This 
keeps p53 levels and activity low in unstressed cells. In the presence of cellular stress,
p53 becomes rapidly stabilized by a mechanism that prevents its interaction with MDM2. 
p53 then accumulates in the nucleus and activates the transcription of the MDM2 gene. 
Subsequently, MDM2 inactivates p53, which results in a dampening of p53 back to 
baseline levels, establishing a feedback loop that prevents the potential detrimental 
effects of excessive p53 activation. In tumors that overexpress MDM2, this negative 
feedback loop is disrupted and stress-induced p53 activation mechanisms become 
insufficient to overcome the negative control of MDM2, resulting in unrestrained 
proliferation of cancer cells. Therefore, blocking the p53-MDM2 interaction is expected 
to restore p53 function, resulting in effective proliferation inhibition and/or killing of
wild-type p53 cancer cells. 
In addition to its tumor cell intrinsic effects, several lines of evidence indicate that p53 
can contribute to anti-cancer immunity through different mechanisms. First, as 
mentioned above, p53 can induce cellular senescence, which is a tumor-suppressive 
program that involves stable cell-cycle arrest and secretion of a variety of immune 
modulators and inflammatory cytokines (Coppe 2008). The latter property, called 
Senescence Associated Secretory Phenotype (SASP), turns senescent cells into 
proinflammatory cells. Accordingly, the ability of the p53-driven senescence program to 
elicit an anti-tumor immune response was demonstrated in a mouse model of RAS 
driven liver carcinoma in which endogenous p53 expression was conditionally regulated 
by RNA interference (RNAi). Reactivation of endogenous p53 in p53-deficient tumors, 
led to complete tumor regression. Importantly, the primary tumor cell response was 
senescence, which was associated with the clearance of the senescent tumor cells by 
components of the innate immune system, including macrophages, neutrophils, and NK 
cells (Xue et al. 2007). Subsequent work focusing on the role of NK cells showed that 
the elimination of senescent tumor cells was dependent on p53-induced secretion of the 
chemokine CCL2, a potent chemoattractant for NK cells. p53-driven senescent tumor 
cells also upregulated cytokines known to activate NK cells, such as interleukin (IL)-12, 
IL-15, and IL-18 (Iannello et al. 2013). As nutlin was shown to induce a senescence-like 
state in p53 wild-type solid tumor cell lines (Shen and Maki 2010), MDM2 antagonism 
has the potential to re-establish the p53-mediated senescence program and promote an 
innate immune tumor attack in patients with p53 wild-type cancers.


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More recent work has expanded the role of p53 in anti-tumor immunity to actions in the 
immune cells themselves. Intra-tumoral injection of nutlin-3a was shown to result in 
complete tumor regression and resistance to tumor re-challenge, indicating the 
establishment of an anti-tumor immune memory. This effect was dependent on p53 
expression in immune cells and relied on two p53-driven effects: the induction of tumor 
cell immunogenic cell death (ICD) and a reduction in the number and function of 
tumor-infiltrating myeloid-derived suppressor cells (MDSCs) (Guo et al. 2017).
Moreover, p53 was shown to promote the differentiation of myeloid cells into immune 
cells with cross-presenting properties that are considered to be required for turning a 
cold tumor microenvironment into an inflamed one.  A particular type of dentritic cell
(DC), called a type 1 conventional dendritic cell (cDC1, also known as CD103DC in 
mice or CD141DC in humans), is capable of cross-presenting tumor antigens to 
activate naive CD8T cells and therefore is considered to be essential for the 
establishment of adaptive anti-tumor immunity and response to cancer immunotherapy 
(Broz et al. 2014, Barry et al. 2018). The cDC1 cells derive from a common DC 
progenitor. A recent study identified a phenotypically similar CD103DC population 
(defined as Ly6cCD11cCD103) emerging in a mouse melanoma model treated by a 
combination of cyclophosphamide (which induces ICD) and a Tregulatory cell targeting 
drug. In contrast to cDC1, this DC subset was shown to stem from from monocyte 
precursors and tumor-associated MDSCs. Importantly the emergence of the 
Ly6cCD11cCD103cells was dependent on p53, as conditional deletion of TP53 in 
the myeloid compartment resulted in the complete absence of these cells from the tumor 
and the loss of therapeutic efficacy of the chemo-immunotherapy combination. 
Conversely, inducing p53 using nutlin-3a was synergistic with checkpoint blockade in an 
otherwise CPI resistant mouse melanoma model (Sharma et al. 2018). Thus p53-driven 
differentiation of a cross-presenting, DC-like subpopulation and the resulting anti-tumor 
adaptive immune response represents yet another mechanism by which MDM2 
antagonism can promote anti-tumor immunity.
A112.3
RATIONALE FOR COMBINING IDASANUTLIN WITH 
CHECKPOINT INHIBITION
As discussed above, by promoting senescence of tumor cells, idasanutlin is expected to 
initiate a NK cell response that is likely to be reinforced by PD-L1 blockade. Indeed, 
increased PD-1 expression was observed in peripheral and tumor-infiltrating NK cells in 
patients with GI tumors, including CRC (Liu et al. 2017).  Moreover, PD-1 was shown to 
function as a checkpoint for NK cells, and PD-1 blockade in tumor models, whose tumor 
surveillance was dependent on NK cells, showed significant anti-tumor activity (Hsu
et al. 2018).
Furthermore, idasanutlin has been shown to promote the differentiation of myeloid cells 
to antigen presenting cells that are capable of antigen cross presentation to CD8


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T cells thereby initiating an anti-tumor response.  This mechanism of action could restore
antigen presentation and T-cell priming, which are steps that are considered to be 
missing in MSS CRC, resulting in resistance to immune checkpoint inhibitors (Legitimo 
et al., 2014). The tumor-specific, cytotoxic CD8T-cells thus primed will eventually 
experience T-cell exhaustion due to the negative feedback regulation by the PD-1/PD-L1 
axis that invariably occur in the tumor bed (Ribas and Wolchok 2018), an effect that can 
be counteracted by PD-L1 blockade.
Therefore, the two key effectors of the anti-tumor immunity activated by idasanutlinNK 
cells and CD8T-cells are expected to act synergistically to initiate an anti-tumor 
immune response. In order to prevent the exhaustion of activated NK cells and T-cells,
resulting from the upregulation of the PD1/PDL1 axis, idasanutlin will be combined with 
atezolizumab to promote a sustainable immune response. 
A112.4
BENEFITRISK ASSESSMENT
This study will enroll patients with mCRC who have become refractory to first- and 
second-line standard therapies. This patient population has a median OS of less than 
6 months with currently available treatments. Treatment options have shown limited 
efficacy and are often poorly tolerated. 
Despite the success of single agent checkpoint inhibition (CPI) in the MSI-H patient 
population, the vast majority of CRC patients have MSS tumors and do not respond to 
single agent CPI, highlighting the need for safe and effective combination treatments.  
As discussed in detail above, the combination of idasanutlin and atezolizumab is 
expected to boost anti-cancer immunity in this patient population with high unmet 
medical need by mobilizing two key effectors of the anti-tumor immune response,
NK-cells and CD8+ T-cells, providing the necessary ground for antiPD-L1 efficacy. 
As of 13 September 2018, a total of 205 adult patients with solid tumors have been 
treated with idasanutlin in four studies (NP27872, NP28902, NP29910, and NP39051),
which tested a dose range of 100 mg to 3200 mg. Across these four studies in solid 
tumors, 97% of patients had at least one adverse event with an incidence rate of at least 
10%.  Diarrhea, nausea, vomiting, decreased appetite, and fatigue were the most 
frequently reported adverse events. The most common (30%) treatment-related 
adverse events were diarrhea, nausea, and vomiting.
Grade 3 adverse events were reported in 50% of patients, most commonly within the 
system organ classes of blood and lymphatic system disorders, gastrointestinal (GI) 
disorders, and metabolism and nutrition disorders. Thrombocytopenia, anemia, 
neutropenia, and nausea were the most common (5% of patients) Grade 3 adverse 
events reported.  Serious adverse events were reported in 26% of patients in the pooled 
dataset.  The most commonly reported serious adverse events (2% of patients) were


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thrombocytopenia (6.3%), febrile neutropenia (2.4%), pyrexia (2.4%), and anemia (2.0%).  
In 14% of patients, serious adverse events were considered related to idasanutlin, with 
the most commonly reported (2% of patients) being thrombocytopenia (6.3%) and 
febrile neutropenia (2.4%).  A total of 13 patient deaths were recorded across all four 
studies, of which 9 deaths were attributed to progressive disease. Of the remaining 4 
deaths, 1 death was considered remotely related to idasanutlin (pulmonary embolism); 
the other three deaths were considered unrelated (intracranial hemorrhage, intra-
abdominal hemorrhage, and aspiration pneumonia).
The majority of the adverse events recorded for idasanutlin treatment are transient in 
nature and reversible. Clinical experience to date suggests that there is a 
dose-relationship for idasanutlin and GI adverse events, with an increased incidence of 
nausea, vomiting, and diarrhea at higher dose levels. Cytopenias, manifesting as 
thrombocytopenia and neutropenia, are expected to occur at higher dose/exposure 
levels and appears to be related to toxicity on normal early hematopoietic progenitors. 
Frequent monitoring of hematologic values (count of blood cells, including differential) is 
therefore required. The doses of idasanutlin that are planned to be administered in this 
study (150 mg and 200 mg) are lower than the maximum tolerated dose (MTD) in solid 
tumor patients (250 mg) (See Section A113.2).
Regarding clinical activity, the best overall response to idasanutlin monotherapy in solid 
tumors was stable disease (SD), with SD rates ranging from 30.6% (Study NP27872) to 
41.1% (Study NP28902).  The median duration of stable disease was 72.5 days, ranging 
from 8 days to 696 days (Study NP27872). The observed clinical activity is consistent 
with idasanutlin monotherapy acting mostly as a cytostatic agent in solid tumors.
Safety data are available for single-agent atezolizumab in patients with solid tumors, 
including CRC. Potential overlapping toxicities with idasanutlin may occur within the 
system organ class of GI disorders, respiratory, blood and lymphatic system and 
hepatobiliary disorders. The relevant corresponding overlapping toxicities of 
atezolizumab include colitis, pneumonitis, autoimmune hemolytic anemia, 
thrombocytopenia and hepatitis, all of which are considered to be immune related. 
Given the distinct mechanisms of action of atezolizumab and idasanutlin, it is anticipated 
that adverse reactions observed with either agent will not result in additive and/or 
synergistic toxic effects.
In summary, the investigation of the safety of each molecule as a single agent in patients 
with solid tumors has not revealed findings that would prohibit the investigation of the 
idasanutlin and atezolizumab combination in the setting of a Phase Ib/II study.  Given 
the high unmet medical need in third line CRC for well tolerated and effective treatments, 
the rationale for the combination of atezolizumab and idasanutlin, and the anticipated 
safety profile of the combination, the benefitrisk profile is considered positive.


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For the evaluation of the impact of the coronavirus disease 2019 (COVID-19) pandemic 
on the benefitrisk assessment, please refer to Section 1.4.
A113 RATIONALE FOR DOSE AND SCHEDULE FOR ATEZO+IDASA ARM
A113.1
RATIONALE FOR ATEZOLIZUMAB DOSE AND SCHEDULE
Atezolizumab will be administered at a fixed dose of 840 mg every 2 weeks (Q2W) 
(840 mg on Days 1 and 15 of each 28-day cycle).  The average concentration following 
the 840 mg Q2W dosage is expected to be equivalent to that of 1200 mg every 3 weeks 
(Q3W), an approved dosage for atezolizumab, as outlined in the prescribing information.  
Anti-tumor activity has been observed across doses ranging from 1 to 20 mg/kg Q3W.  
In Study PCD4989g, the MTD of atezolizumab was not reached and no dose-limiting 
toxicities (DLTs) were observed at any dose.  The fixed dose of 1200 mg Q3W 
(equivalent to an average body weightbased dose of 15 mg/kg Q3W) was selected on 
the basis of both nonclinical studies (Deng et al. 2016) and available clinical 
pharmacokinetic, efficacy, and safety data (refer to the Atezolizumab Investigator's 
Brochure for details).
A113.2
RATIONALE FOR IDASANUTLIN DOSE AND SCHEDULE
During Phase I development, two different formulations of idasanutlin were tested:  a 
microprecipitated bulk powder (MBP) formulation and a spray-dried powder (SDP) 
formulation.  The choice of the idasanutlin dose regimen for this study is based on the 
experience with the initial MBP formulation in single-agent testing (Studies NP27872 and 
NP28902) in patients with solid tumors in the evaluation of the combination with 1 g/m2
cytarabine in Study NP28679 in patients with AML and the bioequivalence study with the 
SDP formulation NP28902.  
Serum levels of macrophage inhibitory cytokine (MIC-1), a secreted protein that is 
strongly induced by activated p53, were used to assess the pharmacodynamic effects of 
the idasanutlin MBP formulation in Studies NP27872 and NP28679. Analysis of patients 
treated with a tested dose range of 100 to 3200 mg/day of idasanutlin showed an 
exposure-related increase in MIC-1 response. A comparison of MIC-1 elevation 
between different idasanutlin dosing schedules (all administered in a 28-day cycle) 
showed that daily schedules were more effective at inducing MIC-1 than a weekly 
schedule. In contrast to the once daily for 5 days (QD5d) regimen, the once daily for 
3 days regimen did not achieve steady-state exposure, did not alleviate 
thrombocytopenia, and patients did not achieve as long a duration of stable disease.  
Therefore, the QD5d regimen, followed by a 23-day drug-free interval (QD5d Q4W) 
was chosen for future clinical trials.  
Clinical pharmacokinetic (PK) data showed approximate dose-proportionality in the 
exposure parameter of area under the concentration–time curve from 0 to 24 hours


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(AUC024) on Day 5 of the QD5d schedule for the test range of 100 to 2400 mg/day 
with inter-patient variability of approximatively 40%50%. The half-life (T1/2) of 
idasanutlin is approximatively one day, and there were no major effects of high-fat or 
low-fat food on PK exposure. 
In Study NP27872 of patients with solid tumors, the QD5d Q4W MTD for the MBP 
formulation was determined to be 500 mg.  Thrombocytopenia, neutropenia, febrile 
neutropenia, and diarrhea were dose-limiting toxicities (DLTs).  In Study NP28679, the 
lowest dose where responses were seen in AML was 400 mg of the MBP formulation in 
combination with cytarabine 1 g/m2 and this dose proved to have an acceptable safety 
profile. 
The alternative drug formulation SDP of idasanutlin was developed to improve drug 
substance stability and chosen for all future studies, including Study CO39612. PK data 
from a relative bioavailability study (NP28902, Part 2) demonstrated that the SDP 
formulation has an increase in the maximum concentration (Cmax) and exposure (AUC) 
of 47% and 42%, respectively, compared with the MDP formulation. Therefore, the 
exposure achieved by the SDP formulation is considered to be approximatively twice the 
exposure achieved with the MDP formulation, and the resulting SDP equivalent of the 
MTD determined for the QD5d Q4W schedule in the solid tumor Study NP27872 is 
determined to be 250 mg.
Based on the above information, idasanutlin will be administered orally at a dose of 
200-mg QD5d Q4W (SDP formulation), which is anticipated to be associated with an 
acceptable safety profile. However, to account for potential toxicities, special caution will 
be taken by starting idasanutlin at a lower dose of 150 mg QD5d during Cycle 1 and 
continuing idasanutlin at the 200-mg dose in all subsequent cycles in (at a minimum) the 
first 5 patients. If this regimen is determined to be safe and well tolerated (see Section 
A114.1.2.2), all subsequent patients will receive 200 mg QD5 Q4W in combination 
with atezolizumab during all cycles.
Note that due to the MTD at 250 mg in solid tumor patients, the idasanutlin dose 
increase will be limited to 200 mg to balance the potential for improving a patient’s
response with higher exposure with the potential for increased side effects.


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A114 MATERIALS AND METHODS SPECIFIC TO ATEZO+IDASA ARM
A114.1
TREATMENT IN ATEZO+ IDASA ARM
A114.1.1 Formulation, Packaging, and Handling
A114.1.1.1
Atezolizumab
The atezolizumab drug product will be supplied by the Sponsor as a sterile liquid in a 
single-use, 20-mL glass vial.  The vial contains approximately 20 mL (1200 mg) of 
atezolizumab solution.
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure.
A114.1.1.2
Idasanutlin 
Idasanutlin will be supplied by the Sponsor as film-coated tablets (SDP formulation) at
three dose strengths:  50 mg, 150 mg, and 200 mg.  
For information on the formulation and handling of idasanutlin, see the Idasanutlin 
Investigator’s Brochure.
A114.1.2 Dosage, Administration, and Compliance
Patients enrolled in the AtezoIdasa arm will receive treatment as outlined in 
Tables A111 and A112 until unacceptable toxicity or loss of clinical benefit as
determined by the investigator after an integrated assessment of radiographic and 
biochemical data, local biopsy results (if available), and clinical status (e.g., symptomatic 
deterioration such as pain secondary to disease; see Section 3.1.1 in the protocol body 
for details).  It is recommended that treatment be initiated no later than 7 days after 
randomization.  Treatment with AtezoIdasa when idasanutlin is administered at 
150 mg or at 200 mg is described in Table 1 and 2, respectively. 
Table 1
Initial Treatment Regimen for AtezoIdasa Arm a
Cycle Length
Dose, Route, and Regimen
(drugs listed in order of administration)
28 days

Idasanutlin 150 mg orally once daily on Days 15 of each cycle a

Atezolizumab 840 mg IV on Days 1 and 15
AtezoIdasaatezolizumab plus idasanutlin.
a For details regarding intra-patient dose increase and dose increase after the safety 
evaluation phase, refer to Section A114.1.2.2.


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Table 2
Treatment Regimen for AtezoIdasa Arm after Dose Increase
Cycle Length
Dose, Route, and Regimen
(drugs listed in order of administration)
28 days

Idasanutlin 200 mg orally once daily on Days 15 of each cycle

Atezolizumab 840 mg IV on Days 1 and 15
AtezoIdasaatezolizumab plus idasanutlin.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Refer to Section A115.1.4 for information on treatment interruptions for patients who 
experience toxicities.  Atezolizumab and idasanutlin treatment interruptions for reasons 
other than toxicity (e.g., surgical procedures) may be allowed.  The acceptable length of 
treatment interruption must be based on an assessment of benefitrisk by the 
investigator and in alignment with the protocol requirements for the duration of 
treatment and documented by the investigator. The Medical Monitor is available to 
advise as needed.
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 5.3.5.12. 
No safety data related to atezolizumab or idasanutlin overdose are available. 
A114.1.2.1
Atezolizumab
Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Days 1 
and 15 of each 28-day cycle.  
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 5.  
Atezolizumab infusions will be administered per the instructions outlined in Table 3.


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Table 3
Administration of First and Subsequent Atezolizumab Infusions
First Infusion
Subsequent Infusions

No premedication is permitted prior to the 
atezolizumab infusion.

Vital signs (pulse rate, respiratory rate, 
pulse oximetry, blood pressure, and 
temperature) should be recorded within 
60 minutes prior to the infusion.

Atezolizumab should be infused over 
60 (15) minutes.

If clinically indicated, vital signs should be 
recorded every 15 (5) minutes during the 
infusion and 30 (10) minutes after the 
infusion.

Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms.

If the patient experienced an 
infusion-related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator.

Vital signs should be recorded within 
60 minutes prior to the infusion.

Atezolizumab should be infused over 
30 (10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion.

If the patient experienced an infusion-
related reaction with the previous infusion 
or if clinically indicated, vital signs should 
be recorded during the infusion and at 
30 (10) minutes after the infusion.
Guidelines for medical management of IRRs for atezolizumab are provided in 
Appendix 6.
No dose modification for atezolizumab is allowed.  Guidelines for atezolizumab 
treatment interruption or discontinuation because of toxicities are provided in 
Section A115.1.4.  
A114.1.2.2
Idasanutlin
Idasanutlin will be administered orally at a dose of 200 mg QD5d Q4W; however 
initially, a minimum of 5 patients will receive idasanutlin tablets at a starting dose of 
150 mg (either three 50-mg tablets or one 150-mg tablet) orally QD on Days 1 through 5 
of the first 28-day cycle (QD5d). If, based on the considerations listed below, 
treatment with idasanutlin 150 mg QD5d plus atezolizumab 840 mg Q2W is 
determined to be safe and well tolerated, patients will receive idasanutlin at a dose of 
200 mg (either as one 200-mg tablet, as one 150-mg tablet and one 50-mg table, or as 
four 50-mg tablets) on Days 1 through 5 of each 28-day cycle (QD5d Q4W) in Cycle 2 
and subsequent cycles.  


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Consideration for intra-patient dose increase to 200 mg will be based on a review of 
individual patient data collected from Day 1 of Cycle 1 to Day 1 of Cycle 2, including, but 
not limited to, laboratory and safety data. The dose increase to 200 mg will not be 
allowed if patients dosed at 150 mg develop any of the following toxicities during Cycle 1:

Adverse event of any grade leading to a delay of more than 14 days in the start of 
next treatment cycle 

Increase in liver function tests meeting the criteria of Hy’s Law

Grade 3 non-hematologic adverse event, with the following exceptions:
–
Grade 3 diarrhea that responds to therapy within 48 hours 
–
Grade 3 nausea or vomiting that occurs in the absence of premedication and 
responds to therapy within 72 hours

Hematologic adverse event that meets any of the following criteria:
–
Grade 3 febrile neutropenia
–
Grade 3 or 4 neutropenia in the presence of sustained fever of 38C (lasting 
5 days) or a documented infection
–
Grade 4 neutropenia lasting 7 days
–
Grade 3 or 4 thrombocytopenia if associated with Grade 3 bleeding
–
Grade 4 thrombocytopenia lasting 7 days

Other toxicities that are considered clinically relevant and related to study treatment 
as determined by the investigator and the Medical Monitor
The decision to increase the dose of idasanutlin from 150 mg to 200 mg for an individual 
patient will be made in consultation with the Investigator and Sponsor, including the 
Medical Monitor and Safety Science Leader. During this evaluation period, patients who 
withdraw for any reason not related to an adverse event and who have completed 
2 cycles of the treatment regimen will be replaced.
After approximately 6 patients have been dosed, a decision will be made as to whether 
idasanutlin should be dosed at 150 mg or 200 mg for all subsequent patients. If 
treatment with idasanutlin 150 mg for one cycle and subsequent intra-patient dose 
increase to 200 mg for at least one cycle is determined to be safe and well tolerated in a 
minimum of 5 out of 6 patients, the Sponsor may decide to administer idasanutlin at a 
starting dose of 200 mg in the next enrolled patients. Otherwise, the Sponsor may 
decide to maintain the idasanutlin dose at 150 mg in the next enrolled patients.
Each idasanutlin dose should be taken approximately 24 hours apart, once in the 
morning.  On Day 1 of each cycle, patients should take their tablets in the clinic prior to 
the atezolizumab infusion, as directed by site personnel.  Idasanutlin may be taken with 
or without food.  Tablets should be swallowed intact with water and should not be 


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opened, broken, or chewed.  Missed or vomited doses will not be made up. If vomiting 
occurs within 15 minutes and expelled tablets are intact, another dose may be given.
To assess patient compliance with self-administration of idasanutlin, patients will be 
required to record the time and date they took each dose in a medication diary; missed 
doses will also be recorded.  Patients will be instructed to bring all unused study 
medication and their medication diaries at specified study visits for assessments of 
compliance.
To mitigate the risk of idasanutlin-related GI toxicities, all patients should receive the 
premedications outlined in Table 4.
Table 4
Premedication for Idasanutlin
Premedication/Indication
Timepoint
Administration
Mandatory Premedication
5-HT3 receptor antagonist:  
To reduce the incidence and 
severity of nausea and 
vomiting 
Day 1, 3060 minutes prior to 
first administration of study 
medication (for long-acting 
anti-emetics, such as 
palonosetron); otherwise prior to 
each study medication 
administration (Days 15, for 
short acting anti-emetics, such 
as ondansetron or granisetron) a
Palonosetron IV 0.25 mg or 
PO 0.5 mg, or 
granisetron transdermal 
system, or
oral ondansetron or 
granisetron b according to 
prescribing information
Recommended Premedication (at the discretion of the investigator)
Loperamide:  To reduce the 
incidence and severity of 
diarrhea
Day 1, 30 minutes prior first 
administration of study 
medication a
Loading dose of loperamide 
4 mg orally
POby mouth
a Premedication to be repeated for every cycle.
b Palonosetron is the recommended option because of its efficacy against delayed nausea and 
lack of QT interval–prolonging effects.
Guidelines for idasanutlin dose modification, treatment interruption, or discontinuation 
because of toxicities are provided in Section A115.1.4. 
A114.1.3 Stage 2 Treatment
Patients in Stage 1 who experience loss of clinical benefit as determined by the 
investigator (as described in Section 3.1.1 in the protocol body) or unacceptable toxicity 
may be eligible to receive a different treatment combination during during Stage 2, 
provided a Stage 2 treatment is available for enrollment and they meet the eligibility 
criteria of that treatment regimen. Stage 2 treatment must begin within 3 months after 


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the patient has experienced loss of clinical benefit or unacceptable toxicity.  However, it 
is recommended that patients begin Stage 2 treatment as soon as possible, but no 
earlier than 2 weeks after the last dose of treatment in Stage 1. 
Tumor assessments performed prior to or at the time of loss of clinical benefit or 
unacceptable toxicity during Stage 1 may serve as baseline assessments for Stage 2, 
provided the tumor assessments are performed within 28 days prior to initiation of 
Stage 2 treatment (i.e., Day 1 of Cycle 1).  Stage 2 treatment will continue until 
unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Table 5
Stage 2 Treatment Regimens Available for the AtezoIdasa Arm
Study Treatment
Appendix
No Stage 2 treatment currently available 

A114.2
CONCOMITANT THERAPY FOR ATEZOIDASA ARM
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated study treatment from 
7 days prior to initiation of study treatment to the treatment discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.
A114.2.1 Permitted Therapy for AtezoIdasa Arm
Patients are permitted to use the following therapies during the study:

Oral contraceptives

Hormone-replacement therapy

Prophylactic anticoagulation 
Prophylactic anticoagulation for the patency of venous access devices is 
allowed provided the activity of the agent results in an INR 1.5upper limit of 
normal (ULN) and aPTT is within normal limits within 14 days prior to Day 1.
Prophylactic use of low molecular weight heparin (i.e., enoxaparin 40 mg/day) 
is allowed.

Prophylactic antibiotic or anti viral treatment administered according to institutional 
standards

Vaccinations (such as influenza, COVID-19)
Live, attenuated vaccines are not permitted (see Section A114.2.3).

Prophylactic standard anti-emetic therapy


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
Megestrol acetate administered as an appetite stimulant after initiation of study 
treatment

Mineralocorticoids (e.g., fludrocortisone)

Inhaled corticosteroids administered for chronic obstructive pulmonary disease or 
asthma

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency

Hormonal therapy with gonadotropin releasinghormone agonists or antagonists for 
prostate cancer

Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below:
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  
Treatment with atezolizumab and idasanutlin may be continued during palliative 
radiotherapy.

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.
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).


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A114.2.2 Cautionary Therapy for AtezoIdasa Arm
Corticosteroids, Immunosuppressive Medications, and Tumor Necrosis 
FactorInhibitors
Systemic corticosteroids, immunosuppressive medications, and tumor necrosis factor
(TNF) inhibitors may attenuate potential beneficial immunologic effects of treatment 
with atezolizumab.  Therefore, in situations in which systemic corticosteroids,
immunosuppressive medications, or TNFinhibitors would be routinely administered, 
alternatives, including antihistamines, should be considered.  If the alternatives are not 
feasible, systemic corticosteroids, immunosuppressive medications, and TNF-
inhibitors may be administered at the discretion of the investigator.
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy (refer to Appendix 6 for details).
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer (see 
Section A114.2.3) may be used during the study at the discretion of the investigator.
A114.2.3 Prohibited Therapy for AtezoIdasa Arm
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, may be prohibited 
prior to starting study treatment, depending on the agent and is prohibited during 
study treatment until disease progression is documented and the patient has 
discontinued study treatment, with the exception of palliative radiotherapy and local 
therapy under certain circumstances outlined above in Section A11-4.2.1.

Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 28 days prior to initiation of study treatment and during study treatment.

Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with atezolizumab, and for 5 months 
after the last dose of atezolizumab.

Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin-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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
Strong/moderate inhibitors and strong/moderate inducers of CYP3A4 and CYP2C8,
as well as CYP2C8 or OATP1B1/3 substrates, are prohibited within 14 days prior to 
initiation of idasanutlin and during treatment with idasanutlin (see Tables 6, 7, and 8).
Table 6
Prohibited CYP2C8 Substrates, Inhibitors, and Inducer
Substrates
Inhibitors
Inducer
Paclitaxel
Gemfibrozil
Rifampicin
Repaglinide
Pioglitazone
Rosiglitazone
Torasemide
Note:  Caution should be taken with the use of ibuprofen, monteleukast (CYP2C8 
substrates), and trimethoprim (CYP2C8 inhibitor). These are only permitted outside of the 
5-day treatment window with idasanutlin.
Table 7
Prohibited CYP3A4 Inducers
Inducers (Strong)
Carbamazepine
Cyproterone
Efavirenz
Etravirine
Modafinil
Nevirapine
Oxcarbazepine
Phenobarbital
Phenytoin
Rifampicin
St. John’s wort


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Table 8
Prohibited OATP1B1/3 Substrates
OATP1B1/3 Substrates
Atorvastatin
Atrasentan
Bosentan
Ezetimibe
Fluvastatin
Glyburide
Irinotecan
Pitavastatin
Pravastatin
Repaglinide
Rifampin
Rosiglitazone
Rosuvastatin
Simvastatin Acid
OATP1B1/3organic 
anion-transporting polypeptide 1B1/3.

In patients considered eligible for the study because they are able to tolerate 
anti-coagulant/anti-platelet treatment interruption, these agents must be 
discontinued 7 days (or 5 half-lives, whichever is shorter) prior to initiating study 
medication.  After the study drug completion/discontinuation visit, treatment with 
anti-coagulant/anti-platelet agents may be re-initiated for patients with 
transfusion-independent adequate platelet levels as clinically indicated. 

In patients remaining transfusion-dependent or patients with an adverse event 
requiring anti-thrombotic therapy during the study treatment period, the clinical
benefit of using anti-coagulation therapy (acute risk of thromboembolism/stroke) 
should be carefully weighed against its risks (acute risk of hemorrhage/uncontrolled 
bleeding) and only initiated if anti-coagulant/anti-platelet use is acutely required and 
use cannot be postponed until after the study drug completion/discontinuation visit.  
Close monitoring of platelet levels is recommended.  Frequent measurement of 
peak anti-Xa levels and tight maintenance between 0.5 and 1.0 IU/ml are advised 
and may improve the risk/benefit ratio.  The maintenance of anti-thrombotic 
treatment should be continuously re-assessed.  Sustained use over time must be 
clinically warranted.  Anti-thrombotic treatment should be reserved for those patients 
with established conditions, such as venous thromboembolism.  Low molecular 
weight heparin (LMWH) preparations or unfractionated heparin (UFH) with doses 
adjusted to platelet levels are allowed and would be the preferred therapeutic 


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intervention.  LMWH and UFH are recommended for patients who do not have 
contraindications to anticoagulant use.
A114.3
CONTRACEPTION REQUIREMENTS FOR ATEZOIDASA ARM
Contraception requirements for women and men in the AtezoIdasa arm are outlined 
below:

For women of childbearing potential:  agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for 5 months after the last dose of 
atezolizumab and for 6 weeks after the last dose of idasanutlin.  Women must 
refrain from breastfeeding during this same period of time.
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, hormonal contraceptives that inhibit 
ovulation, hormone releasing intrauterine devices, 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 a condom, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for
90 days after the last dose of idasanutlin to avoid exposing the embryo.  Men 
must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
A115 ASSESSMENT OF SAFETY FOR ATEZO + IDASA ARM
A115.1
SAFETY PLAN FOR ATEZO + IDASA ARM
The safety plan for patients in this study is based on clinical experience with 
atezolizumab and idasanutlin in completed and ongoing studies.  The anticipated 
important safety risks are outlined below (see Sections A115.1.1, A115.1.2, and
A115.1.3).  Guidelines for the management of patients who experience specific 
adverse events are provided in Section A115.1.4.


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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.  Because of the potential for overlapping toxicities identified for 
atezolizumab and idasanutlin, special caution will be taken by performing a planned 
safety evaluation for patients randomized to this arm.  A minimum of 6 patients must 
complete at least one cycle of treatment (i.e., receive at least two doses of atezolizumab 
and 5 doses of idasanutlin) and complete at least 23 days of safety follow-up after the 
last dose of idasanutlin before additional patients can be enrolled. If the combination is 
determined sufficiently safe and well tolerated, randomization will be resumed. 
If the intra-patient dose increase during Cycle 2 was allowed and determined to be safe 
and well tolerated in at least 5 out of 6 patients, the next enrolled patients will receive 
Idasanutlin at 200 mg from Cycle 1.  If the intra-patient dose increase during Cycle 2 
was not allowed or was determined not to be safe and well tolerated in at least 5 out of 
6 patients, the idasanutlin dose will be maintained at 150 mg in the next enrolled patients 
(see Section A114.1.2.2).
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 in the protocol body.
A115.1.1 Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, hypophysitis, adrenal insufficiency, Guillain-Barré
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
myocarditis, nephritis, myositis, and severe cutaneous adverse reactions.  
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), 
which are considered to be potential risks for atezolizumab.  Refer to Appendix 6 of the 
protocol and Section 6 of the Atezolizumab Investigator's Brochure for a detailed 
description of anticipated safety risks for atezolizumab.  
A115.1.2 Risks Associated with Idasanutlin
Diarrhea, nausea, vomiting, decreased appetite/anorexia, fatigue/asthenia, 
thrombocytopenia and increased hemorrhagic risk, neutropenia, febrile neutropenia, 
anaemia, pyrexia, sepsis, pneumonia, fungal infections, electrolyte disorders, and 
tumour lysis syndrome (TLS) are identified risks for idasanutlin. Some of these risks (i.e.,
sepsis, TLS) are more specific to hematological malignancies.


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
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Across the solid tumor studies, 97% of patients had at least one adverse event; diarrhea, 
nausea, vomiting, decreased appetite, and fatigue were the most frequent (10% 
incidence).  The most common treatment-related adverse events (30% incidence) were 
diarrhea, nausea, and vomiting.
Refer to Section 6 of the Idasanutlin Investigator's Brochure for a detailed description of 
anticipated safety risks for idasanutlin.  
A115.1.3 Risks Associated with Combination Use of Atezolizumab and 
Idasanutlin
The following adverse events are potential overlapping toxicities associated with 
combination use of atezolizumab and idasanutlin: diarrhea/colitis, electrolyte disorder, 
pneumonia/pneumonitis, thrombocytopenia, anemia, and hepatic toxicity. 
A115.1.3.1
Gastrointestinal Toxicity
Gastrointestinal adverse events reported in Phase I idasanutlin studies were primarily 
diarrhea, nausea, vomiting, abdominal pain, constipation, and anorexia.  Diarrhea was 
the most common adverse event.  Nausea and vomiting were also frequently reported 
but to a lesser extent, and the majority of adverse events were Grade 1 and Grade 2. 
Diarrhoea, nausea, and vomiting were very commonly observed in patients treated with
atezolizumab (10% patients). Colitis was less commonly observed in patients treated
with atezolizumab (1%10% of patients).
Please refer to Table A114 for additional information on mandatory premedication for 
idasanutlin.  For detailed instructions for the management of gastrointestinal toxicities, 
please refer to Table A119.
A115.1.3.2
Pneumonia and Pneumonitis
Patients treated with idasanutlin are at increased risk for infections due to the effect on 
bone marrow progenitors and the related cytopenia. Severe, life threatening and 
sometimes fatal infections (i.e., pneumonia) have been reported. Pneumonia was more 
commonly observed in patients with acute myeloid leukemia (AML) treated with 
idasanutlin compared with solid cancer.
Pulmonary events, such as dyspnea, pneumonia, and pneumonitis have been 
associated with the use of atezolizumab. Pneumonia was more commonly observed in 
patients with nonsmall cell lung cancer.
For detailed instructions for the management of pulmonary events, please refer to 
Table A119.


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
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A115.1.3.3
Hematologic Toxicities
Bone marrow toxicity induced by idasanutlin may manifest as cytopenias (i.e., 
pancytopenia, neutropenia, febrile neutropenia, thrombocytopenia, and anemia).  In 
Study NP27872, which evaluated idasanutlin in patients with solid tumors, possible 
exposure-dependent neutropenia and thrombocytopenia were observed; these events 
were reversible and manageable.  Blood counts must be monitored closely throughout 
study treatment; any Grade 3 decrease in neutrophil and thrombocyte counts must be 
followed until resolution.
For detailed instructions for the management of hematologic toxicities, please refer to 
Table A119.
A115.1.3.4
Hepatic Events
Hepatotoxicity is a potential risk for idasanutlin based on the results from nonclinical 
toxicology studies.  In the clinical setting, the majority of hepatic events were non-serious, 
transient, and isolated elevations of bilirubin.
Cases of hepatitis, some leading to fatal outcomes, have been observed in clinical trials 
with atezolizumab.  Most of the hepatic events identified were non-serious elevations of 
liver enzymes.  
Liver function tests should be monitored during treatment. For detailed instructions for 
the management of hepatic events, please refer to Table A119.
A115.1.3.5
Electrolyte Disorders
Hypokalemia, hypophosphatemia, and hypomagnesemia were commonly observed in 
patients treated with idasanutlin. Electrolytes should be monitored during treatment, and 
electrolyte disorders should be treated according to institutional guidelines.
A115.1.4 Management of Patients Who Experience Adverse Events in 
AtezoIdasa Arm
A115.1.4.1
Dose Modifications
There will be no dose modifications for atezolizumab in this study.
The dose of idasanutlin can be reduced in 50-mg increments to 100 mg QD5d Q4W.  If 
further dose reduction below 100 mg for idasanutlin is indicated, the patient must 
discontinue idasanutlin.  After dose reduction for idasanutlin, the dose should not be 
re-escalated during subsequent administrations. However, if the investigator believes 
the patient is likely to derive clinical benefit, the idasanutlin dose can be re-escalated 
after dose reduction.  The Medical Monitor is available to advise, as needed.


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
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A115.1.4.2
Treatment Interruption for Toxicities
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 more 
than 12 weeks, the patient will be discontinued from the study.  However, atezolizumab 
may be withheld for more than 12 weeks to allow for patients to taper off corticosteroids 
prior to resuming treatment.  Atezolizumab can be resumed after being withheld for more 
than 12 weeks if the patient is likely to derive clinical benefit.  The decision to 
re-challenge patients with atezolizumab should be based on investigator’s assessment of 
benefitrisk and documented by the investigator.  The Medical Monitor is available to 
advise as needed.
Idasanutlin treatment may be temporarily suspended in patients who experience toxicity 
considered to be related to study treatment (see Table A119). All treatment-related 
toxicities should be resolved to Grade 1 or the baseline grade prior to beginning the 
next cycle, except for hematologic toxicities, which should be resolved to Grade 2.  If 
idasanutlin has been withheld for more than 2 cycles (i.e., a maximum of 56 days) 
because of toxicity, the patient should be discontinued from idasanutlin.  However, if the 
investigator believes the patient is likely to derive clinical benefit, idasanutlin can be 
resumed after being withheld for 56 days.  The Medical Monitor is available to advise 
as needed.
If atezolizumab or idasanutlin is permanently discontinued, the other agent should also 
be discontinued unless the patient is likely to derive clinical benefit from single-agent use, 
as determined by the investigator. The Medical Monitor is available to advise as needed.
Refer to Section A11-4.1.2 for information on dose interruptions for reasons other than 
toxicity.
A115.1.4.3
Management Guidelines for Adverse Events
Guidelines for the management of patients who experience specific adverse events are 
provided below in Table A119 for events related to overlapping toxicities or idasanutlin 
treatment.
For cases in which management guidelines are not covered in Appendix 6 or
Table A119, patients should be managed and treatments should be withheld or
discontinued as deemed appropriate by the investigator according to best medical 
judgment.  


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
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193/Protocol CO39612, Version 11
Table 9
Guidelines for Management of Patients Who Experience Adverse Events in AtezoIdasa Arm
Event
Action to Be Taken
IRRs, CRS, anaphylaxis, and 
hypersensitivity reactions
Guidelines for management of IRRs and CRS for atezolizumab are provided in Appendix 6.
For anaphylaxis precautions, see Appendix 5.
Hepatic Events
Hepatic event, Grade 1 (including 
ALT or AST 3ULN or bilirubin 
ULN to 1.5ULN)
Continue atezolizumab and idasanutlin.
Monitor LFTs until values resolve to within normal limits.
Hepatic event, Grade 2 (including 
ALT or AST 3.05.0ULN or 
bilirubin 1.53.0ULN)
All events:
Withhold idasanutlin.
If event improves to Grade 1 or better, resume idasanutlin at full dose.
Monitor LFTs until values resolve to within normal limits.
For suspected immune-mediated events that recur or persist > 5 days:  Withhold atezolizumab 
for up to 12 weeks after event onset. a, b
Initiate 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
Hepatic event, Grade 3 or 4 
(including ALT or AST 5.0ULN; 
and/or bilirubin 3.0ULN)
Permanently discontinue atezolizumab and idasanutlin and contact Medical Monitor. c
Consider patient referral to GI specialist for evaluation and liver biopsy to establish etiology of 
hepatic injury.
Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.
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.


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
Table 9
Guidelines for Management of Patients Who Experience Adverse Events in AtezoIdasa Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
194/Protocol CO39612, Version 11
Event
Action to Be Taken
Gastrointestinal Events
Diarrhea or colitis, Grade 1
Continue atezolizumab and idasanutlin.
Rule out other or concomitant causes, including, medications, malabsorption/lactose intolerance, 
fecal impaction, and dietary supplements high in fiber.
Dietary measures:  Discontinue all lactose-containing products, alcohol, and high-osmolar 
supplements; instruct patients to eat frequent small meals (e.g., bananas, rice, apples, and toast).
Initiate loperamide treatment as per institutional practice
- Suggested initial dose of 4 mg followed by 2 mg every 4 hours or after every unformed stool up to 
a maximum dose of 16 mg/day
- Recommend continuation of loperamide treatment until diarrhea free for 24 hours
If event persists for 24 hours, test for C. difficile infection.  If patient has a confirmed infection, 
follow C. difficile infection guidelines below.
Endoscopy is recommended if symptoms persist for > 7 days.
Monitor closely.


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
Table 9
Guidelines for Management of Patients Who Experience Adverse Events in AtezoIdasa Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
195/Protocol CO39612, Version 11
Event
Action to Be Taken
Diarrhea or colitis, Grade 2
Withhold atezolizumab for up to 12 weeks after event onset. a, b  Continue idasanutlin.
Rule out other or concomitant causes, including, medications, malabsorption/lactose intolerance, 
fecal impaction, and dietary supplements high in fiber.
Dietary measures:  Discontinue all lactose-containing products, alcohol, and high-osmolar 
supplements; instruct patients to eat frequent small meals (e.g., bananas, rice, apples, and toast).
Initiate loperamide treatment as per institutional practice
- Suggested initial dose of 4 mg followed by 2 mg every 4 hours or after every unformed stool up to 
a maximum dose of 16 mg/day
- Recommend continuation of loperamide treatment until diarrhea free for 24 hours
If event persists for more than 24 hours, test for C. difficile infection.  If patient has a confirmed 
infection, follow C. difficile infection guidelines below.
If event persists for more than 24 hours and patient experiences any additional symptoms (e.g., 
blood and/or mucus in stools, abdominal pain and cramps, dehydration), referral to a GI specialist is 
recommended for further evaluation, including biopsy.
If event persists after 48 hours of treatment with loperamide, consider second-line agents (e.g., 
diphenoxylate and atropine, octreotide, budesonide, or tincture of opium).
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, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently 
discontinue atezolizumab and contact Medical Monitor. c


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
Table 9
Guidelines for Management of Patients Who Experience Adverse Events in AtezoIdasa Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
196/Protocol CO39612, Version 11
Event
Action to Be Taken
Diarrhea or colitis, Grade 3
Withhold atezolizumab for up to 12 weeks after event onset. a, b  Withhold idasanutlin until event has 
improved to Grade 1 or better.
Dietary measures:  Discontinue all lactose-containing products, alcohol, and high-osmolar 
supplements; instruct patients to eat frequent small meals (e.g., bananas, rice, apples, and toast).
Monitor electrolytes daily (i.e., potassium, magnesium, calcium, and sodium).
Initiate loperamide treatment as per institutional practice
- Suggested initial dose of 4 mg followed by 2 mg every 4 hours or after every unformed stool up to 
a maximum dose of 16 mg/day
- Recommend continuation of loperamide treatment until diarrhea free for 24 hours
Test for C. difficile infection.  If patient has a confirmed C. difficile infection, follow guidelines below.
If colitis is suspected, or if event persists for more than 24 hours, 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, resume atezolizumab.b  If event resolves to Grade 1 or better 
within 28 days, resume idasanutlin with a 50-mg dose reduction (lowest idasanutlin dose is 100 mg), 
with continued supportive care or prophylaxis.
If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently 
discontinue atezolizumab and contact Medical Monitor. c
If event does not resolve to Grade 1 or better while withholding idasanutlin and with provision of 
maximal supportive care by 28 days, permanently discontinue idasanutlin and contact Medical 
Monitor.


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
Table 9
Guidelines for Management of Patients Who Experience Adverse Events in AtezoIdasa Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
197/Protocol CO39612, Version 11
Event
Action to Be Taken
Diarrhea or colitis, Grade 3 
(recurrent)
If Grade 3 diarrhea recurs despite provision of supportive care and idasanutlin dose reduction, 
withhold idasanutlin until the diarrhea resolves to Grade 1 or better.  Follow atezolizumab 
management guidelines for Grade 3 events.
If event resolves to Grade 1 or better within 28 days, then the idasanutlin dose will be re-introduced 
at the previously reduced dose (lowest idasanutlin dose is 100 mg).
If event does not resolve to Grade 1 or better within 28 days, idasanutlin should be permanently 
discontinued.
If the diarrhea recurs at Grade 3 after the second idasanutlin reintroduction, idasanutlin should be 
permanently discontinued.
Diarrhea or colitis, Grade 4
Permanently discontinue atezolizumab and idasanutlin and contact Medical Monitor. c
Test for C. difficile infection.  If patient has a confirmed infection, follow C. difficile infection 
guidelines below.
Monitor electrolytes daily (i.e., potassium, magnesium, calcium, and sodium).
Administer IV fluids as clinically indicated and aim at all times for electrolyte correction.
If the patient is currently receiving loperamide at the maximum recommended daily dose 
(i.e., 16 mg/24 hours), consider second-line agents (i.e., diphenoxylate, atropine, octreotide, 
budesonide, or tincture of opium).
Refer patient to GI specialist for evaluation and confirmation 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.


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
Table 9
Guidelines for Management of Patients Who Experience Adverse Events in AtezoIdasa Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
198/Protocol CO39612, Version 11
Event
Action to Be Taken
Clostridium difficile infection
If loperamide at the maximum recommended daily dose (i.e., 16 mg/24 hours) does not improve the 
severity of diarrhea within 24 hours, test for C. difficile toxin and toxin-producing C. difficile in stool.
Consider clinically appropriate empirical therapy before microbiological evidence is found, such as 
the following:
- Metronidazole:  If the initial episode is mild CDI, administer 500 mg orally, three times daily for 
10–14 days.
- Vancomycin:  If recurrent disease is suspected or moderate to severe CDI is present, administer 
125 mg orally four times daily for 10–14 days.
Once a C. difficile infection is confirmed, perform the following:
Discontinue unnecessary antimicrobial therapy.
Maintain adequate replacement of fluid and electrolytes.
Avoid any anti-motility medications/dietary supplements.
Use of proton pump inhibitors should be reviewed, as it has been shown to increase CDI 
susceptibility (Garey et al. 2008; Janarthanan et al. 2012).
Discontinue loperamide, if therapy is still ongoing.
Administer vancomycin as the preferred antibiotic of choice (125 mg orally four times daily for 10–14 
days or 500 mg four times daily for 10 days).  If CDI is severe or recurs, administer fidaxomicin 
(200 mg twice daily for 10 days) as an alternative to vancomycin.
Vomiting, Grade 1, 2, or 3 
Continue atezolizumab and idasanutlin.
If vomiting occurs within 15 minutes of taking idasanutlin and all expelled tablets are still intact, 
another dose may be given and the second dose should be noted in the medication diary. 
Otherwise, no replacement dose is to be given.
Vomiting, Grade 4
Permanently discontinue idasanutlin and atezolizumab and contact Medical Monitor. c
Pulmonary Events
Pulmonary event, Grade 1
Continue atezolizumab and idasanutlin and monitor closely. 


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
Table 9
Guidelines for Management of Patients Who Experience Adverse Events in AtezoIdasa Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
199/Protocol CO39612, Version 11
Event
Action to Be Taken
Re-evaluate on serial imaging. 
Consider patient referral to pulmonary specialist.
For Grade 1 pneumonitis, consider withholding atezolizumab.
Pulmonary event, Grade 2
Withhold atezolizumab for up to 12 weeks and idasanutlin for up to 56 days after event onset.. a, b
Refer patient to pulmonary and infectious disease specialists and consider bronchoscopy or BAL. 
Initiate treatment with 12 mg/kg/day oral prednisone or equivalent, if there is no suspicion of 
pulmonary infection. 
If event resolves to Grade 1 or better, resume atezolizumab. b  If event resolves to Grade 1 or better, 
resume idasanutlin with a 50-mg dose reduction (lowest idasanutlin dose is 100 mg).
If event does not resolve to Grade 1 or better while withholding atezolizumab and idasanutlin, 
permanently discontinue atezolizumab and idasanutlin and contact Medical Monitor. c
For recurrent events, or events with no improvement after 4872 hours of corticosteroids, treat as 
a Grade 3 or 4 event.
Pulmonary event, Grade 3 or 4
Permanently discontinue atezolizumab and idasanutlin and contact Medical Monitor. c
Bronchoscopy or BAL is recommended. 
Initiate treatment with 12 mg/kg/day IV methylprednisolone, if there is no suspicion of pulmonary 
infection. 
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.
Hematologic Toxicity
General guidance
Due to the potential for myelosuppression with idasanutlin, standard precautions for neutropenia, 
thrombocytopenia, and anemia will be used for patients in this trial.
Frequent blood monitoring is strongly recommended.  Institutional guidelines for use of growth factor 
support, transfusions, and antibiotics should be followed with consideration for prohibited 


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
Table 9
Guidelines for Management of Patients Who Experience Adverse Events in AtezoIdasa Arm (cont.)
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200/Protocol CO39612, Version 11
Event
Action to Be Taken
medications.
Hematologic toxicity, Grade 1
and 2
Hb8 g/dL d
or
Nadir WBC2109/L (2000/L) d
or
Nadir ANC1 109/L (1000/L) d
or
Nadir platelets 50109/L
(50,000/L) d
Continue idasanutlin and atezolizumab.
Hematologic toxicity, Grade 3
and 4
Hb8 g/dL d
or
Nadir WBC2109/L (2000/L) d
or
Nadir ANC1 109/L (1000/L) d
or
Nadir platelets 50109/L
(50,000/L) d
or
Febrile neutropenia
First occurrence:
Withhold idasanutlin and atezolizumab. a
Administer RBCs or platelets as required.
Idasanutlin:  If event improves to Grade 1 or better within 56 days, and platelet count is 100109/L 
(100,000/mL), resume idasanutlin with a 50-mg dose reduction (lowest idasanutlin dose is 100 mg).  
If not, permanently discontinue idasanutlin. 
Atezolizumab:  If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab. a  If not, 
permanently discontinue atezolizumab.
Second occurrence:
Follow guidelines for the first occurrence for atezolizumab.
Permanently discontinue idasanutlin.
Thrombocytopenia, Grade 3 or 4 of 
any duration if associated with 
Grade 3 bleeding
Permanently discontinue idasanutlin.
Idasanutlin-related toxicities not described above


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
Table 9
Guidelines for Management of Patients Who Experience Adverse Events in AtezoIdasa Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
201/Protocol CO39612, Version 11
Event
Action to Be Taken
Grade 1 or 2
Continue idasanutlin and atezolizumab.
Grade 3
First occurrence:
Withhold idasanutlin.  Continue atezolizumab.
If event resolves to Grade 1 or better within 56 days, resume idasanutlin with a 50-mg dose 
reduction (lowest idasanutlin dose is 100 mg).  If not, permanently discontinue idasanutlin e.
Second occurrence:
Permanently discontinue idasanutlin.  Atezolizumab may be continued at the discretion of the 
investigator per medical judgement.
Grade 4
Permanently discontinue idasanutlin.  Atezolizumab may be continued at the discretion of the 
investigator per medical judgement.
Atezolizumab-related toxicities not described above
Grade 1 or 2
Follow guidelines for atezolizumab in Appendix 6.
Continue idasanutlin.
Grade 3
Follow guidelines for atezolizumab in Appendix 6.
Withhold idasanutlin.
If event resolves to Grade 2 or better within 56 days, resume idasanutlin.  If not, permanently 
discontinue idasanutlin.e
Grade 4
Follow guidelines for atezolizumab in Appendix 6.
Withhold idasanutlin.
If event resolves to Grade 2 or better within 56 days, and if Medical Monitor agrees, resume 
idasanutlin.  If not, permanently discontinue idasanutlin.
BALbronchoscopic alveolar lavage; CDIC.difficile infection; CRS cytokine release syndrome; GIgastrointestinal; IRRinfusion-related 
reaction; ULNupper limit of normal. 


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
Table 9
Guidelines for Management of Patients Who Experience Adverse Events in AtezoIdasa Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
202/Protocol CO39612, Version 11
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 based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone before atezolizumab 
can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-mediated event.  
The decision to re-challenge patients with atezolizumab should be based on investigator's assessment of benefitrisk and documented by the 
investigator (or an appropriate delegate).  The Medical Monitor is available to advise as needed.
d Nadir of the prior cycle. 
e If the investigator believes the patient is likely to derive clinical benefit, idasanutlin can be resumed after being withheld for 56 days.  The 
Medical Monitor is available to advise as needed.


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
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203/Protocol CO39612, Version 11
A115.2
ADVERSE EVENTS OF SPECIAL INTEREST FOR ATEZOIDASA 
ARM (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 in the protocol body for reporting instructions).  Adverse events of special 
interest for the AtezoIdasa arm are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7 in the protocol body) 

Suspected transmission of an infectious agent by the study treatment, as defined 
below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of study treatment is suspected.

Pneumonitis

Colitis

Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis

Hepatitis, including AST or ALT 10 upper limit of normal

Systemic lupus erythematosus

Neurologic disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis

Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, influenza-like illness, HLH, and MAS

Nephritis

Ocular toxicities (e.g., uveitis, retinitis, and optic neuritis)

Myositis

Myopathies, including rhabdomyolysis

Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Vasculitis

Autoimmune hemolytic anemia

Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis)


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
204/Protocol CO39612, Version 11

Grade 3 thrombocytopenia or Grade 2 thrombocytopenia if associated with 
bleeding

Grade 3 neutropenia, including febrile neutropenia 

Grade 2 diarrhea 

Grade 2 C. difficile infection
A115.3
REPORTING REQUIREMENTS FOR PREGNANCIES IN 
ATEZOIDASA ARM
A115.3.1 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 atezolizumab and within 6 weeks after the last dose of idasanutlin.  A paper 
Clinical Trial Pregnancy Reporting Form should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  The investigator should discontinue study treatment and counsel 
the patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the
course and outcome of the pregnancy becomes available.  
A115.3.2 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 two weeks before the first dose 
of idasanutlin treatment, during the study, or within 90 days after the last dose of 
idasanutlin.  A paper Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Attempts should be made to 
collect and report details of the course and outcome of any pregnancy in the partner of a 
male patient exposed to idasanutlin.  When permitted by the site, 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.  If the authorization has been signed, 
the investigator should submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  An 
investigator who is contacted by the male patient or his pregnant partner may provide 


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
205/Protocol CO39612, Version 11
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the investigator and/or obstetrician.
A115.3.3 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 in the protocol body).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
A115.3.4 Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment should be classified as a serious adverse event, recorded on the Adverse 
Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2 in the protocol body).


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
206/Protocol CO39612, Version 11
A116. SCHEDULE OF ACTIVITIES AND SAMPLE COLLECTION FOR ATEZOIDASA ARM
Table 10: Schedule of Activities for AtezoIdasa Arm
Assessment/
Procedure
Stage 1 
Screen.
Treatment Cycles (28-Day Cycles) a
Stage 2 
Screen. c
or Treat. 
Discon. d
Follow-Up d
Cycles 1 b
Cycle 2
Cycles 3
Every 
3 Months
(7 days)
D –28 to –1
D1
D5
D15 
(3d)
D22 
(3d)
D1 
(3d)
D5 
D15 
(3d)
D22 
(3d)
D1 
(3d)
D15 
(3d)
Molecular profile of 
CRC (if available)
See
Appendix 15
Whenever updated information becomes available
Vital signs e
x
x
x
x
x
x
x
x
x
x
x
Weight
x f
x f
x f
x
Complete physical 
examination g
x
Limited physical 
examination h
x f
x f
x f
x f
x f
x f
x f
x f
x f
x f
ECOG 
Performance 
Status
x f
x f
x f
x
ECG i
x f
x f
xj
Hematology k
x l, m
x l
x l
x l
x l
x l
x l
x l
x l
x l
x
Chemistry n
x l, m
x l
x l
x l
x l
x l
x l
x l
x l
x l
x
Coagulation (INR 
and aPTT)
xj


Appendix 11:  Study Details Specific to AtezoIdasa Arm
Table 10: Schedule of Activities for AtezoIdasa Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
207/Protocol CO39612, Version 11
Assessment/
Procedure
Stage 1 
Screen.
Treatment Cycles (28-Day Cycles) a
Stage 2 
Screen. c
or Treat. 
Discon. d
Follow-Up d
Cycles 1 b
Cycle 2
Cycles 3
Every 
3 Months
(7 days)
D –28 to –1
D1
D5
D15 
(3d)
D22 
(3d)
D1 
(3d)
D5 
D15 
(3d)
D22 
(3d)
D1 
(3d)
D15 
(3d)
TSH, free T3 (or 
total T3), and free 
T4 o
x l
x l, o
Viral serology (if 
applicable)
x j, p
C-reactive protein
x j
Plasma CEA q
x l
x l, q
LDH
x j
Pregnancy test r
x l,m
x l
x l
x s
x r
Urinalysis t
See
Appendix 15
Perform as clinically indicated
x j, s
Serum 
autoantibody 
sample u
Perform if a patient experiences a suspected immune-mediated adverse event
x j
Serum or plasma 
PK sample
Refer to Table 11 below
Serum ADA 
sample
Refer to Table 11 below


Appendix 11:  Study Details Specific to AtezoIdasa Arm
Table 10: Schedule of Activities for AtezoIdasa Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
208/Protocol CO39612, Version 11
Assessment/
Procedure
Stage 1 
Screen.
Treatment Cycles (28-Day Cycles) a
Stage 2 
Screen. c
or Treat. 
Discon. d
Follow-Up d
Cycles 1 b
Cycle 2
Cycles 3
Every 
3 Months
(7 days)
D –28 to –1
D1
D5
D15 
(3d)
D22 
(3d)
D1 
(3d)
D5 
D15 
(3d)
D22 
(3d)
D1 
(3d)
D15 
(3d)
Plasma, serum, 
and PBMC 
biomarker samples
Refer to Table 11 below
Blood sample for 
RBR
(optional) v
x
Tumor biopsy
x w
Tumor biopsy 
(optional)
x x
Tumor response 
assessments
See
Appendix 15
x y, z, aa
Concomitant
medications bb
x
x
x
x
x
x
x
x
x
x
x
Adverse events cc
x
x
x
x
x
x
x
x
x
x
x cc
x
Atezolizumab 
administration dd, ee
x
x
x
x
x
x
Dispense
idasanutlin ee, ff
x
x
x


Appendix 11:  Study Details Specific to AtezoIdasa Arm
Table 10: Schedule of Activities for AtezoIdasa Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
209/Protocol CO39612, Version 11
Assessment/
Procedure
Stage 1 
Screen.
Treatment Cycles (28-Day Cycles) a
Stage 2 
Screen. c
or Treat. 
Discon. d
Follow-Up d
Cycles 1 b
Cycle 2
Cycles 3
Every 
3 Months
(7 days)
D –28 to –1
D1
D5
D15 
(3d)
D22 
(3d)
D1 
(3d)
D5 
D15 
(3d)
D22 
(3d)
D1 
(3d)
D15 
(3d)
Study drug 
accountability gg
x
x
x
Survival follow-up 
and anti-cancer 
treatment
x hh
ADAanti-drug antibody; Atezo Idasaatezolizumab plus idasanutlin; CT computed tomography; D, dDay, day; Discondiscontinuation; 
ECOGEastern Cooperative Oncology Group; eCRF electronic Case Report Form; HBcAbhepatitis B core antibody; HBsAghepatitis B 
surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; MRImagnetic resonance imaging; PKpharmacokinetic; RBRResearch 
Biosample Repository; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; Screen screening; T3triiodothyronine; 
T4thyroxine; Treat.treatment; TSHthyroid-stimulating hormone.
Note:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.
a If a visit is precluded because of a holiday, vacation, or other circumstance, it may occur outside of the specified window.
b It is recommended that treatment be initiated no later than 7 days after randomization.
c Patients who experience loss of clinical benefit defined as (1) confirmed disease progression or (2) lack of continued benefit as determined 
by the investigator (see Section 3.1.1 in the protocol body for details) or unacceptable toxicity may be given the option of receiving a 
different treatment combination during Stage 2 of the study (as outlined in Section 3.1.2 in the protocol body provided Stage 2 is open for 
enrollment) and will undergo screening assessments to determine eligibility.  Study details specific to the Stage 2 treatment regimens are 
provided in the appropriate appendix.  Written informed consent must be obtained before performing screening evaluations for Stage 2.
d Patients will return to the clinic for a Stage 2 screening or treatment discontinuation visit not more than 30 days after the last dose of study 
treatment.  The visit at which loss of clinical benefit is confirmed may be used as the Stage 2 screening or treatment discontinuation visit.  
Treatment discontinuation assessments must be performed for all patients, regardless of whether they enter Stage 2.  Patients who do not 
enter Stage 2 will undergo follow-up assessments after completing the treatment discontinuation visit.


Appendix 11:  Study Details Specific to AtezoIdasa Arm
Table 10: Schedule of Activities for AtezoIdasa Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
210/Protocol CO39612, Version 11
e Vital signs include respiratory rate, pulse rate, pulse oximetry, systolic and diastolic blood pressure while the patient is in a seated position, 
and temperature.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  Refer to 
Section A114.1.2 for details related to vital signs monitoring during atezolizumab infusions. 
f
Assessment may be performed within 24 hours prior to dosing during the treatment period.
g Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.  Record new or worsened clinically significant abnormalities on the Adverse Event 
eCRF.
h Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  Record 
abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.administered.  The skin examination 
should be extended according to medical need.
i
ECGs from Cycles 2 onward are mandatory only for patients with significant ECG abnormalities at prior timepoints or for patients who have 
QTc prolongation (30 ms) at any timepoint during study or as clinically indicated.  It is recommended that patients be resting in a supine 
position for at least 10 minutes prior to ECG recording.
j
Assessments to be performed only for patients undergoing Stage 2 screening.
k Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells).
l
Laboratory tests must be performed within 96 hours prior to dosing during the treatment period.
m If screening laboratory assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated.
n Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (per standard of care for the region), sodium, potassium, 
magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, and AST.  
CPK will be performed only on Day 1 of each cycle and at treatment discontinuation.
o TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed at screening and on Day 1 of Cycle 1 and 
every third cycle thereafter (i.e., Cycles 4, 7, 10, etc.).
p At Stage 2, patients without a prior positive HIV test result will undergo an HIV test, unless not permitted per local regulations.  Patients will 
also be tested for HBsAg, total HBcAb, and HCV antibody.  If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient has an HBV infection.  If a patient has a positive HCV 
antibody test at screening, an HCV RNA test must also be performed to determine if the patient has an active HCV infection. 
q CEA will be assessed on Day 1 of Cycle 1 and every 2 cycles thereafter (i.e., Cycles 3, 5, 7, etc.) until disease progression.
r
All women of childbearing potential will have a serum pregnancy test at screening.  Urine or serum pregnancy tests will be performed at 
specified subsequent visits and at 3 months and 6 months after treatment discontinuation.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test.


Appendix 11:  Study Details Specific to AtezoIdasa Arm
Table 10: Schedule of Activities for AtezoIdasa Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
211/Protocol CO39612, Version 11
s Screening laboratory test results must be obtained within 14 days prior to the initiation of study treatment.
t
Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted.
u Autoantibody analysis includes anti-nuclear antibody, antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and 
perinuclear anti-neutrophil cytoplasmic antibody.
v Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate.  RBR sample should be collected prior to study treatment.
w Patients will undergo tumor biopsy sample collection at the time of unacceptable toxicity or loss of clinical benefit as determined by the 
investigator (see Section 3.1.1 for details), if deemed clinically feasible by the investigator.  Biopsies should be performed within 40 days 
after determination of unacceptable toxicity or loss of clinical benefit, or prior to the next anti-cancer therapy, whichever is sooner.  Patients 
enrolled in the mandatory serial-biopsy arm (see Section 3.1.1.2 in the protocol body) will undergo tumor biopsy sample collection 4 weeks 
(7 days) after treatment initiation (if deemed clinically feasible by the investigator).  See Section 4.5.7 in the protocol body for tissue 
sample requirements.
x Patients who consent to optional biopsies will undergo tumor biopsy sample collection 4 weeks (7 days) after treatment initiation, if 
deemed clinically feasible and may undergo additional on-treatment biopsies at any other time during Stage 1 or Stage 2 at the 
investigator's discretion.
y Patients will undergo tumor assessments at baseline, every 6 weeks (1 week) for the first 48 weeks following treatment initiation, and 
every 12 weeks (2 weeks) thereafter, regardless of dose delays, until loss of clinical benefit defined as (1) confirmed disease progression 
or (2) lack of continued benefit as determined by the investigator (see Section 3.1.1 in the protocol body for details).  Thus, tumor 
assessments are to continue according to schedule in patients who discontinue treatment for reasons other than loss of clinical benefit, 
even if they start new nonprotocol-specified anti-cancer therapy.
z All measurable and/or evaluable lesions identified at baseline should be re-assessed at subsequent tumor evaluations according to the 
schedule described above.  Brain metastases identified at baseline that have been treated with radiotherapy or surgery will not be 
considered measurable or evaluable unless there is suspected disease progression in the brain (i.e., the patient becomes symptomatic).  
Thus, subsequent head CT scans are not required unless clinically indicated.  The same radiographic procedures used to assess disease 
sites at screening should be used for subsequent tumor assessments (e.g., the same contrast protocol for CT scans).  
aa For patients who undergo screening for Stage 2, tumor assessments performed prior to or at the time of loss of clinical benefit during 
Stage 1 may serve as baseline assessments for Stage 2, provided the tumor assessments are performed within 28 days prior to initiation 
of Stage 2 treatment (i.e., Day 1 of Cycle 1).
bb Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated study treatment from 7 days prior to initiation of study treatment until the 


Appendix 11:  Study Details Specific to AtezoIdasa Arm
Table 10: Schedule of Activities for AtezoIdasa Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
212/Protocol CO39612, Version 11
treatment discontinuation visit.
cc After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a 
protocol-mandated intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 30 days after
the last dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first.  Serious adverse events and 
adverse events of special interest will continue to be reported until 135 days after the last dose of study treatment or until initiation of new 
systemic anti-cancer therapy, whichever occurs first.  After this period, all deaths, regardless of cause, should be reported.  In addition, the 
Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior exposure 
to study treatment (see Section 5.6 in the protocol body).  The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws 
consent.  Every effort should be made to follow all serious adverse events considered to be related to study treatment or trial-related 
procedures until a final outcome can be reported.
dd Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Days 1 and 15 of each 28-day cycle.  The initial dose of 
atezolizumab will be delivered over 60 (15) minutes.  Subsequent infusions will be delivered over 30 (10) minutes if the previous 
infusion was tolerated without infusion-associated adverse events, or 60 (15) minutes if the patient experienced an infusion-associated 
adverse event with the previous infusion.  
ee Treatment will continue until unacceptable toxicity or loss of clinical benefit defined as (1) confirmed disease progression or (2) lack of 
continued benefit as determined by the investigator (see Section 3.1.1 in the protocol body for details).
ff Premedication is required prior to idasanutlin administration (see Section A114.1.2.2 for details).  Patients will receive idasanutlin orally 
once a day on Days 15 of each cycle.  Each idasanutlin dose should be taken approximately 24 hours apart, once in the morning.  On 
Day 1 of each cycle, patients should take their tablets in the clinic prior to the atezolizumab infusion, as directed by site personnel. 
gg Medication diaries should be collected and reviewed, and unused medications should be collected for assessment of compliance.
hh After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and 
immunotherapy) will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months until death 
(unless the patient withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this 
request must be documented in the source documents and signed by the investigator.  If the patient withdraws from the study, the study 
staff may use a public information source (e.g., county records) to obtain information about survival status only. For an experimental arm in 
which all patients discontinued treatment and passed the safety follow-up window, as well as approximately 80% of patients discontinued 
the study, the Sponsor may conclude the arm (the remaining ~20% of patients will be discontinued from the study).


Appendix 11:  Study Details Specific to AtezoIdasa Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
213/Protocol CO39612, Version 11
Table 11 Schedule of Pharmacokinetic, Immunogenicity, and Biomarker 
Samples for AtezoIdasa Arm:  Preliminary and Expansion 
Phases
Visit
Time
Sample Type
Day 1 of Cycle 1
Prior to study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Idasanutlin PK (plasma) a

Biomarkers (plasma, serum, PBMC)

Biomarkers (PAXgene RNA)
30 (10) minutes after atezolizumab 
infusion

Atezolizumab PK (serum)
2 hours after idasanutlin dose

Idasanutlin PK (plasma) a
4 hours after idasanutlin dose

Idasanutlin PK (plasma) a
Day 5 of Cycle 1
Prior to study treatment

Idasanutlin PK (plasma) a
2 hours after idasanutlin dose

Idasanutlin PK (plasma) a
6 hours after idasanutlin dose

Idasanutlin PK (plasma) a

Biomarkers (PAXgene RNA)
Day 15 of Cycle 1
Prior to study treatment

Atezolizumab PK (serum)

Biomarkers (plasma, serum)
Day 1 of Cycle 2
Prior to study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Idasanutlin PK (plasma) a

Biomarkers (plasma, serum, PBMC)
Day 5 of Cycle 2
6 hours after idasanutlin dose

Biomarkers (PAXgene RNA)
Day 1 of Cycle 3
Prior to study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)
Day 1 of Cycle 4
Prior to study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Idasanutlin PK (plasma) a

Biomarkers (plasma, serum)
Day 1 of Cycle 6
Prior to study treatment

Idasanutlin PK (plasma) a
Day 1 of Cycle 8
Prior to study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Idasanutlin PK (plasma) a

Biomarkers (plasma, serum)
Day 1 of Cycles 12 
and 16
Prior to study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Idasanutlin PK (plasma) a


Appendix 11:  Study Details Specific to AtezoIdasa Arm
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
214/Protocol CO39612, Version 11
Table 11 Schedule of Pharmacokinetic, Immunogenicity, and Biomarker 
Samples for AtezoIdasa Arm:  Preliminary and Expansion 
Phases (cont.)
Visit
Time
Sample Type
Treatment 
discontinuation visit 
(30 days after 
last dose)
At visit

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Idasanutlin PK (plasma) a

Biomarkers (plasma, serum)
ADAanti-drug antibody; Atezoatezolizumab; Idasaidasanutlin; PBMCperipheral blood 
mononuclear cell; PKpharmacokinetic.
Note:  Based on emerging safety and efficacy data, the number of PK, ADA, and/or biomarker 
samples may be reduced/removed and/or the timing of samples may be modified.
a Idasanutlin and its metabolite(s) will be tested.


Appendix 11:  Study Details Specific to AtezoIdasa Arm
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tumor microenvironments in melanoma. Nat Med 2018;24:117891.
Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on 
tumor-specific T cells as a mechanism of immune evasion: implications for tumor 
immunotherapy. Cancer Immunol Immunother 2005;54:30714.
Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T cell exhaustion: 
an update on implications for chronic infections and tumor evasion. Cancer 
Immunol Immunother 2007;56:73945.
Broz M, Binnewies M, Boldajipour B, et al. Dissecting the tumor myeloid compartment 
reveals rare activating antigen presenting cells, critical for T cell immunity. Cenacer 
Cell 2014;26:63852.
Butte MJ, Keir ME, Phamduy TB, et al. Programmed death-1 ligand 1 interacts 
specifically with the B7-1 costimulatory molecule to inhibit T cell responses. 
Immunity 2007;27:11122.
Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation 
immunotherapyinhibiting programmed death-ligand 1 and programmed death-1. 
Clin Cancer Res 2012;18:65807.
Coppé JP, Desprez PY, Krtolica A, et al. The senescence-associated secretory 
phenotype: the dark side of tumor suppression. Annu Rev Pathol 2010;5:99118.
Deng R, Bumbaca D, Pastuskovas CV, et al. Preclinical pharmacokinetics, 
pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 
monoclonal antibody, an immune checkpoint inhibitor. MAbs 2016;8:593603.
Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients 
with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-
label, phase 2 randomised controlled trial. Lancet 2016;387:183746.
Guo G, Yu M, Xiao W, et al. Local activation of p53 in the tumor microenvironment 
overcomes immune suppression and enhances antitumor immunity. Cancer Res 
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Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients 
with metastatic melanoma. N Engl J Med 2010;363:71123.
Hsu J, Jodgins JJ, Marathe M, et al. Contribution of NK cells to immunotherapy 
mediated by PD-1/PD-L1 blockade. J Clin Invest 2018;128:465468.
Iannello A, Thompson TW, Ardolino M, et al. p53-dependent chemokine production by 
senescent tumor cells supports NKG2D-dependent tumor elimination by natural 
killer cells. J Exp Med 2013;210:205769.


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Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for 
castration-resistant prostate cancer. N Engl J Med 2010;363:41122.
Kastenhuber ER and Lowe SW. Putting p53 in context. Cell 2017;170:106278.
Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. 
Annu Rev Immunol 2008;26:677704.
Kussie PH, Gorina S, Marechal V, et al. Structure of the MDM2 oncoprotein bound to the 
p53 tumor suppressor transactivation domain. Science 1996;274:94853.
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair 
deficiency. N Engl J Med 2015;372:250920.
Legitimo A, Consolini R, Failli A, et al. Dendritic cell defects in colorectal cancer. Hum 
Vaccin Immunother 2014;10:322435.
Liu Y, Cheng Y, Xu Y, et al. Increased expression of programmed cell death protein 1 on 
NK cells inhibits NK-cell-mediated anti-tumor function and indicates poor prognosis 
in digestive cancers. Oncogene 2017;614353.
Ribas and Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 
2018;359:135055.
Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following 
treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 
trial. Lancet 2016;387:190920.
Shangary S and Wang S. Targeting the MDM2-p53 interaction for cancer therapy. Clin 
Cancer Res 2008;14:531824.
Sharma MD, Rodriguez PC, Koehn BH, et al. Activation of p53 in immature myeloid 
precursor cells controls differentiation into Ly6cCD103monocytic antigen-
presenting cells in tumors. Immunity 2018;48:91106.
Shen H and Maki CG. P53 and p21(Waf1) are recruited to distinct PML-containing 
nuclear foci in irradiated and Nutlin-3a-treated U2OS cells. J Cell Biochem 
2010;111:128090.
Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small 
molecule antagonists of MDM2. Science 2004;303:8448.
Wade M, Li YC, and Wahl GM. MDM2, MDMX and p53 in oncogenesis and cancer 
therapy. Nat Rev Cancer 2013;13:8396.
Xue W, Zender L, Miething C, et al. Senescence and tumour clearance is triggered by 
p53 restoration in murine liver carcinomas. Nature 2007;445:65660.


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Yang J, Riella LV, Chock S, et al. The novel costimulatory programmed death ligand 
1/B7.1 pathway is functional in inhibiting alloimmune responses in vivo. J Immunol 
2011;187:11139. 


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Appendix 12
Study Details Specific to AtezoRegorafenib Arm 
TABLE OF CONTENTS
A121.
Background on AtezoRegorafenib Arm
A121.1 Background on Atezolizumab
A121.2 Background on Regorafenib
A122.
Rationale for AtezoRegorafenib Arm
A122.1 The PD-L1 Pathway
A122.2 Regorafenib as a Multi-Targeted Anti-Angiogenic and 
Immunomodulatory Agent
A122.3 Rationale for Combining Regorafenib with Checkpoint Inhibition
A122.4 BenefitRisk Assessment
A123.
Rationale for Dose and Schedule for AtezoReografenib Arm
A123.1 Rationale for Atezolizumab Dose and Schedule
A123.2 Rationale for Regorafenib Dose and Schedule
A124.
Materials and Methods Specific to AtezoRegorafenib Arm
A124.1 Treatment in AtezoRegorafenib Arm
A124.1.1 Formulation, Packaging, and Handling
A124.1.2 Dosage, Administration, and Compliance
A124.1.3 Stage 2 Treatment
A124.2 Concomitant Therapy for AtezoRegorafenib Arm
A124.2.1 Permitted Therapy for AtezoRegorafenib Arm
A124.2.2 Cautionary Therapy for AtezoRegorafenib Arm
A124.2.3 Prohibited Therapy for AtezoRegorafenib Arm
A124.3 Contraception Requirements for AtezoRegorafenib Arm
A125.
Assessment of Safety for AtezoRegorafenib Arm 
A125.1 Safety Plan for AtezoRegorafenib Arm
A125.1.1 Risks Associated with Atezolizumab 
A125.1.2 Risks Associated with Regorafenib 
A125.1.3 Risks Associated with Combination Use of Atezolizumab 
and Regorafenib 
A125.1.4 Management of Patients Who Experience Adverse 
Events in AtezoRegorafenib Arm
A125.2 Adverse Events of Special Interest for AtezoRegorafenib Arm 
(Immediately Reportable to the Sponsor) 
A125.3 Reporting Requirements for Pregnancies in AtezoRegorafenib Arm
A125.3.1 Pregnancies in Female Patients 
A125.3.2 Pregnancies in Female Partners of Male Patients 
A125.3.3 Abortions
A125.3.4 Congenital Anomalies/Birth Defects
A126.
Schedule of Activities and Sample Collection for AtezoRegorafenib Arm 


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A121 BACKGROUND FOR ATEZOREGORAFENIB ARM
A121.1
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated antibody 
mediated clearance of activated effector T cells.
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy.
Atezolizumab has been generally well tolerated.  Adverse events with potentially 
immune-mediated causes consistent with an immunotherapeutic agent, including rash, 
influenza like illness, endocrinopathies, hepatitis or transaminitis, pneumonitis, colitis, 
and myasthenia gravis, have been observed (see the Atezolizumab Investigator's 
Brochure for detailed safety results).  To date, these events have been manageable with 
treatment. 
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer, small-cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, 
and melanoma.
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies.
A121.2
BACKGROUND ON REGORAFENIB
Regorafenib is an orally administered multikinase inhibitor, which targets signaling 
pathways implicated in multiple tumor-promoting processes.  Its targets include the 
pro-angiogenic kinases, vascular endothelial growth factor receptor 1-3 (VEGFR 1-3) 
and tyrosine receptor kinase 2, and kinases promoting a pro-tumorigenic 
microenvironment, such as platelet-derived growth factor receptors and fibroblast growth 
factor.  This agent also inhibits the mutant oncogenic kinases KIT, RET, and B-RAF, as 
well as the growth factor receptor for macrophages colony stimulating factor 1 receptor 
(CSF-1R) (Wilhelm et al. 2010; Uitdehaag et al. 2014).  Regorafenib exhibited potent 


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tumor growth inhibition in nonclinical models, including colon tumor models (Wilhelm et 
al. 2010; Abou-Elkacem et al. 2013). 
Regorafenib conferred a survival benefit over best supportive care in patients with 
refractory metastatic colorectal cancer (mCRC) in randomized, double-blind, placebo-
controlled trials both in Western and Asian populations (Grothey et al. 2013; Li et al. 
2015).  The most common adverse events included handfoot syndrome, fatigue, 
diarrhea, hypertension, voice changes, oral mucositis, and rash/desquamation. 
Regorafenib is approved worldwide (under the tradename of Stivarga) for the treatment 
of patients with mCRC who previously received fluoropyrimidine-based, 
oxaliplatin-based, and irinotecan-based chemotherapy; prior anti-VEGF therapy; and, if 
patients have a KRAS wild-type tumour, previous anti-EGFR therapy.  It is also 
approved in Europe in unresectable or metastatic gastrointestinal (GI) tumours and in 
patients with hepatocellular carcinoma who were previously treated with sorafenib.
A122 RATIONALE FOR ATEZOREGORAFENIB ARM
A122.1
THE PD-L1 PATHWAY 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies (Hodi et al. 
2010; Kantoff et al. 2010; Chen et al. 2012).
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that downregulates immune responses through binding 
to its two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor expressed on T cells 
following T-cell activation, and expression is sustained in states of chronic stimulation 
(Blank et al. 2005; Keir et al. 2008).  B7-1 is a molecule expressed on antigen presenting 
cells and activated T cells.  Binding of PD-L1 to PD-1 and B7-1 inhibits T-cell 
proliferation and activation, cytokine production, and cytolytic activity, leading to the 
functional inactivation or exhaustion of T cells (Butte et al. 2007; Yang et al. 2011).  
Overexpression 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 pathway represents an attractive strategy for restoring tumor 
specific T-cell immunity.
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed standard-of-care therapies.  Objective 
responses have been observed across a broad range of malignancies, including NSCLC, 
urothelial carcinoma, renal cell carcinoma, melanoma, CRC, head and neck cancer, 


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gastric cancer, breast cancer, and sarcoma (see the Atezolizumab Investigator's 
Brochure for detailed efficacy results).  
Early clinical data had shown encouraging results with the antiPD-1 checkpoint inhibitor 
pembrolizumab as a single agent in patients with mCRC assessed as having high 
microsatellite instability (MSI-H) status but not with microsatellite stable (MSS) status 
(Le et al. 2015).  These data resulted in the May 2017 approval of pembrolizumab in 
adult and pediatric patients with tumors characterized as MSI-H or deficient for mismatch 
repair genes based on objective response rate (ORR) and durability of the response.  
ORR was similar irrespective of whether patients were diagnosed with CRC (36%) or a 
different cancer type (46% across the 14 other MSI-H cancer types).  Similar response 
rates were observed in patients with second line or later mCRC enrolled in a Phase Ia 
study investigating atezolizumab as single agent (Roche Study PCD4989g) and a Phase 
Ib study investigating the combination of atezolizumab plus bevacizumab (Roche Study 
GP28328, Arm A).  In Study PCD4989g, there was 1 responder reported in 14 patients 
with MSS status per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 
v1.1).  In the 10 patients with MSI-H status enrolled in Study GP28328, the investigator 
assessed confirmed ORR per RECIST v1.1 was 40% (95% CI: 12.2, 73.8), with all 
4 responders having partial responses.  No objective responses were seen in the 
14 patients with MSS tumors.
A122.2
REGORAFENIB AS A MULTI-TARGETED ANTI-ANGIOGENIC 
AND IMMUNOMODULATORY AGENT
Consistent with its inhibitory activity on VEGFR 1-3, regorafenib demonstrated stronger 
anti-angiogenic activity compared with a selective anti-VEGFR2 antibody in a mouse 
colon tumor model (Abou-Elkacem et al. 2013).  In addition to its inhibitory effect on 
angiogenesis, regorafenib also displayed immunomodulatory effects in nonclinical 
models (Abou-Elkacem et al. 2013; Hoff et al. 2017).  Regorafenib treatment reduced 
tumor associated macrophage abundance in both MC38 and CTC26 colon tumors and 
also promoted their switch from the pro-tumorigenic M2 phenotype to the anti-
tumorigenic M1 phenotype in colon tumor models (Abou-Elkacem et al. 2013; Hoff et al. 
2017).  These effects could result from the counteracting of the immune suppressive 
properties of VEGF signaling (Chen and Hurwitz 2018) or from the blockade CSF1-
Rdependent signaling (Hoff et al. 2017), which positively regulates macrophage 
migration, differentiation, and survival (DeNardo and Ruffell 2019).
A122.3
RATIONALE FOR COMBINING REGORAFENIB WITH 
CHECKPOINT INHIBITION
The immune suppressive role of VEGF is now well established, and the combination of 
anti-VEGF therapies with blockade of the PD-L1/PD-1 axis has shown synergy in 
nonclinical models and has resulted in positive outcomes in Phase I to III clinical studies 
(Chen and Hurwitz 2018).  In addition, M2-macrophages are considered a central driver 


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of the immunosuppressive tumor microenvironment through their ability to suppress DC 
differentiation and function and T-cell effector function.  As a result, macrophage 
depletion can unleash CD8T-cell response and increase the efficacy of checkpoint 
blockade in nonclinical tumor models (DeNardo and Ruffell 2019).  Therefore, among 
the multi-targeted mechanisms of action of regorafenib, blockade of VEGF and CSF-1R 
signaling is expected to show combinatorial efficacy with checkpoint inhibition (CPI).  
Accordingly, the combination of regorafenib with antiPD-1 blockade showed superior 
anti-tumor activity compared with either individual agent in murine colon tumor models 
(Hoff et al. 2017).
Clinical data from the REGONIVO trial presented at ASCO 2019 (Fukuoka et al. 2019) 
showed promising results when combining the standard-of-care treatment regorafenib 
with the antiPD-1 checkpoint inhibitor antibody nivolumab in patients with advanced, 
metastatic colorectal or gastric cancer (GC).  An objective tumor response was observed 
in 19 patients (38%), including 11 patients with MSS GC, 7 patients with MSS CRC, and 
1 patient with MSI-H CRC, with corresponding ORRs of 44% in GC and 29% in MSS 
CRC.  At a median follow-up of 8.0 months, the median PFS time was 6.3 months.  
These outcomes outperform the clinical activity of regorafenib and anti-PD1 antibody 
when used as a single-agent therapy in MSS mCRC where ORRs of 2% and 0% were 
observed, respectively (Grothey et al. 2013; Le et al. 2015; Li et al. 2015; Eng et al. 
2019).  Taken together, these data suggest a synergy between PD-1 blockade and 
regorafenib.  The regorafenib plus nivolumab combination is currently being investigated 
further in a randomized Phase III trial compared with single-agent regorafenib in patients 
with MSS mCRC.
These data provide a rationale to further investigate combination strategies of 
regorafenib with checkpoint inhibitors, such as atezolizumab, in patients with MSS CRC. 
A122.4
BENEFITRISK ASSESSMENT
This study will enroll patients with mCRC who have become refractory to first- and 
second-line standard therapies.  This patient population has a median OS of less than 
9 months with currently available treatments.  Treatment options have shown limited 
efficacy and are often poorly tolerated. 
Despite the success of single-agent CPI in the MSI-H patient population, the vast 
majority of patients with CRC have MSS tumors and do not respond to single-agent CPI, 
highlighting the need for safe and effective combination treatments.  In addition, the 
benefit of single-agent regorafenib over best supportive care is limited.  Therefore, there 
remains a great need for investigating new cancer immunotherapy combinations to 
improve the outcome of this difficult-to-treat patient population.


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The most frequently observed adverse drug reactions (30%) in patients receiving 
regorafenib are pain, handfoot skin reaction, asthenia/fatigue, diarrhea, decreased 
appetite and food intake, hypertension, and infection.  These toxicities occur early and 
may be dose-dependent (Grothey 2019).  A randomized Phase II study (the ReDOS trial) 
showed that using a weekly dose-escalation strategy (from 80 mg/day to 160 mg/day) 
enabled patients to stay on treatment longer and decreased the incidence of Grade 3 
and 4 toxicities when compared with using the approved starting dose of 160 mg/day 
(Bekaii-Saab et al. 2019).  
In the dose-escalation cohort of the REGONIVO study, patients were treated with 80-mg, 
120-mg, or 160-mg doses of regorafenib once per day for 21 days in a 28-day cycle plus
3 mg of nivolumab every 2 weeks.  Treatment-related adverse events (all grades) were 
reported in 100% of patients across the 3 dose groups.  The rate of Grade 3 treatment-
related adverse events was 40%.  The most common Grade 3 treatment-related 
adverse events were rash (12%), proteinuria (12%), palmar-plantar erythrodysesthesia 
(10%), and liver dysfunction (6%).  In patients who received regorafenib at the 80-mg 
dose, the rate of Grade 3 treatment-related adverse events was 27% compared with 44% 
in those who received the 120-mg dose.  These toxicities were considered to be 
manageable by the investigators and were balanced with the unprecedented efficacy 
signal in this heavily pre-treated patient population.  The dose of regorafenib that is 
planned to be administered in this study is 120 mg/day, which is the maximum tolerated 
dose (MTD) that was identified in the REGONIVO study.  Moreover, dose escalation 
from 80 mg/day to 120 mg/day during Cycle 1 will be allowed in order to improve the 
safety profile of regorafenib in combination with CPI. 
Safety data are available for single-agent atezolizumab in patients with solid tumors, 
including CRC.  Potential overlapping toxicities with regorafenib may occur within the 
system organ class of GI, hepatobiliary, cardiac, skin, nervous system and blood and 
lymphatic system disorders.  The relevant corresponding overlapping toxicities of 
atezolizumab include immune-related colitis, hepatitis, myocarditis, skin rash, 
meningoencephalitis, and thrombocytopenia.  Given the distinct mechanisms of action of 
atezolizumab and regorafenib, it is anticipated that adverse reactions observed with 
either agent will not result in synergistic toxic effects.  In summary, the investigation of 
the safety of each single agent in patients with solid tumors and of the combination of 
regorafenib with the antiPD-1 antibody nivolumab have not revealed findings that would 
prohibit the investigation of the regorafenib and atezolizumab combination in the setting 
of a Phase Ib/II study.  
Considering the potentially synergistic mechanisms of action of regorafenib and 
atezolizumab, as well as the preliminary efficacy and manageable safety profile of the 
combination of regorafenib with nivolumab reported in the REGONIVO study, treatment 


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with atezolizumab and regorafenib appears to have promising therapeutic potential in 
solid tumors, such as MSS mCRC.
For the evaluation of the impact of the coronavirus disease 2019 (COVID-19) pandemic 
on the benefitrisk assessment, please refer to Section 1.4.
A123 RATIONALE FOR DOSE AND SCHEDULE FOR 
ATEZOREGORAFENIB ARM
A123.1
RATIONALE FOR ATEZOLIZUMAB DOSE AND SCHEDULE
Atezolizumab will be administered at a fixed dose of 840 mg every 2 weeks (Q2W) 
(840 mg on Days 1 and 15 of each 28-day cycle).  The average concentration following 
the 840 mg Q2W dosage is expected to be equivalent to that of 1200 mg every 3 weeks 
(Q3W), an approved dosage for atezolizumab , as outlined in the prescribing information.  
Anti-tumor activity has been observed across doses ranging from 1 to 20 mg/kg Q3W.  
In Study PCD4989g, the MTD of atezolizumab was not reached and no dose-limiting 
toxicities (DLTs) were observed at any dose.  The fixed dose of 1200 mg Q3W 
(equivalent to an average body weightbased dose of 15 mg/kg Q3W) was selected on 
the basis of both nonclinical studies (Deng et al. 2016) and available clinical 
pharmacokinetic, efficacy, and safety data (refer to the Atezolizumab Investigator's 
Brochure for details).
A123.2
RATIONALE FOR REGORAFENIB DOSE AND SCHEDULE
The approved dose for regorafenib is 160 mg/day.  In the REGONIVO study evaluating 
regorafenib in combination with nivolumab in Asian patients, DLTs were reported at the 
160-mg/day dose and Grade 3 skin toxicities were reported in 20% of the patients 
treated with the 120-mg/day dose.  This resulted in the use of the 80-mg/day dose of 
regorafenib in the expansion cohort.  However, modeling and simulation analyses of 
data from the CORRECT and CONCUR trials showed that a starting dose of 80 mg/day 
might result in reduced efficacy if not escalated to doses of either 120 mg/day or 
160 mg/day (Grothey 2019).  Therefore, to ensure an efficacious dose is administered, 
as well as to account for the fact that this study will be conducted in a global population 
(inclusive of Caucasian patients with potential differences in body size, drug metabolism, 
and toxicities), regorafenib will be used at a dose of 120 mg/day on Days 121 of each 
28-day cycle.  Furthermore, to account for the results from the ReDOS trial (Bekaii-Saab 
et al. 2019) showing a lower incidence of adverse events, a starting dose of 80 mg/day 
of regorafenib will be allowed, followed by a dose escalation to 120 mg/day (as per 
institutional guidelines) during Cycle 1 if no significant drug-related toxicity is observed.


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A124 MATERIALS AND METHODS SPECIFIC TO ATEZOREGORAFENIB
ARM
A124.1
TREATMENT IN ATEZOREGORAFENIB ARM
A124.1.1 Formulation, Packaging, and Handling
A124.1.1.1
Atezolizumab
The atezolizumab drug product will be supplied by the Sponsor as a sterile liquid in a 
single-use, 20-mL glass vial.  The vial contains approximately 20 mL (1200 mg) of 
atezolizumab solution.
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure.
A124.1.1.2
Regorafenib
For information on the formulation, packaging, and handling of regorafenib, refer to the 
local prescribing information. 
A124.1.2 Dosage, Administration, and Compliance
Patients in the AtezoRegorafenibarm will receive treatment as outlined in Table 1 until 
unacceptable toxicity or loss of clinical benefit defined as (1) confirmed disease 
progression or (2) lack of continued benefit as determined by the investigator, after an 
integrated assessment of radiographic and biochemical data, local biopsy results (if 
available), and clinical status (e.g., symptomatic deterioration such as pain secondary to 
disease) (see Section 3.1.1 in the protocol body for details).  It is recommended that 
treatment be initiated no later than 7 days after randomization. 
Table 1
Treatment Regimen for AtezoRegorafenib Arm
Cycle Length
Dose, Route, and Regimen
(drugs listed in order of administration)
28 days

Atezolizumab 840 mg IV on Days 1 and 15 of each cycle

Regorafenib 120 mg by mouth once daily on Days 121 a
Atezoatezolizumab.
a Regorafenib should be initiated at 80 mg, allowing sufficient time to monitor 
drug-related toxicities before considering dose escalation to 120 mg.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Guidelines for dose modification and treatment interruption or discontinuation because of 
toxicities are provided in Section A125.1.4.  Atezolizumab or regorafenib treatment 
interruptions for reasons other than toxicity (e.g., surgical procedures) may be allowed.  


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The acceptable length of treatment interruption must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator. The Medical Monitor is 
available to advise as needed.
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 5.3.5.12.  No safety data related to atezolizumab overdose are available.  The 
highest dose of regorafenib studied clinically is 220 mg per day.  The most frequently 
observed adverse drug reactions at this dose were dermatologic events, dysphonia, 
diarrhea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and 
fatigue.  There is no specific antidote for regorafenib overdose.  In the event of 
suspected overdose, interrupt regorafenib, institute supportive care, and observe until 
clinical stabilization. 
A124.1.2.1
Atezolizumab
Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Days 1 
and 15 of each 28-day cycle.  
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 5.  
Atezolizumab infusions will be administered per the instructions outlined in Table 2.


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Table 2
Administration of First and Subsequent Atezolizumab Infusions
First Infusion
Subsequent Infusions

No premedication is permitted prior to the 
atezolizumab infusion.

Vital signs (pulse rate, respiratory rate, 
pulse oximetry, blood pressure, and 
temperature) should be recorded within 
60 minutes prior to the infusion.

Atezolizumab should be infused over 
60 (15) minutes.

If clinically indicated, vital signs should be 
recorded every 15 (5) minutes during the 
infusion and 30 (10) minutes after the 
infusion.

Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms.

If the patient experienced an 
infusion-related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator.

Vital signs should be recorded within 
60 minutes prior to the infusion.

Atezolizumab should be infused over 
30 (10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion.

If the patient experienced an infusion-
related reaction with the previous infusion 
or if clinically indicated, vital signs should 
be recorded during the infusion and at 
30 (10) minutes after the infusion.
Guidelines for medical management of infusion-related reactions (IRRs) for 
atezolizumab are provided in Appendix 6.
No dose modification for atezolizumab is allowed.  Guidelines for atezolizumab 
treatment interruption or discontinuation because of toxicities are provided in 
Section A125.1.4.  
A124.1.2.2
Regorafenib
Regorafenib will be used in the commercially available formulation.
Patients will receive regorafenib at a dose level of 120 mg (three tablets of 40 mg each) 
orally once daily on Days 121 of a 28-day cycle (see Table 1).  This 4-week period is 
considered a treatment cycle.  Regorafenib should be initiated at 80 mg, allowing 
sufficient time to monitor drug-related toxicities before considering dose escalation to 
120 mg.
Regorafenib should be taken at the same time each day.  On clinic visit days when PK 
samples are collected, patients should take their regorafenib dose in the clinic.  The 
tablets should be swallowed whole with water after a light meal that contains 30% fat.  
An example of a light (low-fat) meal would include one portion of cereal (about 30 g), 


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one glass of skimmed milk, one slice of toast with jam, one glass of apple juice, and one 
cup of coffee or tea (520 calories, 2 g fat).
To assess patient compliance with self-administration of regorafenib, patients will be 
required to record the time and date they took each dose in a medication diary; missed 
doses will also be recorded.  Patients will be instructed to bring all unused study 
medication and their medication diaries at specified study visits for assessments of 
compliance.
Guidelines for regorafenib dose modification and treatment interruption or 
discontinuation because of toxicities are provided in Section A125.1.4.
A124.1.3 Stage 2 Treatment
Patients in Stage 1 who experience loss of clinical benefit as determined by the 
investigator (as described in Section 3.1.1 in the protocol body) or unacceptable toxicity 
may be eligible to receive a different treatment combination during during Stage 2, 
provided a Stage 2 treatment is available for enrollment and they meet the eligibility 
criteria of that treatment regimen.  Stage 2 treatment must begin within 3 months after 
the patient has experienced loss of clinical benefit or unacceptable toxicity.  However, it 
is recommended that patients begin Stage 2 treatment as soon as possible, but no 
earlier than 2 weeks after the last dose of treatment in Stage 1. 
Tumor assessments performed prior to or at the time of loss of clinical benefit or 
unacceptable toxicity during Stage 1 may serve as baseline assessments for Stage 2, 
provided the tumor assessments are performed within 28 days prior to initiation of 
Stage 2 treatment (i.e., Day 1 of Cycle 1).  Stage 2 treatment will continue until 
unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Table 3
Stage 2 Treatment Regimens Available for the 
AtezoRegorafenib Arm
Study Treatment
Appendix
No Stage 2 treatment currently available 



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A124.2
CONCOMITANT THERAPY FOR ATEZOREGORAFENIB ARM
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated study treatment from 
7 days prior to initiation of study treatment to the treatment discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.
For more detailed information on permitted, prohibited, or cautionary therapy; prohibited 
foods; and other restrictions (as applicable) for regorafenib, refer to the local prescribing 
information. 
A124.2.1 Permitted Therapy for AtezoRegorafenib Arm
Patients are permitted to use the following therapies during the study:

Oral contraceptives

Hormone-replacement therapy

Prophylactic anticoagulation 
Prophylactic anticoagulation for the patency of venous access devices is 
allowed provided the activity of the agent results in an INR 1.5upper limit of 
normal (ULN) and aPTT is within normal limits within 14 days prior to Day 1.
Prophylactic use of low molecular weight heparin (i.e., enoxaparin 40 mg/day) 
is allowed.

Prophylactic antibiotic or anti-viral treatment administered according to institutional 
standards

Vaccinations (such as influenza, COVID-19)
Live, attenuated vaccines are not permitted (see Section A124.2.3).

Prophylactic standard anti-emetic therapy

Megestrol acetate administered as an appetite stimulant after initiation of study 
treatment

Mineralocorticoids (e.g., fludrocortisone)

Inhaled corticosteroids administered for chronic obstructive pulmonary disease or 
asthma

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency

Hormonal therapy with gonadotropin releasinghormone agonists or antagonists for 
prostate cancer

Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below:


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Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  
Treatment with atezolizumab and regorafenib may be continued during 
palliative radiotherapy.

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.
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).


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A124.2.2 Cautionary Therapy for AtezoRegorafenib Arm
Corticosteroids, Immunosuppressive Medications, and Tumor Necrosis 
FactorInhibitors
Systemic corticosteroids, immunosuppressive medications, and tumor necrosis factor
(TNF) inhibitors may attenuate potential beneficial immunologic effects of treatment 
with atezolizumab.  Therefore, in situations in which systemic corticosteroids, 
immunosuppressive medications, or TNFinhibitors would be routinely administered, 
alternatives, including antihistamines, should be considered.  If the alternatives are not 
feasible, systemic corticosteroids, immunosuppressive medications, and TNF-
inhibitors may be administered at the discretion of the investigator.
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy (refer to Appendix 6 for details).
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer (see 
Section A124.2.3) may be used during the study at the discretion of the investigator.
UDP-Glucuronosyltransferase 1-1 and UDP-Glucuronosyltransferase 1-9
Regorafenib is metabolized by UDP-glucuronosyltransferase 1-1 (UGT1A1), and 
regorafenib and its metabolites are inhibitors of UGT1A1 and 
UDP-glucuronosyltransferase 1-9 (UGT1A9).  Therefore, inhibitors of UGT1A1 (e.g., 
erlotinib, nilotinib, pazopanib, lapatinib, sorafenib) and substrates of UGT1A1 (e.g., 
irinotecan with its active metabolite SN-38, raltegravir, bazedoxifene, eltrombopag) and 
substrates of UGT1A9 (e.g., sorafenib, mycophenolic acid) should be used with caution.  
Breast Cancer Resistance Protein 
Patients receiving substrates of the breast cancer resistance protein (BCRP) transporter 
(e.g., methotrexate, fluvastatin, atorvastatin) should be monitored for signs and 
symptoms of increased exposure.
A124.2.3 Prohibited Therapy for AtezoRegorafenib Arm
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, may be prohibited 
prior to starting study treatment, depending on the agent and is prohibited during 
study treatment until disease progression is documented and the patient has 


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discontinued study treatment, with the exception of palliative radiotherapy and local 
therapy under certain circumstances outlined above in Section A124.2.1.

Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 28 days prior to initiation of study treatment and during study treatment.

Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with atezolizumab, and for 5 months 
after the last dose of atezolizumab.

Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin 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.

Strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, 
and St. John’s Wort) and strong inhibitors of CYP3A4 activity (e.g., clarithromycin, 
grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and 
voriconazole) are prohibited.
A124.3
CONTRACEPTION REQUIREMENTS FOR 
ATEZOREGORAFENIB ARM
Contraception requirements for women and men in the AtezoRegorafenib arm are 
outlined below:

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for 5 months after the last dose of 
atezolizumab and for 2 months after the last dose of regorafenib.  Women must 
refrain from breastfeeding during this same period of time.  
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, hormonal contraceptives that inhibit 
ovulation, hormone releasing intrauterine devices, 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 a condom, and agreement to refrain from donating sperm, as defined below:


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With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for 
2 months after the last dose of regorafenib to avoid exposing the embryo.  Men 
must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
A125 ASSESSMENT OF SAFETY FOR ATEZOREGORAFENIB ARM
A125.1
SAFETY PLAN FOR ATEZOREGORAFENIB ARM
The safety plan for patients in this study is based on clinical experience with 
atezolizumab and regorafenib in completed and ongoing studies.  The anticipated 
important safety risks are outlined below (see Sections A125.1.1, A125.1.2, and 
A125.1.3).  Guidelines for the management of patients who experience specific 
adverse events are provided in Section A125.1.4.
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.  Because of the potential for overlapping toxicities identified for 
atezolizumab and regorafenib, special caution will be taken by performing a planned 
safety evaluation for patients randomized to this arm (see Section 3.1.1.1). 
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 in the protocol body.
A125.1.1 Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, hypophysitis, adrenal insufficiency, Guillain-Barré
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
myocarditis, nephritis, myositis, and severe cutaneous adverse reactions.  
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), 
which are considered to be potential risks for atezolizumab.  Refer to Appendix 6 of the 
protocol and Section 6 of the Atezolizumab Investigator's Brochure for a detailed 
description of anticipated safety risks for atezolizumab.  


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A125.1.2 Risks Associated with Regorafenib
The overall safety profile of regorafenib is based on data from more than 4800 treated 
patients in clinical trials, including placebo-controlled Phase III data for 636 patients with 
mCRC, 132 patients with GI stromal tumors, and 374 patients with hepatocellular 
carcinoma.  The most serious adverse drug reactions in patients receiving regorafenib 
are severe liver injury, hemorrhage, GI perforation, and infection.  The most frequently 
observed adverse drug reactions (30%) in patients receiving regorafenib are pain, 
hand-foot skin reaction, asthenia/fatigue, diarrhea, decreased appetite and food intake, 
hypertension, and infection.
Refer to the regorafenib local prescribing information for complete information regarding 
clinical safety.
A125.1.3 Risks Associated with Combination Use of Atezolizumab and 
Regorafenib
The following adverse events are potential overlapping toxicities associated with 
combination use of atezolizumab and regorafenib:  gastrointestinal toxicities 
(diarrhea/colitis), hepatic toxicity, cardiac toxicities (cardiac ischemia, myocardial 
infarction/myocarditis), dermatological toxicity/skin rash, Posterior Reversible 
Encephalopathy Syndrome (PRES)/meningoencephalitis, and 
hemorrhage/thrombocytopenia. 
A125.1.4 Management of Patients Who Experience Adverse Events in 
AtezoRegorafenib Arm
A125.1.4.1
Dose Modifications
There will be no dose modifications for atezolizumab in this study.
For management of drug-related toxicities, the dose of regorafenib can be reduced by a 
decrement of 40 mg once a day (one dose level) from 120 mg to 80 mg.  During the 
allowed dose escalation (Section A124.1.2.2), the continuation of a dose of 80 mg/day 
for as long as required for the management of drug-related toxicities is also allowed.  If 
further dose reduction below 80 mg is indicated, the patient must discontinue 
regorafenib, unless the patient is likely to derive clinical benefit as determined by the 
investigator.  The Medical Monitor is available to advise as needed.  After dose 
reduction, the dose of regorafenib may be re-escalated at the investigator's discretion, 
provided there are no safety concerns.
A125.1.4.2
Treatment Interruption for Toxicities
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 


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equivalent before atezolizumab can be resumed.  If atezolizumab is withheld for more 
than 12 weeks, the patient will be discontinued from the study.  However, atezolizumab 
may be withheld for more than 12 weeks to allow for patients to taper off corticosteroids 
prior to resuming treatment.  Atezolizumab can be resumed after being withheld for more 
than 12 weeks if the patient is likely to derive clinical benefit.  The decision to 
re-challenge patients with atezolizumab should be based on investigator’s assessment of 
benefitrisk and documented by the investigator.  The Medical Monitor is available to 
advise as needed.
Regorafenib treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If regorafenib has been withheld for more 
than 42 days because of toxicity, the patient should be discontinued from regorafenib.  
However, regorafenib can be resumed after being withheld for more than 42 days if the 
patient is likely to derive clinical benefit.  The Medical Monitor is available to advise as 
needed.
If atezolizumab or regorafenib is permanently discontinued, the other agent should also 
be discontinued unless the patient is likely to derive clinical benefit from single-agent use, 
as determined by the investigator. The Medical Monitor is available to advise as needed.
Refer to Section A12-4.1.2 for information on dose interruptions for reasons other than 
toxicity.
A125.1.4.3
Management Guidelines for Adverse Events
Guidelines for the management of patients who experience specific adverse events are 
provided below in Table 4 for events related to overlapping toxicities or regorafenib 
treatment.
For cases in which management guidelines are not covered in Appendix 6 or Table 4, 
patients should be managed and treatments should be withheld or discontinued as 
deemed appropriate by the investigator according to best medical judgment.  


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Table 4
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenib Arm
Event
Action to Be Taken
IRRs, CRS, anaphylaxis, and 
hypersensitivity reactions
Guidelines for management of IRRs and CRS for atezolizumab are provided in Appendix 6.
For anaphylaxis precautions, see Appendix 5.
Dermatologic toxicity (rash, handfoot skin reaction/palmarplantar erythrodysesthesia)
General Guidance
A dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy should be 
considered unless contraindicated.
Dermatologic event, Grade 1
Continue atezolizumab.  Continue regorafenib at the same dose level.
Immediately institute supportive measures for symptomatic relief.
If rash is suspected to be related to atezolizumab, consider treatment with topical corticosteroids and/or 
other symptomatic therapy (e.g. antihistamines).


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Table 4:
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenib Arm 
(cont.)
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Event
Action to Be Taken
Dermatologic event, Grade 2
Continue atezolizumab.  Continue regorafenib and decrease dose by one level. a  
For suspected atezolizumab-related events:
Consider patient referral to dermatologist for evaluation and, if indicated, biopsy.
Initiate treatment with topical corticosteroids.
Consider treatment with higher-potency topical corticosteroids if event does not improve.
If unresponsive to topical corticosteroids, consider oral prednisone 0.5 mg/kg/day.
For suspected regorafenib-related events:
Immediately institute supportive measures.
First occurrence:
If event does not resolve to Grade 1 or better after dose reduction, withhold regorafenib for a minimum of 
7 days.  If event resolves to Grade 1 or better within 42 days, resume regorafenib at the reduced dose 
level. a  If not, permanently discontinue regorafenib. e
A dose re-escalation is permitted at the investigator’s discretion.
If event does not resolve within 7 days or at second or third occurrence:  
Withhold regorafenib for a minimum of 7 days.  If event resolves to Grade 1 or better within 42 days, 
resume regorafenib with a one-level dose reduction. a  If not, permanently discontinue regorafenib. e
Fourth occurrence:
Permanently discontinue regorafenib. e


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Table 4:
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenib Arm 
(cont.)
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Event
Action to Be Taken
Dermatologic event, Grade 3
Withhold atezolizumab for up to 12 weeks after event onset. b  Withhold regorafenib for a minimum of 
7 days or until toxicity resolves to Grade 1 or better.
For suspected atezolizumab-related events:
Refer patient to dermatologist for evaluation and, if indicated, biopsy.
Initiate treatment with corticosteroids equivalent to 10 mg/day oral prednisone, increasing dose to 
12 mg/kg/day if event does not improve within 4872 hours.
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab. b, c  If not, permanently 
discontinue atezolizumab and contact Medical Monitor. d
If event resolves to Grade 1 or better within 42 days, resume regorafenib with a one-level dose 
reduction.a  If not, permanently discontinue regorafenib and contact Medical Monitor.
For suspected regorafenib-related events:
Institute supportive measures immediately
First and second occurrence:  
If event resolves to Grade 1 or better within 42 days, resume regorafenib with a one-level dose 
reduction. a, g  If not, permanently discontinue regorafenib. e
For first occurrence, a dose re-escalation is permitted at the investigator’s discretion
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab. b  If not, permanently 
discontinue atezolizumab and contact Medical Monitor d
Third occurrence:  
Permanently discontinue regorafenib. e
Dermatologic event, Grade 4
Permanently discontinue atezolizumab and regorafenib and contact Medical Monitor. d, e
Suspected Stevens-Johnson 
syndrome or toxic epidermal 
necrolysis (any grade)
Follow guidelines for atezolizumab in Appendix 6.
Permanently discontinue regorafenib and contact Medical Monitor.


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Table 4:
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenib Arm 
(cont.)
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Event
Action to Be Taken
Hepatic toxicity (elevations in ALT, AST, and/or bilirubin)
5ULN elevations in 
ALT/AST (maximum Grade 2)
Continue atezolizumab.  Continue regorafenib at the same dose level.
Monitor LFTs more frequently until return to 3 ULN (Grade 1) or baseline.
For suspected immune-mediated events of 5 days duration:  
Withhold atezolizumab for up to 12 weeks after event onset. b  Regorafenib can be continued at the 
same dose level at the investigator’s discretion.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral prednisone.
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab. b, c  If not, permanently 
discontinue atezolizumab and contact Medical Monitor. d


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Table 4:
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenib Arm 
(cont.)
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Event
Action to Be Taken
5ULN but 20ULN 
elevations in ALT/AST 
(Grade 3)
For suspected regorafenib-related/nonimmune-mediated elevations in ALT/AST:
Withhold atezolizumab for up to 12 weeks after event onset. b  Withhold regorafenib for up to 42 days. 
Monitor LFTs at least weekly for at minimum of 4 weeks until transaminases return to 3 ULN (Grade 1) 
or baseline.
Consider patient referral to GI specialist for evaluation and liver biopsy to establish etiology of hepatic 
injury.
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab. b  If not, permanently 
discontinue atezolizumab and contact Medical Monitor. d
First occurrence:  
If event resolves to Grade 1 or better within 42 days, resume regorafenib with a one-level dose 
reduction. a, g  If not, permanently discontinue regorafenib. e
Second occurrence:  
Permanently discontinue regorafenib. g
For suspected immune-mediated events:
Permanently discontinue atezolizumab and contact Medical Monitor. d  Withhold regorafenib.
Consider patient referral to GI specialist for evaluation and liver biopsy to establish etiology of hepatic 
injury. 
Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral prednisone.
If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.
If event resolves to Grade 1 or better within 12 weeks, taper corticosteroids over 1 month. b
If event resolves to Grade 1 or better within 42 days, resume regorafenib with a one-level dose 
reduction. a  If not, permanently discontinue regorafenib. e


Appendix 12:  Study Details Specific to AtezoRegorafenib Arm 
Table 4:
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenib Arm 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
241/Protocol CO39612, Version 11
Event
Action to Be Taken
20ULN elevations in 
ALT/AST (Grade 4)
Permanently discontinue atezolizumab and regorafenib and contact Medical Monitor. d, e
Follow Grade 3 management guidelines for suspected immune-mediated events.
3ULN elevations in 
ALT/AST (Grade 2 or higher) 
with concurrent bilirubin 
2ULN
Permanently discontinue atezolizumab and regorafenib and contact Medical Monitor. d, e
Monitor liver function at least weekly until values return to baseline.
Investigate causes for elevated bilirubin and initiate treatment per institutional guidelines. 
Exception:  Patients with Gilbert syndrome who develop elevated transaminases should be managed as 
per the above outlined recommendations for the respective observed elevation of ALT and/or AST.
GI toxicities 
Any GI perforation or fistula
Permanently discontinue regorafenib. e
Diarrhea or colitis, Grade 1
Continue atezolizumab.  Continue regorafenib at the same dose level.
Initiate symptomatic treatment.
Endoscopy is recommended if symptoms persist for 7 days.
Monitor closely.
Diarrhea or colitis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset b.  Regorafenib may be continued at the 
same dose level at the investigator’s discretion.

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 

If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab. b, c  If not, permanently 
discontinue atezolizumab and contact Medical Monitor. d

If regorafenib was withheld and event resolves to Grade 1 or better within 42 days after event onset, 
decrease by one dose level when resuming treatment. a, g


Appendix 12:  Study Details Specific to AtezoRegorafenib Arm 
Table 4:
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenib Arm 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
242/Protocol CO39612, Version 11
Event
Action to Be Taken
Diarrhea or colitis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset. b  Withhold regorafenib for up to 42 days. 
For suspected immune-mediated events (including colitis):

Refer patient to GI specialist for evaluation and confirmatory biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.

If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab. b, c  If not, permanently 
discontinue atezolizumab and contact Medical Monitor. d
For regorafenib-related events:
First and second occurrence:  
If event resolves to Grade 1 or better within 42 days, resume regorafenib with a one-level dose 
reduction. a  If not, consider permanent discontinuation of regorafenib. e
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab.b  If not, consider 
permanent discontinuation of atezolizumab and contact medical monitord.
Third occurrence:  
Consider permanent discontinuation of regorafenib. e
Diarrhea or colitis, Grade 4

Permanently discontinue atezolizumab and regorafenib and contact Medical Monitor. d, e

Refer patient to GI specialist for evaluation and confirmation biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 1 month.


Appendix 12:  Study Details Specific to AtezoRegorafenib Arm 
Table 4:
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenib Arm 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
243/Protocol CO39612, Version 11
Event
Action to Be Taken
Cardiac Toxicities
General guidance
Immune-mediated myocarditis should be suspected in any patient presenting with signs or symptoms 
suggestive of myocarditis, including, but not limited to, laboratory (e.g., B-type natriuretic peptide) or 
cardiac imaging abnormalities, dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, 
or syncope.  
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, e.g., in a patient who reports a recent history of gastrointestinal illness), ischemic 
events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, or progression of 
malignancy.  
Immune-mediated myocarditis, 
Grade 1
Atezolizumab may be continued at the investigator’s discretion.  Regorafenib may be continued at the 
same dose level, at the investigator’s discretion.
Refer patient to cardiologist.
Initiate treatment as per institutional guidelines.
Immune-mediated myocarditis, 
Grade 2
Permanently discontinue atezolizumab and contact Medical Monitor. d  Regorafenib may be continued 
at the same dose level, at the investigator’s discretion.
Refer patient to cardiologist.
Initiate treatment as per institutional guidelines and consider antiarrhythmic drugs, temporary 
pacemaker, ECMO, or VAD as appropriate.
Consider treatment with corticosteroids equivalent to 12 mg/kg/day IV methylprednisolone and convert 
to 12 mg/kg/day oral prednisone or equivalent upon improvement.
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab. b, c  If not, permanently 
discontinue atezolizumab and contact Medical Monitor. d


Appendix 12:  Study Details Specific to AtezoRegorafenib Arm 
Table 4:
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenib Arm 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
244/Protocol CO39612, Version 11
Event
Action to Be Taken
Immune-mediated myocarditis, 
Grade 3
Permanently discontinue atezolizumab and contact Medical Monitor. d  Withhold regorafenib for up to 42 
days. 
Refer patient to cardiologist.
Initiate treatment as per institutional guidelines and consider antiarrhythmic drugs, temporary 
pacemaker, ECMO, or VAD as appropriate.
Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.
If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.
If event resolves to Grade 1 or better within 12 weeks, taper corticosteroids over 1 month.b
If event resolves to Grade 1 or better within 42 days, consider resuming regorafenib.g
Immune-mediated myocarditis, 
Grade 4
Permanently discontinue atezolizumab and regorafenib contact Medical Monitor. d, e
Manage as per Grade 3 guidelines.
New or acute onset cardiac 
ischemia or infarction
Withhold atezolizumab.  Withhold regorafenib.
If the acute cardiac ischemic events resolve and if the potential benefits outweigh the risks of further 
cardiac ischemia, resume atezolizumab and resume regorafenib.  If not, permanently discontinue 
atezolizumab and regorafenib and contact Medical Monitor. d, e
Infection
Infections, Grade 3 or 4 or a 
worsening infection of any 
grade
Withhold regorafenib.  Atezolizumab may be continued at the investigator’s discretion.
If infection resolves within 42 days, resume regorafenib at the same dose level.  If not permanently 
discontinue regorafenib. e
Hemorrhage


Appendix 12:  Study Details Specific to AtezoRegorafenib Arm 
Table 4:
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenib Arm 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
245/Protocol CO39612, Version 11
Event
Action to Be Taken
Hemorrhage, Grade 3 or 4
Permanently discontinue regorafenib and contact Medical Monitor. e, f  
Monitor INR levels more frequently in patients receiving warfarin.
Hypertension
General guidance
Grade 2 or above, start anti-hypertensive therapy.
Hypertension, Grade 2
Withhold regorafenib.  Continue atezolizumab.
If blood pressure is 150/100 mmHg within 42 days, resume regorafenib with the decision to maintain 
the current dose level or to reduce by one dose level at the discretion of the investigator. a
Hypertension, Grade 3
Withhold regorafenib.  Atezolizumab may be continued at the investigator’s discretion.
If blood pressure is 150/100 mmHg within 42 days, resume regorafenib with the decision to maintain 
the current dose level or to reduce by one dose level at the discretion of the investigator. a
If blood pressure is not controlled to 150/100 mmHg with anti-hypertensive therapy, permanently 
discontinue regorafenib and contact Medical Monitor. e
Hypertension, Grade 4 
(includes hypertensive crisis 
and hypertensive 
encephalopathy)
Permanently discontinue atezolizumab and regorafenib and contact Medical Monitor. d, e
Reversible posterior leukoencephalopathy syndrome
Reversible posterior 
leukoencephalopathy 
syndrome
Permanently discontinue regorafenib and contact Medical Monitor. e  


Appendix 12:  Study Details Specific to AtezoRegorafenib Arm 
Table 4:
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenib Arm 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
246/Protocol CO39612, Version 11
Event
Action to Be Taken
Wound dehiscence
Wound dehiscence, any grade 
requiring medical or surgical 
therapy
Permanently discontinue regorafenib and contact Medical Monitor. e  
Regorafenib-related toxicities not described above
Grade 1 or Grade 2 (tolerable)
Continue atezolizumab.  Continue regorafenib at the same dose level.
Grade 2 (intolerable) or Grade 
3
Atezolizumab may be continued at the investigator’s discretion.
First and second occurrence:  
Withhold regorafenib until event resolves to Grade 1 or better within 42 days, then resume regorafenib 
with a one-level dose reduction. a, g  If event does not resolve to Grade 1 or better, permanently 
discontinue regorafenib. e
Third occurrence:  
Consider permanent discontinuation of regorafenib. e
Grade 4
Permanently discontinue atezolizumab and regorafenib and contact Medical Monitor. d, e
Atezolizumab-related toxcities not described above
Grade 1 or 2
Follow guidelines for atezolizumab in Appendix 6.
Continue regorafenib at the same dose level.
Grade 3 or 4
Follow guidelines for atezolizumab in Appendix 6.
Withhold regorafenib. f
If event improves within 42 days, resume regorafenib.g  If not, permanently discontinue regorafenib. e


Appendix 12:  Study Details Specific to AtezoRegorafenib Arm 
Table 4:
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenib Arm 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
247/Protocol CO39612, Version 11
CRS cytokine release syndrome; ECMOextracorporeal membrane oxygenation; GIgastrointestinal; IRRinfusion-related reaction; 
ULNupper limit of normal; VADventricular assist device.
a The dose of regorafenib can be reduced by a decrement of 40 mg, once a day, from 120 mg to 80 mg (i.e., one dose level) for 
management of drug-related toxicities.  Additional dose reductions are not allowed.  If a dose reduction is indicated for a patient receiving 
the 80-mg dose of regorafenib, then that patient should discontinue regorafenib, unless the patient is likely to derive clinical benefit as 
determined by the investigator.  The Medical Monitor is available to advise as needed.  Upon adverse event resolution, a dose 
re-escalation of regorafenib from 80 mg to 120 mg is allowed at the investigator’s discretion.
b 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 based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.
c 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.
d Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-mediated 
event.  The decision to re-challenge patients with atezolizumab should be based on investigator's assessment of benefitrisk and
documented by the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as needed.
e Resumption of regorafenib may be considered in patients who are deriving benefit and and have fully recovered from the toxicity.  The 
decision to re-challenge patients with regorafenib should be based on investigator's assessment of benefitrisk and documented by the 
investigator (or an appropriate delegate).  The Medical Monitor is available to advise as needed.
f For Grade 3 events not related to regorafenib, regorafenib may be continued at the discretion of the investigator per medical judgement.
g Regorafenib may be withheld for a longer period of time (i.e. 42 days after event onset).  The acceptable length of the extended period of 
time must be based on an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to advise as needed.


Appendix 12:  Study Details Specific to AtezoRegorafenib Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
248/Protocol CO39612, Version 11
A125.2
ADVERSE EVENTS OF SPECIAL INTEREST FOR 
ATEZOREGORAFENIB ARM (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 in the protocol body for reporting instructions).  Adverse events of special 
interest for the AtezoRegorafenib arm are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7 in the protocol body) 

Suspected transmission of an infectious agent by the study treatment, as defined 
below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of study treatment is suspected.

Pneumonitis

Colitis

Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis

Hepatitis, including AST or ALT 10 upper limit of normal

Systemic lupus erythematosus

Neurologic disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis

Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, influenza-like illness, HLH, and MAS

Nephritis

Ocular toxicities (e.g., uveitis, retinitis, and optic neuritis)

Myositis

Myopathies, including rhabdomyolysis

Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Vasculitis

Autoimmune hemolytic anemia

Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis)


Appendix 12:  Study Details Specific to AtezoRegorafenib Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
249/Protocol CO39612, Version 11
A125.3
REPORTING REQUIREMENTS FOR PREGNANCIES IN 
ATEZO+REGORAFENIB ARM
A125.3.1 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 atezolizumab or 2 months after the last dose of regorafenib.  A paper Clinical 
Trial Pregnancy Reporting Form should be completed and submitted to the Sponsor or 
its designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study treatment and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.  
A125.3.2 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 
2 months after the last dose of regorafenib.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study treatment.  
When permitted by the site, the pregnant partner will need to sign an Authorization for 
Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy.  If the authorization has been signed, the investigator should submit a 
Clinical Trial Pregnancy Reporting Form when updated information on the course and 
outcome of the pregnancy becomes available.  An investigator who is contacted by the 
male patient or his pregnant partner may provide information on the risks of the 
pregnancy and the possible effects on the fetus, to support an informed decision in 
cooperation with the investigator and/or obstetrician.
A125.3.3 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, 


Appendix 12:  Study Details Specific to AtezoRegorafenib Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
250/Protocol CO39612, Version 11
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2 in the protocol body).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
A125.3.4 Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment should be classified as a serious adverse event, recorded on the Adverse 
Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2 in the protocol body).


Appendix 12:  Study Details Specific to AtezoRegorafenib Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
251/Protocol CO39612, Version 11
A126. SCHEDULE OF ACTIVITIES AND SAMPLE COLLECTION FOR ATEZOREGORAFENIB ARM
Table 5
Schedule of Activities for AtezoRegorafenib Arm
Assessment/Procedure
Screening
Days
–28 to –1
Treatment Cycles (28-Day Cycles) a
Stage 2 
Screen. c
or Treat. 
Discon. d
Follow-Up
Every 
3 Months
(7 days)
Cycle 1 b
Cycle 2
Cycles 3
Days 
Days 
Days 
1
8
(1 d)
15
(1 d)
22
(1 d)
1
8
(1 d)
15
(1 d)
1
(2d)
15
(2 d)
Molecular profile of CRC (if 
available)
See
Appendix 15
Whenever updated information becomes available
Vital signs e
x
x
x
x
x
x
x
x
x
x
Weight
x f
x f
x f
x
Complete physical examination g
x
Limited physical examination h
x f
x f
x f
x f
x f
x f
x f
x f
x f
ECOG Performance Status
x f
x f
x f
x
ECG i
Perform as clinically indicated f
x o
Hematology j
x k, l
x k
x k
x k
x k
x k
x
Chemistry m
x k, l
x k
x k
x k
x k
x k
x
Coagulation (INR and aPTT) n
x k, l
x k
x k
x o
TSH, free T3 (or total T3), and 
free T4 p
x k, l, p
x
Viral serology q
x o, q
C-reactive protein
x o
Plasma CEA r
x k
x k, r


Appendix 12:  Study Details Specific to Atezo Regorafenib Arm 
Table 5
Schedule of Activities for AtezoRegorafenib Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
252/Protocol CO39612, Version 11
Assessment/Procedure
Screening
Days
–28 to –1
Treatment Cycles (28-Day Cycles) a
Stage 2 
Screen. c
or Treat. 
Discon. d
Follow-Up
Every 
3 Months
(7 days)
Cycle 1 b
Cycle 2
Cycles 3
Days 
Days 
Days 
1
8
(1 d)
15
(1 d)
22
(1 d)
1
8
(1 d)
15
(1 d)
1
(2d)
15
(2 d)
LDH
See
Appendix 15
x o
Pregnancy test s
x k, l
x k
x k
x t
x s
Urinalysis u
x
x
x
x o, t
Serum autoantibody sample v
Perform if patients experience suspected immune-mediated adverse 
event
xo
Blood sample for RBR (optional) w
x
Biomarker samples
Refer to Table 6 below
Serum ADA sample
Refer to Table 6 below
Serum and plasma PK sample
Refer to Table 6 below
Tumor biopsy
x x
Tumor biopsy (optional)
x y
Tumor response assessments
x z, aa, bb
Concomitant medications cc
x
x
x
x
x
x
x
x
x
x
Adverse events dd
x
x
x
x
x
x
x
x
x
x dd
x dd
Administer atezolizumab ee, ff
x
x
x
x
x
x
Dispense regorafenib ff, gg
x
x
x
Study drug accountability hh
x
x
x
x
x
Survival follow-up and anti-cancer 
treatment
x ii


Appendix 12:  Study Details Specific to Atezo Regorafenib Arm 
Table 5
Schedule of Activities for AtezoRegorafenib Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
253/Protocol CO39612, Version 11
ADAanti-drug antibody; CTcomputed tomography; dday; Discondiscontinuation; ECOG Eastern Cooperative Oncology Group; 
eCRFelectronic Case Report Form; HBcAbhepatitis B core antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; 
HCVhepatitis C virus; MRImagnetic resonance imaging; PKpharmacokinetic; RBRResearch Biosample Repository; RECIST 
v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; Screen screening; T3triiodothyronine; T4 thyroxine; Treat.treatment; 
TSHthyroid-stimulating hormone.
Note:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified
a If a visit is precluded because of a holiday, vacation, or other circumstance, it may occur outside of the specified window.
b It is recommended that treatment be initiated no later than 7 days after randomization.
c Patients who experience loss of clinical benefit defined as (1) confirmed disease progression or (2) lack of continued benefit as determined by 
the investigator (see Section 3.1.1 in the protocol body for details) or unacceptable toxicity may be given the option of receiving a different 
treatment combination during Stage 2 of the study (as outlined in Section 3.1.2 in the protocol body provided Stage 2 is open for enrollment) and 
will undergo screening assessments to determine eligibility.  Study details specific to the Stage 2 treatment regimens are provided in the
appropriate appendix.  Written informed consent must be obtained before performing screening evaluations for Stage 2.
d Patients will return to the clinic for a Stage 2 screening or treatment discontinuation visit not more than 30 days after the last dose of study 
treatment.  The visit at which loss of clinical benefit is confirmed may be used as the Stage 2 screening or treatment discontinuation visit.  
Treatment discontinuation assessments must be performed for all patients, regardless of whether they enter Stage 2.  Patients who do not enter 
Stage 2 will undergo follow-up assessments after completing the treatment discontinuation visit.
e Vital signs include respiratory rate, pulse rate, pulse oximetry, systolic and diastolic blood pressure while the patient is in a seated position, and 
temperature.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  Refer to Section 
A12-4.1.2 for details related to vital signs monitoring during atezolizumab infusions.
f
Assessment may be performed within 24 hours prior to dosing during the treatment period.
g Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.  Record new or worsened clinically significant abnormalities on the Adverse Event 
eCRF.
h Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  Record abnormalities 
observed at baseline on the General Medical History and Baseline Conditions eCRF.administered.  The skin examination should be extended 
according to medical need.
i
ECG recordings will be obtained during screening and as clinically indicated at other timepoints.  It is recommended that patients be resting in a 
supine position for at least 10 minutes prior to ECG recording.
j
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).
k Laboratory tests must be performed within 96 hours prior to dosing during the treatment period.
l
If screening laboratory assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated.


Appendix 12:  Study Details Specific to Atezo Regorafenib Arm 
Table 5
Schedule of Activities for AtezoRegorafenib Arm (cont.)
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m Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (per standard of care for the region), sodium, potassium, 
magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, and AST.  CPK will 
be performed only on Day 1 of each cycle and at treatment discontinuation.
n Monitoring of INR/aPTT should be performed more frequently if clinically indicated.
o Assessments to be performed only for patients undergoing Stage 2 screening.
p TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed at screening and on Day 1 of Cycle 1 and every 
third cycle thereafter (i.e., Cycles 4, 7, 10, etc.).
q At Stage 2, patients without a prior positive HIV test result will undergo an HIV test, unless not permitted per local regulations.  Patients will also 
be tested for HBsAg, total HBcAb, and HCV antibody.  If a patient has a negative HBsAg test and a positive total HBcAb test at screening, an 
HBV DNA test must also be performed to determine if the patient has an HBV infection.  If a patient has a positive HCV antibody test at 
screening, an HCV RNA test must also be performed to determine if the patient has an active HCV infection. 
r
CEA will be assessed on Day 1 of Cycle 1 and every 2 cycles thereafter (i.e., Cycles 3, 5, 7, etc.) until disease progression.
s All women of childbearing potential will have a serum pregnancy test at screening.  Urine or serum pregnancy tests will be performed at 
specified subsequent visits and at 3 months and 6 months after treatment discontinuation.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test.
t
Screening laboratory test results must be obtained within 14 days prior to initiation of study treatment.
u Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted.  Patients with 2+protein on dipstick urinalysis must 
undergo a 24-hour urine collection and demonstrate 3.5 g of protein in 24 hours. Urinalysis may be performed up to 72 hours prior to Day 1 
of each cycle, as results must be available prior to treatment administration.
v Autoantibody analysis includes anti-nuclear antibody, antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and 
perinuclear anti-neutrophil cytoplasmic antibody.
w Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate.  RBR sample should be collected prior to study treatment.
x Patients will undergo tumor biopsy sample collection at the time of unacceptable toxicity or loss of clinical benefit as determined by the 
investigator (see Section 3.1.1 for details), if deemed clinically feasible by the investigator.  Biopsies should be performed within 40 days after 
determination of unacceptable toxicity or loss of clinical benefit, or prior to the next anti-cancer therapy, whichever is sooner.  Patients enrolled 
in the mandatory serial-biopsy arm (see Section 3.1.1.2 in the protocol body) will undergo tumor biopsy sample collection 4 weeks (7 days) 
after treatment initiation (if deemed clinically feasible by the investigator).  See Section 4.5.7 in the protocol body for tissue sample 
requirements.
y Patients who consent to optional biopsies will undergo tumor biopsy sample collection 4 weeks (7 days) after treatment initiation, if deemed 
clinically feasible and may undergo additional on-treatment biopsies at any other time during Stage 1 or Stage 2 at the investigator's discretion.


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Table 5
Schedule of Activities for AtezoRegorafenib Arm (cont.)
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z Patients will undergo tumor assessments at baseline, every 6 weeks (1 week) for the first 48 weeks following treatment initiation, and every 
12 weeks (2 weeks) thereafter, regardless of dose delays, until loss of clinical benefit defined as (1) confirmed disease progression or (2) lack 
of continued benefit as determined by the investigator (see Section 3.1.1 in the protocol body for details).  Thus, tumor assessments are to 
continue according to schedule in patients who discontinue treatment for reasons other than loss of clinical benefit, even if they start new 
nonprotocol-specified anti-cancer therapy.
aa All measurable and/or evaluable lesions identified at baseline should be re-assessed at subsequent tumor evaluations according to the schedule 
described above.  Brain metastases identified at baseline that have been treated with radiotherapy or surgery will not be considered measurable 
or evaluable unless there is suspected disease progression in the brain (i.e., the patient becomes symptomatic).  Thus, subsequent head CT 
scans are not required unless clinically indicated.  The same radiographic procedures used to assess disease sites at screening should be used 
for subsequent tumor assessments (e.g., the same contrast protocol for CT scans).  
bb For patients who undergo screening for Stage 2, tumor assessments performed prior to or at the time of loss of clinical benefit during Stage 1 
may serve as baseline assessments for Stage 2, provided the tumor assessments are performed within 28 days prior to initiation of Stage 2 
treatment (i.e., Day 1 of Cycle 1).
cc Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by a patient in addition to protocol-mandated study treatment from 7 days prior to initiation of study treatment until the treatment 
discontinuation visit.
dd After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first.  Serious adverse events and adverse events of special 
interest will continue to be reported until 135 days after the last dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first.  After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6 in 
the protocol body).  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is 
assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study treatment or trial-related procedures until a final outcome can be reported.
ee Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Days 1 and 15 of each 28-day cycle.  The initial dose of 
atezolizumab will be delivered over 60 (15) minutes.  Subsequent infusions will be delivered over 30 (10) minutes if the previous infusion was 
tolerated without infusion-associated adverse events, or 60 (15) minutes if the patient experienced an infusion-associated adverse event with 
the previous infusion.  
ff Treatment will continue until unacceptable toxicity or loss of clinical benefit defined as (1) confirmed disease progression or (2) lack of continued 
benefit as determined by the investigator (see Section 3.1.1 in the protocol body for details).


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Table 5
Schedule of Activities for AtezoRegorafenib Arm (cont.)
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gg Patients will receive regorafenib orally on Days 121 of each cycle. At least 7 days off regorafenib are required prior to starting a new treatment
cycle (See Section A124.1.2.2 for more details).  On clinic visit days when PK samples are collected, patients should take their regorafenib 
dose in the clinic.
hh Medication diaries should be collected and reviewed, and unused medications should be collected for assessment of compliance.
ii After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) 
will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months until death (unless the patient 
withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this request must be documented 
in the source documents and signed by the investigator.  If the patient withdraws from the study, the study staff may use a public information 
source (e.g., county records) to obtain information about survival status only. For an experimental arm in which all patients discontinued 
treatment and passed the safety follow-up window, as well as approximately 80% of patients discontinued the study, the Sponsor may conclude 
the arm (the remaining ~20% of patients will be discontinued from the study).


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Table 6
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker 
Samples for AtezoRegorafenib Arm:  Preliminary and 
Expansion Phases 
Visit
Time
Sample Type
Day 1 of Cycle 1
Prior to study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Regorafenib PK (plasma) a

Biomarkers (plasma, serum, PBMC)
30 (10) minutes after atezolizumab 
infusion

Atezolizumab PK (serum)
Day 8 of Cycle 1
Prior to study treatment

Regorafenib PK (plasma) a
Day 15 of Cycle 1
Prior to study treatment

Regorafenib PK (plasma) a

Biomarkers (plasma, serum)
Day 22 of Cycle 1
24 hours after regorafenib dose

Regorafenib PK (plasma) a
Day 1 of Cycle 2
Prior to study treatment
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Biomarkers (plasma, serum, PBMC)
Day 1 of Cycle 3
Prior to study treatment
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 1 of Cycles 4 
and 8
Prior to study treatment
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Biomarkers (plasma, serum)
Day 1 of Cycles 
12 and 16
Prior to study treatment
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Treatment 
discontinuation visit 
(30 days after 
last dose)
At visit

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Biomarkers (plasma, serum)
Atezo atezolizumab; ADA anti-drug antibody; PBMCperipheral blood mononuclear cell; 
PK pharmacokinetic.
Note:  Based on emerging safety/efficacy data the number of PK/ADA and/or biomarker samples 
may be reduced/removed and/or the timing of samples may be modified. Samples may be 
banked in the preliminary phase and ungated at expansion as appropriate.
a Regorafenib PK includes regorafenib, regorafenib M-2, and regorafenib M-5.


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REFERENCES
Abou-Elkacem L, Arns S, Brix G, et al. Regorafenib inhibits growth, angiogenesis, and 
metastasis in a highly aggressive, orthotopic colon cancer model. Mol Cancer Ther 
2013;12:132231.
Barry KC, Hsu J, Broz ML, et al. A natural killer/dendritic cell axis defines responsive 
tumor microenvironments in melanoma. Nat Med 2018;24:117891.
Bekaii-Saab Ts, Ou FS, Ahn DS, et al. Regorafenib dose-optimisation in patients with 
refractory metastatic colorectal cancer (ReDOS): a randomized, multicentre, open-
label, phase 2 study. Lancet Oncol 2019;20:107082.
Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on 
tumor-specific T cells as a mechanism of immune evasion: implications for tumor 
immunotherapy. Cancer Immunol Immunother 2005;54:30714.
Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T cell exhaustion: 
an update on implications for chronic infections and tumor evasion. Cancer 
Immunol Immunother 2007;56:73945.
Broz M, Binnewies M, Boldajipour B, et al. Dissecting the tumor myeloid compartment 
reveals rare activating antigen presenting cells, critical for T cell immunity. Cancer 
Cell 2014;26:63852.
Butte MJ, Keir ME, Phamduy TB, et al. Programmed death-1 ligand 1 interacts 
specifically with the B7-1 costimulatory molecule to inhibit T cell responses. 
Immunity 2007;27:11122.
Chen DS and Hurwitz H. Combination of bevacizumab with cancer immunotherapy. 
Cancer J 2018;24:193204.
Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation 
immunotherapyinhibiting programmed death-ligand 1 and programmed death-1. 
Clin Cancer Res 2012;18:65807.
Coppé JP, Desprez PY, Krtolica A, et al. The senescence-associated secretory 
phenotype: the dark side of tumor suppression. Annu Rev Pathol 2010;5:99118.
DeNardo DG and Ruffell B. Macrophages as regulators of tumour immunity and 
immunotherapy. Nat Rev Immunol 2019;19:36982.
Deng R, Bumbaca D, Pastuskovas CV, et al. Preclinical pharmacokinetics, 
pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 
monoclonal antibody, an immune checkpoint inhibitor. MAbs 2016;8:593603.


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Eng C, Tim TW, Bendell J, et al. Atezolizumab with or without cobimetinib versus 
regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a 
multicentre, open-label, phase 3, randomized, controlled trial. Lancet Oncol 
2019;20:84961.
Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients 
with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-
label, phase 2 randomised controlled trial. Lancet 2016;387:183746.
Fukuoka S, Hara H, Takahashi N, et al. Regorafenib plus nivolumab in patients with 
advanced gastric (GC) or colorectal cancer (CRC): an open-label, dose-finding, 
and dose-expansion phase 1b trial (REGONIVO, EPOC1603). J Clin Oncol 
2019;37(suppl_15):2522.
Grothey A, Van Custem E, Sobrero A, et al. Regorafenib monotherapy for previously 
treated metastatic cancer (CORRECT): an international, multicentre, randomized, 
placebo-controlled, phase 3 trial. Lancet 2013;381:30312.
Grothey A. Exploration of efficacious alternative regorafenib regimens to manage hand-
foot skin reaction. ESMO poster 2019. Unpublished as 20 October 2019.
Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients 
with metastatic melanoma. N Engl J Med 2010;363:71123.
Hoff S, Grünewald S, Röse L, et al. Immunomodulation by regorafenib alone and in 
combination with anti PD1 anbitody on murine models of colorectal cancer. Annals 
of Oncology 2017;28(Issue suppl_5).
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair 
deficiency. N Engl J Med 2015;372:250920.
Legitimo A, Consolini R, Failli A, et al. Dendritic cell defects in colorectal cancer. Hum 
Vaccin Immunother 2014;10:322435.
Li J, Qin S, Xu R, et al. Regorafenib plus best supportive care versus placebo plus best 
supportive are in Asian patients with previously treated metastatic colorectal 
cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. 
Lancet Oncol 2015;16:61929.
Ribas and Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 
2018;359:135055.
Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following 
treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 
trial. Lancet 2016;387:190920.
Tecentriq(atezolizumab) Summary of Product Characteristics, Genentech. 


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Tecentriq(atezolizumab) U.S. Package Insert, Genentech.
Uitdehaag JC, de Roos JA, van Doornmalen AM, et al. Comparison of the cancer gene 
targeting and biochemical selectivities of all targeted kinase inhibitors approved for 
clinical use. PloS One 2014;9:e92416.
Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73-4506): a new oral 
multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine 
kinases with potent preclinical antitumor activity. Int J Cancer 2011;129:24555. 


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Appendix 13
Study Details Specific to AtezoRegorafenibAB928 Arm 
TABLE OF CONTENTS
A131.
Background on Atezo Regorafenib AB928 Arm
A131.1 Background on Atezolizumab
A131.2 Background on Regorafenib
A131.3 Background on AB928
A132.
Rationale for Atezo Regorafenib AB928 Arm
A132.1 The PD-L1 Pathway
A132.2 Regorafenib as a Multi-Targeted Anti-Angiogenic and 
Immunomodulatory Agent
A132.3 The Adenosine Pathway
A132.4 Rationale for Combining AB928 with Checkpoint Inhibition and 
Regorafnib
A132.5 BenefitRisk Assessment
A133.
Rationale for Dose and Schedule for Atezo Regorafenib AB928 Arm 
A133.1 Rationale for Atezolizumab Dose and Schedule
A133.2 Rationale for Regorafenib Dose and Schedule
A133.3 Rationale for AB928 Dose and Schedule
A134.
Materials and Methods Specific to Atezo Regorafenib AB928 Arm 
A134.1 Treatment in Atezo Regorafenib AB928 Arm 
A134.1.1 Formulation, Packaging, and Handling
A134.1.2 Dosage, Administration, and Compliance
A134.1.3 Stage 2 Treatment
A134.2 Concomitant Therapy for Atezo Regorafenib AB928 Arm 
A134.2.1 Permitted Therapy for Atezo Regorafenib AB928 Arm 
A134.2.2 Cautionary Therapy for Atezo Regorafenib AB928 
Arm 
A134.2.3 Prohibited Therapy for Atezo Regorafenib AB928 
Arm 
A134.3 Contraception Requirements for Atezo Regorafenib AB928 Arm 
A135.
Assessment of Safety for Atezo Regorafenib AB928 Arm 
A135.1 Safety Plan for Atezo Regorafenib AB928 Arm 
A135.1.1 Risks Associated with Atezolizumab
A135.1.2 Risks Associated with Regorafenib
A135.1.3 Risks Associated with AB928
A135.1.4 Risks Associated with Combination Use of Atezolizumab,
Regorafenib, and AB928 
A135.1.5 Management of Patients Who Experience Adverse 
Events in Atezo Regorafenib AB928 Arm 
A135.2 Adverse Events of Special Interest for Atezo Regorafenib AB928 
Arm (Immediately Reportable to the Sponsor)
A135.3 Reporting Requirements for Pregnancies in 
Atezo Regorafenib AB928 Arm 
A135.3.1 Pregnancies in Female Patients
A135.3.2 Pregnancies in Female Partners of Male Patients
A135.3.3 Abortions


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A135.3.4 Congenital Anomalies/Birth Defects
A136.
Schedule of Activities and Sample Collection for Atezo Regorafenib AB928 
Arm 


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A131 BACKGROUND FOR ATEZOREGORAFENIBAB928 ARM
A131.1
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated antibody 
mediated clearance of activated effector T cells.
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy.
Atezolizumab has been generally well tolerated.  Adverse events with potentially 
immune-mediated causes consistent with an immunotherapeutic agent, including rash, 
influenza like illness, endocrinopathies, hepatitis or transaminitis, pneumonitis, colitis, 
and myasthenia gravis, have been observed (see the Atezolizumab Investigator's 
Brochure for detailed safety results).  To date, these events have been manageable with 
treatment. 
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer, small-cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, 
and melanoma.
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies.
A131.2
BACKGROUND ON REGORAFENIB
Regorafenib is an orally administered multikinase inhibitor, which targets signaling 
pathways implicated in multiple tumor-promoting processes.  Its targets include the 
pro-angiogenic kinases, vascular endothelial growth factor receptor 1-3 (VEGFR 1-3) 
and tyrosine receptor kinase 2, and kinases promoting a pro-tumorigenic 
microenvironment, such as platelet-derived growth factor receptors and fibroblast growth 
factor.  This agent also inhibits the mutant oncogenic kinases KIT, RET, and B-RAF, as 
well as the growth factor receptor for macrophages colony stimulating factor 1 receptor 
(CSF-1R) (Wilhelm et al. 2010; Uitdehaag et al. 2014).  Regorafenib exhibited potent 
tumor growth inhibition in nonclinical models, including colon tumor models (Wilhelm et 
al. 2010; Abou-Elkacem et al. 2013). 


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Regorafenib conferred a survival benefit over best supportive care in patients with 
refractory metastatic colorectal cancer (mCRC) in randomized, double-blind, placebo-
controlled trials both in Western and Asian populations (Grothey et al. 2013; Li et al. 
2015).  The most common adverse events included handfoot syndrome, fatigue, 
diarrhea, hypertension, voice changes, oral mucositis, and rash/desquamation. 
Regorafenib is approved worldwide (under the tradename of Stivarga) for the treatment 
of patients with mCRC who previously received fluoropyrimidine-based, 
oxaliplatin-based, and irinotecan-based chemotherapy; prior anti-VEGF therapy; and, if 
patients have a KRAS wild-type tumour, previous anti-EGFR therapy. It is also 
approved in Europe in unresectable or metastatic gastrointestinal (GI) tumours and in 
patients with hepatocellular carcinoma who were previously treated with sorafenib.
A131.3
BACKGROUND ON AB928
AB928 is a low molecular weight, orally bioavailable, selective dual antagonist of the 
adenosine 2a receptor (A2aR) and the adenosine 2b receptor (A2bR).  Adenosine, a 
cellular metabolite that can inhibit the activation of various immune cell types, is present 
at high concentrations in many tumors and may play a key role in creating an 
immune-suppressed tumor microenvironment (TME).  Within the TME, adenosine can 
be generated from several extracellular sources (e.g., adenosine triphosphate [ATP]) 
and is present at higher concentrations compared with healthy tissue.  The therapeutic 
rationale for the clinical development of AB928 derives from the observation that most 
tumors contain high extracellular levels of adenosine, which activates A2aR and A2bR on 
T cells and myeloid cells, respectively, resulting in impaired T-cell activation and 
proliferation.  Through the use of biochemical and cell-based assays and nonclinical 
models, AB928 has been shown to selectively reverse the immunosuppressive effects 
caused by high concentrations of adenosine, without causing any immune activation 
effects on its own.
Refer to the AB928 Investigator’s Brochure for details on nonclinical studies.
A132 RATIONALE FOR ATEZOREGORAFENIBAB928 ARM
A132.1
THE PD-L1 PATHWAY 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies (Hodi et al. 
2010; Kantoff et al. 2010; Chen et al. 2012).
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that downregulates immune responses through binding 
to its two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor expressed on T cells 


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following T-cell activation, and expression is sustained in states of chronic stimulation 
(Blank et al. 2005; Keir et al. 2008).  B7-1 is a molecule expressed on antigen presenting 
cells and activated T cells.  Binding of PD-L1 to PD-1 and B7-1 inhibits T-cell 
proliferation and activation, cytokine production, and cytolytic activity, leading to the 
functional inactivation or exhaustion of T cells (Butte et al. 2007; Yang et al. 2011).  
Overexpression 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 pathway represents an attractive strategy for restoring tumor 
specific T-cell immunity.
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed standard of care therapies.  Objective 
responses have been observed across a broad range of malignancies, including NSCLC, 
urothelial carcinoma, renal cell carcinoma, melanoma, CRC, head and neck cancer, 
gastric cancer, breast cancer, and sarcoma (see the Atezolizumab Investigator's 
Brochure for detailed efficacy results).  
Early clinical data had shown encouraging results with the antiPD-1 checkpoint inhibitor 
pembrolizumab as a single agent in patients with mCRC assessed as having high 
microsatellite instability (MSI-H) status, but not with microsatellite stable (MSS) status 
(Le et al. 2015).  These data resulted in the May 2017 approval of pembrolizumab in 
adult and pediatric patients with tumors characterized as MSI-H or deficient for mismatch 
repair genes based on objective response rate (ORR) and durability of the response.  
ORR was similar irrespective of whether patients were diagnosed with CRC (36%) or a 
different cancer type (46% across the 14 other MSI-H cancer types).  Similar response 
rates were observed in patients with second line or later mCRC enrolled in a Phase Ia 
study investigating atezolizumab as single agent (Roche Study PCD4989g) and a Phase 
Ib study investigating the combination of atezolizumab plus bevacizumab (Roche Study 
GP28328, Arm A).  In Study PCD4989g, there was 1 responder reported in 14 patients 
with MSS status per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 
v1.1).  In the 10 patients with MSI-H status enrolled in Study GP28328, the investigator 
assessed confirmed ORR per RECIST v1.1 was 40% (95% CI: 12.2, 73.8), with all 
4 responders having partial responses.  No objective responses were seen in the 
14 patients with MSS tumors.
A132.2
REGORAFENIB AS A MULTI-TARGETED ANTI-ANGIOGENIC 
AND IMMUNOMODULATORY AGENT
Consistent with its inhibitory activity on VEGFR 1-3, regorafenib demonstrated stronger 
anti-angiogenic activity compared with a selective anti-VEGFR2 antibody in a mouse 
colon tumor model (Abou-Elkacem et al. 2013).  In addition to its inhibitory effect on 
angiogenesis, regorafenib also displayed immunomodulatory effects in nonclinical 
models (Abou-Elkacem et al. 2013; Hoff et al. 2017).  Regorafenib treatment reduced 


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tumor associated macrophage abundance in both MC38 and CTC26 colon tumors and 
also promoted their switch from the pro-tumorigenic M2 phenotype to the 
anti-tumorigenic M1 phenotype in colon tumor models (Abou-Elkacem et al. 2013; Hoff 
et al. 2017).  These effects could result from the counteracting of the immune 
suppressive properties of VEGF signaling (Chen and Hurwitz 2018) or from the blockade 
CSF1-Rdependent signaling (Hoff et al. 2017), which positively regulates macrophage 
migration, differentiation, and survival (DeNardo and Ruffell 2019).
A132.3
THE ADENOSINE PATHWAY
Research over the past decade has led to the discovery of several new 
immunomodulatory pathways, including the CD39/CD73adenosine axis, which has 
emerged as one of the most promising pathways to therapeutically target in 
immuno-oncology (Le Mercier et al. 2015; Marin-Acevedo et al. 2018).
One hallmark of immunogenic cell death is the release of ATP into the extracellular 
space within the TME, which contributes to T-cell activation and anti-tumor responses 
(Kroemer et al. 2013). However, this extracellular ATP undergoes rapid degradation by 
two ectonucleotidases: CD39 and CD73.  CD39 converts ATP to adenosine 
monophosphate (AMP), and, subsequently, CD73 converts AMP to adenosine. Multiple 
cell types within the TME, including tumor cells, cancer-associated fibroblasts, 
endothelial cells, and immune cells, express CD39 and CD73. Adenosine is present at 
high concentrations in many tumors types and has been shown to have multiple 
pro-tumoral effects, including the promotion of tumor cell growth, survival and 
dissemination; angiogenesis; and tumor immune evasion (Vigano et al. 2019). 
Adenosine is immunosuppressive for multiple immune cell types through signaling via 
A2aR and A2bR. Downstream signaling through A2aR primarily impacts the biology of 
T-cells and NK cells by impairing their effector function (i.e., proliferation and 
inflammatory cytokine production).  Downstream signaling through A2bR mostly acts on 
myeloid cells by increasing their immunosuppressive function. This includes the 
promotion of macrophage M2 polarization through the induction and upregulation of 
arginase-1, interleukin 10, and VEGF production.  In addition, adenosine signaling 
inhibits the differentiation of monocytes to dendritic cells (DCs) through A2bR and 
interferes with their Th1priming activity through both A2aR and A2bR (Vigano et al. 2019). 
Targeted blockade of the adenosine pathway was shown to effectively promote 
anti-tumor immunity and tumor control in various nonclinical models (Beavis et al. 2015; 
Dahan and Ravetch, 2016; Allard et al. 2017; Perrot et al. 2019). Therefore, targeting 
adenosine receptors to block the deleterious effects of high concentrations of
extracellular adenosine has emerged as novel approach to stimulate antitumor immunity. 
AB928 was developed as a low molecular weight, orally bioavailable, selective dual 
antagonist of A2aR and A2bR.  Nonclinical data have shown that AB928 selectively 
reverses the immunosuppressive effects caused by high concentrations of adenosine, 


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without causing any immune activation effects of its own. Targeting the adenosine 
pathway by dual inhibition of A2aR and A2bR combines the advantages of (1) blockade of 
adenosine signaling downstream of the redundant pathways that generate adenosine
and (2) broad interference with the multiple pro-tumorigenic and immunosuppressive 
activities of adenosine. 
Recent evidence suggests a pro-tumorigenic role for the adenosine pathway in the 
biology of CRC. First, the immunosuppressive role of the adenosine pathway has been 
documented in nonclinical colon tumor models through apoptotic T-regulatory cells. Maj 
et al. reported the presence of apoptotic T-regulatory cells in the TME of human ovarian 
cancer samples, as well as in murine tumors, including the syngenic MC38 colon 
carcinoma. However, these T-regulatory cells retained strong immunosuppressive 
properties and abolished the anti-tumor effect of immunotherapy. The authors further 
showed that apoptotic T-regulatory cells suppressed effector T-cells through the release 
of large amounts of ATP and the conversion to adenosine via the CD39 and CD73 
ectonucleotidases (Maj et al. 2017). Analyses of clinical samples further support a role 
of adenosine in T-regulatory cellmediated suppression in CRC. Sundström et al 
showed that T-regulatory cells isolated from patients with CRC expressed high levels of 
CD39 and were able to prevent migration of CD8+ T cells, which could be rescued by 
blocking CD39 (Sundström et al. 2016).  Another study also showed that CD39+ 
T-regulatory cells accumulate in tumors and peripheral blood of patients with CRC and 
that the peripheral CD39+ T-regulatory cells isolated from these patients suppress 
proliferation of T-cells, suggesting CD39 as a potential therapeutic target in CRC
(Ahlmanner et al. 2018).
Furthermore, several correlative studies also suggest a prognostic role for the adenosine 
pathway in CRC. Data from the The Cancer Genome Analysis showed that, of the many
tumor types that express high levels of CD73, CRC is among the highest across tumor 
types (Direnzo et al. 2019) and high expression of CD73 was correlated with decreased 
overall survival (OS) in CRC (Wu et al. 2012). Additionally, selected single nucleotide 
polymorphisms in the ENTPD1 gene encoding for CD39 may affect the clinical outcome 
of patients with mCRC treated with FOLFIRI and bevacizumab. Indeed, patients with 
any C allele in CD39 rs11188513 had a significantly shorter median PFS and OS
compared with patients with the T/T variant (Tokunaga et al. 2019). 
Taken together, nonclinical and clinical data suggest that targeting the adenosine
pathway may improve outcomes for patients with CRC.
A132.4
RATIONALE FOR COMBINING AB928 WITH CHECKPOINT 
INHIBITION AND REGORAFENIB
The immune suppressive role of VEGF is now well established, and the combination of 
anti-VEGF therapies with blockade of the PD-L1/PD-1 axis has shown synergy in 


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nonclinical models and has resulted in positive outcomes in Phase I to III clinical studies 
(Chen and Hurwitz 2018).  In addition, M2-macrophages are considered a central driver
of the immunosuppressive TME through their ability to suppress DC differentiation and 
function and T-cell effector function.  As a result, macrophage depletion can unleash 
CD8T-cell response and increase the efficacy of checkpoint blockade in nonclinical 
tumor models (DeNardo and Ruffell 2019).  Therefore, among the multi-targeted 
mechanisms of action of regorafenib, blockade of VEGF and CSF-1R signaling is 
expected to show combinatorial efficacy with checkpoint inhibition (CPI).  Accordingly, 
the combination of regorafenib with antiPD-1 blockade showed superior anti-tumor 
activity compared with either individual agent in murine colon tumor models (Hoff et al. 
2017).
Clinical data from the REGONIVO trial presented at ASCO 2019 (Fukuoka et al. 2019) 
showed promising results when combining the standard-of-care treatment regorafenib 
with the antiPD-1 checkpoint inhibitor antibody nivolumab in patients with advanced, 
metastatic colorectal or gastric cancer (GC).  An objective tumor response was observed 
in 19 patients (38%), including 11 patients with MSS GC, 7 patients with MSS CRC, and 
1 patient with MSI-H CRC, with corresponding ORRs of 44% in GC and 29% in MSS 
CRC.  At a median follow-up of 8.0 months, the median PFS time was 6.3 months.  
These outcomes outperform the clinical activity of regorafenib and antiPD-1 antibody 
when used as a single-agent in MSS mCRC where ORRs of 2% and 0%, respectively,
were observed (Grothey et al. 2013; Le et al. 2015; Li et al. 2015; Eng et al. 2019).  
Taken together, these data suggest a synergy between PD-1 blockade and regorafenib 
and provide a rationale to further investigate combinatorial strategies building on the 
backone of regorafenib plus antiPD-L1/PD-1 therapy in MSS CRC.  
Elevated CD73 expression has the potential to increase extracellular levels of adenosine 
that render tumors more resistant to immunotherapies (Serra et al. 2011). Adenosine 
stimulates the adenosine receptors on T cells and NK cells, thereby increasing PD-L1 
expression and suppressing anti-tumor immune responses (Vigano et al. 2019). These 
nonclinical findings appear to be corroborated by clinical correlative data in CRC that 
showed a positive correlation between A2aR expression and PD-L1 expression in 
primary tumor specimens and an independent association for the expression of both
markers with shorter OS (Wu et al. 2012). Additionally, CD73 was shown to be 
upregulated in patients following antiPD-1 treatment, pointing to the adenosine pathway 
as a potential mechanism of resistance to antiPD-1 therapy (Fong et al. 2017). 
Accordingly, recent nonclinical studies have shown that blockade of the adenosine 
receptor with either anti-CD73 antibodies or adenosine receptor antagonists enhances 
the anti-tumor immune response induced by PD-L1/PD-1 inhibitors (Allard et al. 2013; 
Mittal et al. 2014; Beavis et al, 2015; Perrot et al. 2019). Furthermore, a preliminary 
signal of clinical activity has been reported for the combination of the anti-CD73 antibody 


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oleclumab with the antiPD-L1 antibody durvalumab in pancreatic cancer and MSS CRC 
(Overman et al. 2018). These findings underscore the potential for synergy of A2aR/ 
A2bR antagonists plus PD-1/PD-L1 blockade.
Finally, additional mechanisms suggest the potential for combined efficacy of 
regorafenib with adenosine pathway inhibition. Adenosine has direct mitogenic effects 
on vascular cells that may contribute to angiogenesis, although the main pro-angiogenic 
actions of adenosine have been attributed to its ability to regulate the production of 
pro- and anti-angiogenic substances from vascular cells and immune cells within the 
microenvironment of hypoxic tissues, mediated by both A2aR and A2bR signaling
(Feoktistov et al. 2002; Olah and Caldwell, 2003; Desai et al. 2015). In addition, data 
from the REGONIVO study showed a decrease in T-regulatory cell infiltration in 
post-treatment biopsies from patients who responded to the regorafenib plus nivolumab 
combination.  As apoptotic T-regulatory cells can contribute to immunosuppression 
within the TME via the adenosine pathway (Maj et al. 2017), the finding from the
REGONIVO study indicates that adding an inhibitor of the adenosine pathway to the 
combination of a checkpoint inhibitor plus regorafenib will enable a superior inhibition of 
intratumoral T-regulatory cells.
Therefore, the opportunity to evaluate the combination of an adenosine pathway 
inhibitior, such as AB928, an anti-angiogeneic agent, such as regorafenib, and an
antiPD-L1 therapy, such as atezolizumab, could bring together both additive and 
synergistic mechanisms of action, which could ultimately translate into clinical benefit in
patients with mCRC who have become refractory to first- and second-line standard 
therapies.  
A132.5
BENEFITRISK ASSESSMENT
This study will enroll patients with mCRC who have become refractory to first- and 
second-line standard therapies.  This patient population has a median OS of less than 
9 months with currently available treatments.  Treatment options have shown limited 
efficacy and are often poorly tolerated. 
Despite the success of single-agent CPI in the MSI-H patient population, the vast 
majority of patients with CRC have MSS tumors and do not respond to single-agent CPI, 
highlighting the need for safe and effective combination treatments.  In addition, the 
benefit of single-agent regorafenib over best supportive care is limited.  Therefore, there
remains a great need for investigating new cancer immunotherapy combinations to 
improve the outcome of this difficult-to-treat patient population.
The most frequently observed adverse drug reactions (30%) in patients receiving 
regorafenib are pain, handfoot skin reaction, asthenia/fatigue, diarrhea, decreased 
appetite and food intake, hypertension, and infection.  These toxicities occur early and 


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may be dose-dependent (Grothey 2019).  A randomized Phase II study (the ReDOS trial) 
showed that using a weekly dose-escalation strategy (from 80 mg/day to 160 mg/day) 
enabled patients to stay on treatment longer and decreased the incidence of Grade 3 
and 4 toxicities when compared with using the approved starting dose of 160 mg/day 
(Bekaii-Saab et al. 2019).  
In the dose-escalation cohort of the REGONIVO study, patients were treated with 80-mg, 
120-mg, or 160-mg doses of regorafenib once per day for 21 days in a 28-day cycle plus 
3 mg of nivolumab every 2 weeks (Q2W).  Treatment-related adverse events (all grades) 
were reported in 100% of patients across the 3 dose groups.  The rate of Grade 3 
treatment-related adverse events was 40%.  The most common Grade 3 
treatment-related adverse events were rash (12%), proteinuria (12%), palmar-plantar 
erythrodysesthesia (10%), and liver dysfunction (6%).  In patients who received 
regorafenib at the 80-mg dose, the rate of Grade 3 treatment-related adverse events 
was 27% compared with 44% in those who received the 120-mg dose.  These toxicities 
were considered to be manageable by the investigators and were balanced with the 
unprecedented efficacy signal in this heavily pre-treated patient population.  
The dose of regorafenib that is planned to be administered in this study is 120 mg/day, 
which is the maximum tolerated dose (MTD) that was identified in the REGONIVO study.  
Moreover, based on the ReDOS study findings dose escalation from 80 mg/day to 
120 mg/day during Cycle 1 will be allowed in order to improve the safety profile of 
regorafenib in combination with CPI.
Because AB928 is currently being evaluated in cancer patients and efficacy data are not 
yet available, its benefits are unknown at this time. However, based on its mechanism of 
action, nonclinical data demonstrated that AB928 selectively reverses the 
immunosuppressive effects caused by high concentrations of adenosine, without 
causing any immune activation effects of its own. Preliminary safety data from the 
first-in-human Phase I placebo-controlled, blinded study in healthy volunteers 
(Study AB928CSP0001) showed that the investigational product (blinded AB928 or 
matching placebo) was tolerable at all doses tested (i.e., no early stopping rules were 
met) and did not affect any physiologic parameters potentially sensitive to adenosine 
inhibition at a dose of 75 mg. All reported adverse events were of mild or moderate 
severity, and there was no clear pattern of toxicity observed at the dose levels tested, 
other than mild-to-moderate GI symptoms. No clinically significant laboratory findings 
(with the exception of an increase in C-reactive protein in 1 patient who received a single 
10-mg dose of blinded investigational product) or signs of general, cardiac, or neurologic 
toxicity were observed, and no patients discontinued from the study. 
Safety data are also available for the combination of AB928 with the antiPD-1 antibody 
AB122, which is currently undergoing evaluation in an ongoing Phase I, open-label, 


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multicenter, dose-escalation and dose-expansion study (Study AB928CSP0005).  In the 
dose-escalation phase, patients received doses of 75 mg, 150 mg, and 200 mg once 
daily (QD) in combination with AB122 at a dose and schedule of 240 mg Q2W. As of 
03 July 2019, 9 of 12 patients (75%) with previously treated advanced solid tumors 
reported at least one treatment-emergent adverse event.  The most commonly reported 
adverse events (in more than 1 patient) regardless of AB928 dose, severity, or 
relationship to investigational treatment were fatigue (4 patients); nausea and rash 
(3 patients each); and, abdominal pain, headache, pruritus, sinusitis, upper respiratory 
tract infection, and vomiting (2 patients each).  Most adverse events were mild to 
moderate in intensity.  All 4 cases of fatigue were considered related to either AB928 
and/or AB122, which was the most common treatment-related adverse event.  All cases 
of fatigue were Grade 1.  Three patients reported Grade 3 adverse events; none were 
related to AB928.  No Grade 4 or 5 events were observed.  Five serious adverse events
were reported by 3 patients; no serious event was considered related to either AB928 or 
AB122.  One patient who received AB928 at 150 mg QD experienced Grade 2 
maculopapular rash that was considered dose-limiting according to the protocol 
definition as the participant missed >20% of AB928 doses during the dose-limiting 
toxicity (DLT) evaluation period as a result of the event.  No other DLTs were reported.
Safety data are available for single-agent atezolizumab in patients with solid tumors, 
including CRC.  Potential overlapping toxicities for the combination of atezolizumab, 
regorafenib, and AB928 may occur within the system organ classes of GI, hepatobiliary, 
cardiac, skin, nervous system, and blood and lymphatic system disorders. The relevant 
corresponding overlapping toxicities of atezolizumab include immune-related colitis, 
hepatitis, myocarditis, skin rash, meningoencephalitis and thrombocytopenia.  
Exposures to AB928, regorafenib, and regorafenib active metabolites M-2 and M-5 may 
be affected by coadministration of AB928 and regorafenib.  As AB928 is a substrate of 
breast cancer resistance protein (BCRP), regorafenib has potential to increase AB928 
exposure through inhibition of BCRP.  AB928, a CYP3A4 inducer in vitro, may reduce 
regorafenib exposure but increase exposures to active metabolites M-2 and M-5.  AB928, 
regorafenib, M-2, and M-5 exposures in patients will be determined to monitor the 
potential DDI risk.  Additionally, the concomitant use of known strong CYP3A4 inducers 
as well as known BCRP substrates with a narrow therapeutic window that are orally 
administered will be prohibited during study participation.
In summary, the investigation of the safety of each molecule as a single agent in patients 
with solid tumors has not revealed findings that would prohibit the investigation of the 
atezolizumab, regorafenib, and AB928 combination in the setting of a Phase Ib/II study.  
Considering the different but potentially synergistic mechanisms of action of 
atezolizumab, regorafenib, and AB928, as well as the preliminary efficacy and 


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manageable safety profile of the above described combinations, it is hypothesized that 
treatment with atezolizumab, regorafenib, and AB928 has promising therapeutic 
potential in solid tumors such as MSS mCRC.
For the evaluation of the impact of the COVID-19 pandemic on the benefitrisk 
assessment, please refer to Section 1.4.
A133 RATIONALE FOR DOSE AND SCHEDULE FOR 
ATEZOREGORAFENIBAB928 ARM
A133.1
RATIONALE FOR ATEZOLIZUMAB DOSE AND SCHEDULE
Atezolizumab will be administered at a fixed dose of 840 mg Q2W (840 mg on Days 1 
and 15 of each 28-day cycle).  The average concentration following the 840 mg Q2W 
dosage is expected to be equivalent to that of 1200 mg every 3 weeks (Q3W), an
approved dosage for atezolizumab , as outlined in the prescribing information.  
Anti-tumor activity has been observed across doses ranging from 1 to 20 mg/kg Q3W.  
In Study PCD4989g, the MTD of atezolizumab was not reached and no DLTs were 
observed at any dose.  The fixed dose of 1200 mg Q3W (equivalent to an average body 
weightbased dose of 15 mg/kg Q3W) was selected on the basis of both nonclinical
studies (Deng et al. 2016) and available clinical pharmacokinetic, efficacy, and safety 
data (refer to the Atezolizumab Investigator's Brochure for details).
A133.2
RATIONALE FOR REGORAFENIB DOSE AND SCHEDULE
The approved dose for regorafenib is 160 mg/day.  In the REGONIVO study evaluating 
regorafenib in combination with nivolumab in Asian patients, DLTs were reported at the 
160-mg/day dose and Grade 3 skin toxicities were reported in 20% of the patients 
treated with the 120-mg/day dose.  This resulted in the use of the 80-mg/day dose of 
regorafenib in the expansion cohort.  However, modeling and simulation analyses of 
data from the CORRECT and CONCUR trials showed that a starting dose of 80 mg/day 
might result in reduced efficacy if not escalated to doses of either 120 mg/day or 
160 mg/day (Grothey 2019).  Therefore, to ensure an efficacious dose is administered, 
as well as to account for the fact that this study will be conducted in a global population 
(inclusive of Caucasian patients with potential differences in body size, drug metabolism, 
and toxicities), regorafenib will be used at a dose of 120 mg/day on Days 121 of each 
28-day cycle.  Furthermore, to account for the results from the ReDOS trial (Bekaii-Saab 
et al. 2019) showing a lower incidence of adverse events, a starting dose of 80 mg/day 
of regorafenib will be allowed, followed by a dose escalation to 120 mg/day (as per 
institutional guidelines) during Cycle 1 if no significant drug-related toxicity is observed.
A133.3
RATIONALE FOR AB928 DOSE AND SCHEDULE
Preliminary data from Study AB928CSP0001 in healthy volunteers demonstrated that 
the investigational product (blinded AB928 or matching placebo) was tolerable at the 
doses tested (10200 mg) and exhibited a predictable, linear, dose-proportional,


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pharmacokinetic profile. To date, all reported adverse events in participants receiving 
single or multiple doses of AB928 were mild or moderate in severity, and no participants
have discontinued from the study. There was no impact on any physiologic parameters 
that are potentially sensitive to adenosine inhibition at a dose of 200 mg QD.
As of 6 September 2019, AB928 at doses of 75200 mg QD has been assessed in 
combination with multiple backbones in over 40 patients in oncology studies.  The 
recommended dose for expansion of AB928 across all studies in the AB928 program is 
150 mg QD. This dose regimen was selected based on the available pharmacokinetic 
(PK) data, correlation between PK and pharmacodynamic data, and the well-tolerated 
safety profile of AB928 in combination with either a chemotherapy or a PD-1 inhibitor 
(AB122).
A134 MATERIALS AND METHODS SPECIFIC TO 
ATEZOREGORAFENIBAB928 ARM
A134.1
TREATMENT IN ATEZOREGORAFENIBAB928 ARM
A134.1.1 Formulation, Packaging, and Handling
A134.1.1.1
Atezolizumab
The atezolizumab drug product will be supplied by the Sponsor as a sterile liquid in a 
single-use, 20-mL glass vial.  The vial contains approximately 20 mL (1200 mg) of 
atezolizumab solution.
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure.
A134.1.1.2
Regorafenib
For information on the formulation, packaging, and handling of regorafenib, refer to the
local prescribing information. 
A134.1.1.3
AB928
The AB928 drug product will be supplied by the Sponsor as gelatin capsules at a dose
strength of 25 mg.
For information on the formulation and handling of AB928, see the pharmacy manual 
and the AB928 Investigator's Brochure.
A134.1.2 Dosage, Administration, and Compliance
Patients in the AtezoRegorafenibAB928 arm will receive treatment as outlined in 
Table 1 until unacceptable toxicity or loss of clinical benefit defined as (1) confirmed 
disease progression or (2) lack of continued benefit as determined by the investigator, 
after an integrated assessment of radiographic and biochemical data, local biopsy 
results (if available), and clinical status (e.g., symptomatic deterioration such as pain 


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secondary to disease) (see Section 3.1.1 in the protocol body for details).  It is 
recommended that treatment be initiated no later than 7 days after randomization. 
Table 1
Treatment Regimen for AtezoRegorafenibAB928 Arm
Cycle Length
Dose, Route, and Regimen
(drugs listed in order of administration)
28 days

AB928 150 mg by mouth once daily on Days 128 of each cycle

Atezolizumab 840 mg IV on Days 1 and 15 of each cycle

Regorafenib 120 mg by mouth once daily on Days 121 of each 
cycle a
Atezoatezolizumab.
a Regorafenib should be initiated at 80 mg, allowing sufficient time to monitor 
drug-related toxicities before considering dose escalation to 120 mg.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Guidelines for dose modification and treatment interruption or discontinuation because of 
toxicities are provided in Section A135.1.5.  Atezolizumab, regorafenib, or AB928 
treatment interruptions for reasons other than toxicity (e.g., surgical procedures) may be 
allowed.  The acceptable length of treatment interruption must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator. The 
Medical Monitor is available to advise as needed.
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 5.3.5.12.  No safety data related to atezolizumab or AB928 overdose are 
available.  The highest dose of regorafenib studied clinically is 220 mg per day.  The 
most frequently observed adverse drug reactions at this dose were dermatologic events, 
dysphonia, diarrhea, mucosal inflammation, dry mouth, decreased appetite, 
hypertension, and fatigue.  There is no specific antidote for regorafenib overdose.  In the 
event of suspected overdose, interrupt regorafenib, institute supportive care, and 
observe until clinical stabilization.
A134.1.2.1
Atezolizumab
Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Days 1 
and 15 of each 28-day cycle.  


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Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 5.  
Atezolizumab infusions will be administered per the instructions outlined in Table 2.
Table 2
Administration of First and Subsequent Atezolizumab Infusions
First Infusion
Subsequent Infusions

No premedication is permitted prior to the 
atezolizumab infusion.

Vital signs (pulse rate, respiratory rate, 
pulse oximetry, blood pressure, and 
temperature) should be recorded within 
60 minutes prior to the infusion.

Atezolizumab should be infused over 
60 (15) minutes.

If clinically indicated, vital signs should be 
recorded every 15 (5) minutes during the 
infusion and 30 (10) minutes after the 
infusion.

Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms.

If the patient experienced an 
infusion-related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator.

Vital signs should be recorded within 
60 minutes prior to the infusion.

Atezolizumab should be infused over 
30 (10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion.

If the patient experienced an infusion-
related reaction with the previous infusion 
or if clinically indicated, vital signs should 
be recorded during the infusion and at 
30 (10) minutes after the infusion.
Guidelines for medical management of infusion-related reactions (IRRs) for 
atezolizumab are provided in Appendix 6.
No dose modification for atezolizumab is allowed.  Guidelines for atezolizumab 
treatment interruption or discontinuation because of toxicities are provided in 
Section A135.1.5.  
A134.1.2.2
Regorafenib
Regorafenib will be used in the commercially available formulation.
Patients will receive regorafenib at a dose level of 120 mg (three tablets of 40 mg each) 
orally once daily on Days 121 of a 28-day cycle (see Table 1).  This 4-week period is 
considered a treatment cycle.  Regorafenib should be initiated at 80 mg, allowing 
sufficient time to monitor drug-related toxicities before considering dose escalation to 
120 mg.


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Regorafenib should be taken at the same time each day.  On clinic visit days when PK 
samples are collected, patients should take their regorafenib dose in the clinic. The 
tablets should be swallowed whole with water after a light meal that contains 30% fat.  
An example of a light (low-fat) meal would include one portion of cereal (about 30 g), 
one glass of skimmed milk, one slice of toast with jam, one glass of apple juice, and one 
cup of coffee or tea (520 calories, 2 g fat).
To assess patient compliance with self-administration of regorafenib, patients will be 
required to record the time and date they took each dose in a medication diary; missed 
doses will also be recorded.  Patients will be instructed to bring all unused study 
medication and their medication diaries at specified study visits for assessments of 
compliance.
Guidelines for regorafenib dose modification and treatment interruption or 
discontinuation because of toxicities are provided in Section A135.1.5.
A134.1.2.3
AB928
Patients will receive AB928 at a dose of 150 mg (six capsules of 25 mg each) orally 
once daily on Days 1-28 of a 28-day cycle (see Table 1).  
AB928 should be taken at approximately the same time each day.  On clinic visit days
when PK samples are collected, patients should take their AB928 dose in the clinic.  
AB928 capsules should be swallowed whole with a glass of non-carbonated, room-
temperature water (additional water is permitted) and should not be chewed, cut, or 
opened.  If a dose of AB928 is missed (i.e., not taken within 12 hours after the scheduled 
dosing time), the patient should resume dosing with the next scheduled dose.  Missed or 
vomited doses will not be made up.
To assess patient compliance with self-administration of AB928, patients will be required 
to record the time and date they took each dose in a medication diary; missed doses will 
also be recorded.  Patients will be instructed to bring all unused study medication and 
their medication diaries at specified study visits for assessments of compliance
Guidelines for AB928 dose modification and treatment interruption or discontinuation 
because of toxicities are provided in Section A135.1.5.
A134.1.3 Stage 2 Treatment
Patients in Stage 1 who experience loss of clinical benefit as determined by the 
investigator (as described in Section 3.1.1 in the protocol body) or unacceptable toxicity 
may be eligible to receive a different treatment combination during during Stage 2, 


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provided a Stage 2 treatment is available for enrollment and they meet the eligibility 
criteria of that treatment regimen.  Stage 2 treatment must begin within 3 months after 
the patient has experienced loss of clinical benefit or unacceptable toxicity.  However, it 
is recommended that patients begin Stage 2 treatment as soon as possible, but no 
earlier than 2 weeks after the last dose of treatment in Stage 1. 
Tumor assessments performed prior to or at the time of loss of clinical benefit or 
unacceptable toxicity during Stage 1 may serve as baseline assessments for Stage 2, 
provided the tumor assessments are performed within 28 days prior to initiation of 
Stage 2 treatment (i.e., Day 1 of Cycle 1).  Stage 2 treatment will continue until 
unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Table 3
Stage 2 Treatment Regimens Available for the 
AtezoRegorafenibAB928 Arm
Study Treatment
Appendix
No Stage 2 treatment currently available 

A134.2
CONCOMITANT THERAPY FOR 
ATEZOREGORAFENIBAB928 ARM
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated study treatment from 
7 days prior to initiation of study treatment to the treatment discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.
A134.2.1 Permitted Therapy for AtezoRegorafenibAB928 Arm
Patients are permitted to use the following therapies during the study:

Oral contraceptives

Hormone-replacement therapy

Prophylactic anticoagulation 
Prophylactic anticoagulation for the patency of venous access devices is 
allowed provided the activity of the agent results in an INR 1.5upper limit of 
normal (ULN) and aPTT is within normal limits within 14 days prior to Day 1.
Prophylactic use of low molecular weight heparin (i.e., enoxaparin 40 mg/day) 
is allowed.

Prophylactic antibiotic or anti viral treatment administered according to institutional 
standards


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
Vaccinations (such as influenza, COVID-19)
Live, attenuated vaccines are not permitted (see Section A134.2.3).

Prophylactic standard anti-emetic therapy

Megestrol acetate administered as an appetite stimulant after initiation of study 
treatment

Mineralocorticoids (e.g., fludrocortisone)

Inhaled corticosteroids administered for chronic obstructive pulmonary disease or 
asthma

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency

Hormonal therapy with gonadotropin releasinghormone agonists or antagonists for 
prostate cancer

Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below:
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  
Treatment with atezolizumab, regorafenib, and AB928 may be continued during 
palliative radiotherapy.

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.
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 


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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).
A134.2.2 Cautionary Therapy for AtezoRegorafenibAB928 Arm
Corticosteroids, Immunosuppressive Medications, and Tumor Necrosis 
FactorInhibitors
Systemic corticosteroids, immunosuppressive medications, and tumor necrosis factor
(TNF) inhibitors may attenuate potential beneficial immunologic effects of treatment 
with atezolizumab and AB928.  Therefore, in situations in which systemic corticosteroids,
immunosuppressive medications, or TNFinhibitors would be routinely administered, 
alternatives, including antihistamines, should be considered.  If the alternatives are not 
feasible, systemic corticosteroids, immunosuppressive medications, and TNF-
inhibitors may be administered at the discretion of the investigator.
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy (refer to Appendix 6 for details).
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer (see 
Section A134.2.3) may be used during the study at the discretion of the investigator.
UDP-Glucuronosyltransferase 1-1 and UDP-Glucuronosyltransferase 1-9
Regorafenib is metabolized by UDP-glucuronosyltransferase 1-1 (UGT1A1), 
andregorafenib and its metabolites are inhibitors of UGT1A1 and 
UDP-glucuronosyltransferase 1-9 (UGT1A9). Therefore, inhibitors of UGT1A1 
(e.g., erlotinib, nilotinib, pazopanib, lapatinib, sorafenib) and substrates of UGT1A1 
(e.g., irinotecan with its active metabolite SN-38, raltegravir, bazedoxifene, eltrombopag) 
and substrates of UGT1A9 (e.g., sorafenib, mycophenolic acid) should be used with 
caution.
Medications Given with Precaution due to Effects Related to Cytochrome 
P450 Enzymes
AB928 is a substrate of CYP2C8. Caution should be exercised when AB928 is 
concomitantly administered with known CYP2C8 strong inhibitors (e.g., gemfibrozil) 
and/or known strong CYP2C8 inducers.


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Other Potential DrugDrug Interactions with AB928
In vitro nonclinical studies have identified AB928 as a substrate of P-gp, BCRP, CYP3A4, 
CYP2C8, and of multiple isoforms of UGT (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 
2B4, 2B7, and 2B15). AB928 is also a weak to moderate inhibitor of CYP2C8, CYP2C9, 
CYP2C19, and CYP3A4. AB928 is an inhibitor of P-gp, BCRP, BSEP, OAT3, OCT2, 
MATE1, and MATE2-K. Lastly, AB928 is a weak to moderate inducer of CYP3A4. 
Potential drugdrug interactions may occur with concomitant medications acting on 
these pathways.
A134.2.3 Prohibited Therapy for AtezoRegorafenibAB928 Arm
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, may be prohibited 
prior to starting study treatment, depending on the agent, and is prohibited during 
study treatment until disease progression is documented and the patient has 
discontinued study treatment, with the exception of palliative radiotherapy and local 
therapy under certain circumstances outlined above in Section A134.2.1.

Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 28 days prior to initiation of study treatment and during study treatment.

Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with atezolizumab and AB928, for 
5 months after the final dose of atezolizumab, and for 90 days after the final dose of 
AB928.

Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin 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 and AB928.

Known strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, 
phenobarbital, and St. John’s Wort) and strong CYP3A4 inhibitors (e.g., 
clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, 
telithromycin, and voriconazole)

Known breast cancer resistance protein (BCRP) strong inhibitors (e.g., cyclosporin 
A, eltrombopag) and/or BCRP substrates with a narrow therapeutic window 
administered orally (e.g., prazosin, rosuvastatin)

Known P-glycoprotein (P-gp) strong inhibitors (eg, itraconazole, quinidine, verapamil, 
dronedarone ranolazine) and/or P-gp substrates with a narrow therapeutic window 
administered orally (e.g., digoxin)

Strong UGT inhibitors (e.g., atazanavir)


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
Sensitive BSEP substrates 

Sensitive OCT2 substrates

Sensitive MATE-1 substrates
A134.3
CONTRACEPTION REQUIREMENTS FOR 
ATEZOREGORAFENIBAB928 ARM
Contraception requirements for women and men in the Atezo Regorafenib AB928 arm 
are outlined below:

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for 5 months after the last dose of 
atezolizumab, for 2 months after the last dose of regorafenib, and for 30 days after 
the last dose of AB928.  Women must refrain from breastfeeding during this same 
period of time.  
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, hormonal contraceptives that inhibit 
ovulation, hormone releasing intrauterine devices, 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 a condom, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for 2 
months after the last dose of regorafenib and for 30 days after the last dose of 
AB928 to avoid exposing the embryo.  Men must refrain from donating sperm 
during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.


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A135 ASSESSMENT OF SAFETY FOR ATEZOREGORAFENIBAB928
ARM
A135.1
SAFETY PLAN FOR ATEZOREGORAFENIBAB928 ARM
The safety plan for patients in this study is based on clinical experience with 
atezolizumab, regorafenib, and AB928 in completed and ongoing studies.  The 
anticipated important safety risks are outlined below (see Sections A135.1.1, A135.1.2,
A135.1.3, and A135.1.4).  Guidelines for the management of patients who experience 
specific adverse events are provided in Section A135.1.5.
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.  Because of the potential for overlapping toxicities identified for 
atezolizumab, regorafenib, and AB928, special caution will be taken by performing a 
planned safety evaluation for patients randomized to this arm (see Section 3.1.1.1). 
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 in the protocol body.
A135.1.1 Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, hypophysitis, adrenal insufficiency, Guillain-Barré
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
myocarditis, nephritis, myositis, and severe cutaneous adverse reactions.  
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), 
which are considered to be potential risks for atezolizumab.  Refer to Appendix 6 of the 
protocol and Section 6 of the Atezolizumab Investigator's Brochure for a detailed 
description of anticipated safety risks for atezolizumab.  
A135.1.2 Risks Associated with Regorafenib
The overall safety profile of regorafenib is based on data from more than 4800 treated 
patients in clinical trials, including placebo-controlled Phase III data for 636 patients with 
mCRC, 132 patients with GI stromal tumors, and 374 patients with hepatocellular 
carcinoma.  The most serious adverse drug reactions in patients receiving regorafenib 
are severe liver injury, hemorrhage, GI perforation, and infection.  The most frequently 
observed adverse drug reactions (30%) in patients receiving regorafenib are pain, 
hand-foot skin reaction, asthenia/fatigue, diarrhea, decreased appetite and food intake, 


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hypertension, and infection.  Refer to the regorafenib local prescribing information for 
complete information regarding clinical safety.
A135.1.3 Risks Associated with AB928
The safety profile for AB928 is limited and based on data from less than 40 patients with 
advanced cancer and 85 healthy volunteers (data cutoff July 2019).  Patients with 
advanced cancer received AB928 at doses of 75 mg, 150 mg, or 200 mg once daily in 
combination with chemotherapy and/or immunotherapy.  The most frequently observed 
AB928-related adverse events, regardless of dose and combination therapy, occurring in 
2 or more patients, were fatigue, nausea, pruritus, and anemia.  Grade 3 adverse events 
related to AB928 were limited to fatigue and anemia (2 patients each); and nausea, 
neutrophil count decreased, and white blood cell count decreased (1 patient each).  No 
AB928-related Grade 4 or Grade 5 events were reported.  No serious adverse events 
were considered related to AB928.  Based on limited human safety information, no 
adverse drug reactions have been identified for AB928.  Refer to the AB928 
Investigator’s Brochure for detailed safety information from the ongoing clinical program
of AB928.
A135.1.4 Risks Associated with Combination Use of Atezolizumab,
Regorafenib, and AB928
Potential overlapping toxicities for the combination of atezolizumab, regorafenib, and 
AB928 may occur within the system organ classes of GI, hepatobiliary, cardiac, skin, 
nervous system, and blood and lymphatic system disorders and include gastrointestinal 
toxicities (diarrhea/colitis), hepatic toxicity, cardiac toxicities (cardiac ischemia, 
myocardial infarction/myocarditis), dermatological toxicity/skin rash, Posterior Reversible 
Encephalopathy Syndrome (PRES)/meningoencephalitis, and 
hemorrhage/thrombocytopenia. 
A135.1.5 Management of Patients Who Experience Adverse Events in 
AtezoRegorafenibAB928 Arm
A135.1.5.1
Dose Modifications
There will be no dose modifications for atezolizumab in this study.
For management of drug-related toxicities, the dose of regorafenib can be reduced by a 
decrement of 40 mg once a day (one dose level) from 120 mg to 80 mg.  During the 
allowed dose escalation (Section A134.1.2.2), the continuation of a dose of 80 mg/day 
for as long as required for the management of drug-related toxicities is also allowed.  If 
further dose reduction below 80 mg is indicated, the patient must discontinue 
regorafenib, unless the patient is likely to derive clinical benefit as determined by the 
investigator.  The Medical Monitor is available to advise as needed.  After dose reduction, 


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the dose of regorafenib may be re-escalated at the investigator's discretion, provided 
there are no safety concerns.
For management of drug-related toxicities, the dose of AB928 may be reduced up to two 
times as outlined in Table 4.  If further dose reduction below 75 mg is indicated, AB928 
should be discontinued.  After dose reduction, the dose may be escalated during 
subsequent administrations at the investigator's discretion.
Table 4
Recommended Dose Reductions for AB928 
Initial Dose
First Dose Reduction
Second Dose Reduction
AB928
150 mg
100 mg
75 mg
A135.1.5.2
Treatment Interruption for Toxicities
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 more 
than 12 weeks, the patient will be discontinued from the study.  However, atezolizumab 
may be withheld for more than 12 weeks to allow for patients to taper off corticosteroids 
prior to resuming treatment.  Atezolizumab can be resumed after being withheld for more 
than 12 weeks if the patient is likely to derive clinical benefit. The decision to 
re-challenge patients with atezolizumab should be based on investigator’s assessment of 
benefitrisk and documented by the investigator.  The Medical Monitor is available to 
advise as needed.
Regorafenib treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If regorafenib has been withheld for more 
than 42 days because of toxicity, the patient should be discontinued from regorafenib.  
However, regorafenib can be resumed after being withheld for more than 42 days if the 
patient is likely to derive clinical benefit.  The Medical Monitor is available to advise as 
needed.
AB928 treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If AB928 has been withheld for more than 
42 days because of toxicity, the patient should be discontinued from AB928.  However, 
AB928 can be resumed after being withheld for more than 42 days if the patient is likely 
to derive clinical benefit.  The Medical Monitor is available to advise as needed.


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If atezolizumab, regorafenib, or AB928 is permanently discontinued, the other agent or 
agents should also be discontinued unless the patient is likely to derive clinical benefit 
from single-agent use, as determined by the investigator. The Medical Monitor is
available to advise as needed.
Refer to Section A13-4.1.2 for information on dose interruptions for reasons other than 
toxicity.
A135.1.5.3
Management Guidelines for Adverse Events
Guidelines for the management of patients who experience specific adverse events are 
provided below in Table 5 for events related to overlapping toxicities or regorafenib and 
AB928 treatment.
For cases in which management guidelines are not covered in Appendix 6 or Table 5, 
patients should be managed and treatments should be withheld or discontinued as 
deemed appropriate by the investigator according to best medical judgment.  


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Table 5
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenibAB928
Arm
Event
Action to Be Taken
IRRs, CRS, anaphylaxis, and 
hypersensitivity reactions
Guidelines for management of IRRs and CRS for atezolizumab are provided in Appendix 6.
For anaphylaxis precautions, see Appendix 5.
Dermatologic toxicity (rash, handfoot skin reaction/palmarplantar erythrodysesthesia)
General Guidance
A dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy should be 
considered unless contraindicated.
Dermatologic event, Grade 1
Continue atezolizumab.  Continue regorafenib and AB928 at the same dose level.
Immediately institute supportive measures for symptomatic relief.
If rash is suspected to be related to atezolizumab, consider treatment with topical corticosteroids and/or 
other symptomatic therapy (e.g. antihistamines).


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Table 5
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenibAB928 
(cont.)
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Event
Action to Be Taken
Dermatologic event, Grade 2
Continue atezolizumab.  Consider AB928 dose modification as clinically indicated; otherwise continue 
AB928 at the same dose.  Continue regorafenib and decrease dose by one level. a  
For suspected atezolizumab-related events:
Consider patient referral to dermatologist for evaluation and, if indicated, biopsy.
Initiate treatment with topical corticosteroids.
Consider treatment with higher-potency topical corticosteroids if event does not improve.
If unresponsive to topical corticosteroids, consider oral prednisone 0.5 mg/kg/day.
For suspected regorafenib-related events:
Immediately institute supportive measures.
First occurrence:
If event does not resolve to Grade 1 or better after dose reduction, withhold regorafenib for a minimum of 
7 days.  If event resolves to Grade 1 or better within 42 days, resume regorafenib at the reduced dose 
level. a  If not, permanently discontinue regorafenib. g
A dose re-escalation is permitted at the investigator’s discretion.
If event does not resolve within 7 days or at second or third occurrence:  
Withhold regorafenib for a minimum of 7 days.  If event resolves to Grade 1 or better within 42 days, 
resume regorafenib with a one-level dose reduction. a  If not, permanently discontinue regorafenib. g
Fourth occurrence:
Permanently discontinue regorafenib. g
For suspected AB928-related events:
Immediately institute supportive measures.
If the event does not resolve to Grade 1 or better within 7 days, consider dose interruption.  If event 
resolves to Grade 1 or better, resume AB928 at the same dose or with a one-level dose reduction.
A dose re-escalation is permitted at the investigator’s discretion.


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Table 5
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenibAB928 
(cont.)
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Event
Action to Be Taken
Dermatologic event, Grade 3
Withhold atezolizumab for up to 12 weeks after event onset. b  Withhold regorafenib and AB928 for a 
minimum of 7 days or until toxicity resolves to Grade 1 or better.  .
For suspected atezolizumab-related events:
Refer patient to dermatologist for evaluation and, if indicated, biopsy.
Initiate treatment with corticosteroids equivalent to 10 mg/day oral prednisone, increasing dose to 
12 mg/kg/day if event does not improve within 4872 hours.
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab. b, c  If not, permanently 
discontinue atezolizumab and contact Medical Monitor. d
If event resolves to Grade 1 or better within 42 days, resume regorafenib and AB928 with a one-level 
dose reduction. a, j, k  If not, permanently discontinue regorafenib and AB928 and contact Medical 
Monitor. g, i
For suspected regorafenib-related events:
Institute supportive measures immediately
First and second occurrence:  
If event resolves to Grade 1 or better within 42 days, resume regorafenib with a one-level dose 
reduction. a  If not, permanently discontinue regorafenib. g
For first occurrence, a dose re-escalation of regorafenib is permitted at the investigator’s discretion.
If event resolves to Grade 1 or better within 12 weeks for atezolizumab and within 42 days for AB928, 
resume study treatment. b, k If not, permanently discontinue atezolizumab and AB928 and contact 
Medical Monitor d, i
Third occurrence:  
Permanently discontinue regorafenib.


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm
Table 5
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenibAB928 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
289/Protocol CO39612, Version 11
Event
Action to Be Taken
Dermatologic event, Grade 3 
(continued)
For suspected AB928-related events:
Immediately institute supportive measures.
Refer patient to dermatologist.
If event resolves to Grade 1 or better within 42 days, resume AB928 with a one-level dose reduction. k, h  
If not, permanently discontinue AB928 and contact Medical Monitor. i
A dose re-escalation of AB928 is permitted at the investigator’s discretion.
If event resolves to Grade 1 or better within 12 weeks for atezolizumab and within 42 days for 
regorafenib, resume study treatment. b, j  If not, permanently discontinue atezolizumab and regorafenib 
and contact Medical Monitor d, g
Dermatologic event, Grade 4
Permanently discontinue atezolizumab, regorafenib, and AB928 and contact Medical Monitor. d, g, i
Suspected Stevens-Johnson 
syndrome or toxic epidermal 
necrolysis (any grade)
Follow guidelines for atezolizumab in Appendix 6.
Permanently discontinue regorafenib and contact Medical Monitor.
Withhold AB928.  If the event resolves to Grade 1 or better, resume AB928 after consultation with the 
Medical Monitor.  
Permanently discontinue AB928 if withheld for 42 days or if Stevens-Johnson syndrome or toxic 
epidermal necrolysis is confirmed, and contact Medical Monitor.
Hepatic toxicity (elevations in ALT, AST, and/or bilirubin)
5ULN elevations in 
ALT/AST (maximum Grade 2)
Continue atezolizumab.  Continue regorafenib and AB928 at the same dose level.
Monitor LFTs more frequently until return to 3 ULN (Grade 1) or baseline.
For suspected immune-mediated events of 5 days duration:  
Withhold atezolizumab for up to 12 weeks after event onset. b  Regorafenib and AB928 can be continued 
at the same dose level at the investigator’s discretion.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral prednisone.
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab. b, c  If not, permanently 
discontinue atezolizumab and contact Medical Monitor. d


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm
Table 5
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenibAB928 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
290/Protocol CO39612, Version 11
Event
Action to Be Taken
5ULN but 20ULN 
elevations in ALT/AST 
(Grade 3)
For suspected regorafenib-related/nonimmune-mediated elevations in ALT/AST:
Withhold atezolizumab for up to 12 weeks after event onset. b  Withhold regorafenib and AB928 for up to 
42 days.
Monitor LFTs at least weekly for at minimum of 4 weeks until transaminases return to 3 ULN (Grade 1) 
or baseline.
Consider patient referral to GI specialist for evaluation and liver biopsy to establish etiology of hepatic 
injury.
If event resolves to Grade 1 or better within 12 weeks for, atezolizumab and within 42 days for AB928, 
resume study treamentb, k. If not, permanently discontinue atezolizumab and AB928 and contact Medical 
Monitor. d, i
First occurrence:  
If event resolves to Grade 1 or better within 42 days, resume regorafenib with a one-level dose 
reduction. a, j If not, permanently discontinue regorafenib g.
Second occurrence:  
Permanently discontinue regorafenib..g
For suspected immune-mediated events:
Permanently discontinue atezolizumab and contact Medical Monitor. d  Withhold regorafenib and AB928 
for up to 42 days. j, k
Consider patient referral to GI specialist for evaluation and liver biopsy to establish etiology of hepatic 
injury. 
Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral prednisone.
If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.
If event resolves to Grade 1 or better within 12 weeks, taper corticosteroids over 1 month. b
If event resolves to Grade 1 or better within 42 days, resume regorafenib and AB928 with a one-level 
dose reduction. a, h, j, k  If not, permanently discontinue regorafenib and AB928 and contact Medical 
Monitor. g, i


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm
Table 5
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenibAB928 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
291/Protocol CO39612, Version 11
Event
Action to Be Taken
20ULN elevations in 
ALT/AST (Grade 4)
Permanently discontinue atezolizumab, regorafenib, and AB928 and contact Medical Monitor. d, g, i
Follow Grade 3 management guidelines for suspected immune-mediated events.
3ULN elevations in 
ALT/AST (Grade 2 or higher) 
with concurrent bilirubin 
2ULN
Permanently discontinue atezolizumab, regorafenib, and AB928 and contact Medical Monitor. d, g, i
Monitor liver function at least weekly until values return to baseline.
Investigate causes for elevated bilirubin and initiate treatment per institutional guidelines. 
Exception:  Patients with Gilbert syndrome who develop elevated transaminases should be managed as 
per the above outlined recommendations for the respective observed elevation of ALT and/or AST.
GI toxicities 
Any GI perforation or fistula
Permanently discontinue regorafenib. g
Diarrhea or colitis, Grade 1
Continue atezolizumab.  Continue regorafenib and AB928 at the same dose level.
Initiate symptomatic treatment.
Endoscopy is recommended if symptoms persist for 7 days.
Monitor closely.
Diarrhea or colitis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset b.  Regorafenib and AB928 may be 
continued at the same dose level at the investigator’s discretion.

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 

If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab. b, c  If not, permanently 
discontinue atezolizumab and contact Medical Monitor. d

If regorafenib was withheld and event resolves to Grade 1 or better within 42 days decrease by one 
dose level when resuming treatment. j

If AB928 was withheld and event resolves to Grade 1 or better within 42 days, resume AB928 at the 
same dose level. k


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm
Table 5
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenibAB928 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
292/Protocol CO39612, Version 11
Event
Action to Be Taken
Diarrhea or colitis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset. b  Withhold regorafenib and AB928 for up to 
42 days after event onset.
For suspected immune-mediated events (including colitis):

Refer patient to GI specialist for evaluation and confirmatory biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.

If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab. b, c  If not, permanently 
discontinue atezolizumab and contact Medical Monitor. d

If event resolves to Grade 1 or better within 42 days resume regorafenib and AB928 with a one-level 
dose reduction. a, h, j, k  If not, permanently discontinue regorafenib and AB928 and contact Medical 
Monitor. g, i
For regorafenib-related events:
First and second occurrence:  
If event resolves to Grade 1 or better within 42 days, resume regorafenib with a one-level dose 
reduction. a  If not, consider permanent discontinuation of regorafenib.
If event resolves to Grade 1 or better within 12 weeks for, atezolizumab and within 42 days for AB928,
resume study treatement and decrease AB928 by one dose level. b, h, k For AB928, a dose re-escalation 
is permitted at the investigator’s discretion. If not, consider permanent discontinuation of atezolizumab 
and AB928 and contact medical monitor. d, i
Third occurrence:  
Consider permanent discontinuation of regorafenib. g Atezolizumab and AB928 may be continued at the 
investigator’s discretion.


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm
Table 5
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenibAB928 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
293/Protocol CO39612, Version 11
Event
Action to Be Taken
Diarrhea or colitis, Grade 4

Permanently discontinue atezolizumab, regorafenib, and AB928 and contact Medical Monitor. d, g, i

Refer patient to GI specialist for evaluation and confirmation biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
Cardiac Toxicities
General guidance
Immune-mediated myocarditis should be suspected in any patient presenting with signs or symptoms 
suggestive of myocarditis, including, but not limited to, laboratory (e.g., B-type natriuretic peptide) or 
cardiac imaging abnormalities, dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, 
or syncope.  
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, e.g., in a patient who reports a recent history of gastrointestinal illness), ischemic 
events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, or progression of 
malignancy.  
Immune-mediated myocarditis, 
Grade 1
Atezolizumab may be continued at the investigator’s discretion.  Regorafenib and AB928 may be 
continued at the same dose level, at the investigator’s discretion.
Refer patient to cardiologist.
Initiate treatment as per institutional guidelines.


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm
Table 5
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenibAB928 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
294/Protocol CO39612, Version 11
Event
Action to Be Taken
Immune-mediated myocarditis, 
Grade 2
Permanently discontinue atezolizumab and contact Medical Monitor. d  Regorafenib and AB928 may 
be continued at the same dose level, at the investigator’s discretion. 
Refer patient to cardiologist.
Initiate treatment as per institutional guidelines and consider antiarrhythmic drugs, temporary 
pacemaker, ECMO, or VAD as appropriate.
Consider treatment with corticosteroids equivalent to 12 mg/kg/day IV methylprednisolone and convert 
to 12 mg/kg/day oral prednisone or equivalent upon improvement.
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab. b, c  If not, permanently 
discontinue atezolizumab and contact Medical Monitor. d
Immune-mediated myocarditis, 
Grade 3
Permanently discontinue atezolizumab and contact Medical Monitor. d  Withhold regorafenib and AB928 
for up to 42 days. 
Refer patient to cardiologist.
Initiate treatment as per institutional guidelines and consider antiarrhythmic drugs, temporary 
pacemaker, ECMO, or VAD as appropriate.
Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.
If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.
If event resolves to Grade 1 or better within 12 weeks, taper corticosteroids over 1 month. b
If event resolves to Grade 1 or better within 42 days, consider resuming regorafenib and AB928 with one 
dose level reduction. a, h, j, k
Immune-mediated myocarditis, 
Grade 4
Permanently discontinue atezolizumab, regorafenib, and AB928 contact Medical Monitor. d, g, i
Manage as per Grade 3 guidelines
New or acute onset cardiac 
ischemia or infarction
Withhold atezolizumab, regorafenib, and AB928.
If the acute cardiac ischemic events resolve and if the potential benefits outweigh the risks of further 
cardiac ischemia, resume atezolizumab, regorafenib, and AB928.  If not, permanently discontinue 
atezolizumab, regorafenib, and AB928 and contact Medical Monitor. d, g, i


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm
Table 5
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenibAB928 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
295/Protocol CO39612, Version 11
Event
Action to Be Taken
Infection
Infections, Grade 3 or 4 or a 
worsening infection of any 
grade
Withhold regorafenib.  Atezolizumab and AB928 may be continued at the investigator’s discretion.
If infection resolves within 42 days, resume regorafenib at the same dose level.  If not permanently 
discontinue regorafenib. g
Hemorrhage
Hemorrhage, Grade 3 or 4
Permanently discontinue regorafenib and contact Medical Monitor. f, g  Monitor INR levels more 
frequently in patients receiving warfarin.
Hypertension
General guidance
Grade 2 or above, start anti-hypertensive therapy.
Hypertension, Grade 2
Withhold regorafenib.  Continue atezolizumab and AB928.  
If blood pressure is 150/100 mmHg within 42 days, resume regorafenib with the decision to maintain 
the current dose level or to reduce by one dose level at the discretion of the investigator. a
Hypertension, Grade 3
Withhold regorafenib.  Atezolizumab and AB928 may be continued at the investigator’s discretion.
If blood pressure is 150/100 mmHg within 42 days, resume regorafenib with the decision to maintain 
the current dose level or to reduce by one dose level at the discretion of the investigator. a
If blood pressure is not controlled to 150/100 mmHg with anti-hypertensive therapy, permanently 
discontinue regorafenib and contact Medical Monitor. g
Hypertension, Grade 4 
(includes hypertensive crisis 
and hypertensive 
encephalopathy)
Permanently discontinue atezolizumab, regorafenib, and AB928 and contact Medical Monitor. d, g, i
Reversible posterior leukoencephalopathy syndrome
Reversible posterior 
leukoencephalopathy 
syndrome
Permanently discontinue regorafenib and contact Medical Monitor. g  


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm
Table 5
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenibAB928 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
296/Protocol CO39612, Version 11
Event
Action to Be Taken
Wound dehiscence
Wound dehiscence, any grade 
requiring medical or surgical 
therapy
Permanently discontinue regorafenib and contact Medical Monitor. g  
Regorafenib-related toxicities not described above
Grade 1 or Grade 2 (tolerable)
Continue atezolizumab.  Continue regorafenib and AB928 at the same dose level.
Grade 2 (intolerable) or Grade 
3
Atezolizumab and AB928 may be continued at the investigator’s discretion.
First and second occurrence:  
Withhold regorafenib until event resolves to Grade 1 or better within 42 days, then resume regorafenib 
with a one-level dose reduction. a  If event does not resolve to Grade 1 or better, permanently 
discontinue regorafenib. g
Third occurrence:  
Consider permanent discontinuation of regorafenib. g
Grade 4
Permanently discontinue atezolizumab, regorafenib, and AB928 and contact Medical Monitor. d, g, i
Atezolizumab-related toxcities not described above
Grade 1 or 2
Follow guidelines for atezolizumab in Appendix 6.
Continue regorafenib and AB928 at the same dose level.
Grade 3 or 4
Follow guidelines for atezolizumab in Appendix 6.
Withhold regorafenib and AB928.
If event improves, resume regorafenib and AB928.  If not, permanently discontinue regorafenib and 
AB928. g, i


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm
Table 5
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenibAB928 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
297/Protocol CO39612, Version 11
Event
Action to Be Taken
AB928-related toxicities not described above
Grade 1 or 2
Initiate symptom-directed supportive care.
Continue atezolizumab and regorafenib.
Consider AB928 dose modification as clinically indicated; otherwise continue AB928 at the same dose.
Grade 3
Withhold AB928.  Atezolizumab and regorafenib may be continued at the investigator’s discretion.
If event resolves to Grade 1 or better within 42 days, resume AB928 with a one-level dose reduction.  If 
not, or if AB928 is held for 42 days, permanently discontinue AB928. k
Dose re-escalation of AB928 is permitted at the investigator’s discretion.
Grade 4
Permanently discontinue AB928.  Withhold atezolizumab and regorafenib.
If event improves, resume atezolizumab and regorafenib.  If not, permanently discontinue atezolizumab 
and regorafenib. d, g
CRS cytokine release syndrome; ECMOextracorporeal membrane oxygenation; GIgastrointestinal; IRRinfusion-related reaction; 
ULNupper limit of normal; VADventricular assist device.
a The dose of regorafenib can be reduced by a decrement of 40 mg, once a day, from 120 mg to 80 mg (i.e., one dose level) for 
management of drug-related toxicities.  Additional dose reductions are not allowed.  If a dose reduction is indicated for a patient receiving 
the 80-mg dose of regorafenib, then that patient should discontinue regorafenib, unless the patient is likely to derive clinical benefit as 
determined by the investigator.  The Medical Monitor is available to advise as needed.  Upon adverse event resolution, a dose re-
escalation of regorafenib from 80 mg to 120 mg is allowed at the investigator’s discretion.
b 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 based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.
c 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.
d Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-mediated 
event.  The decision to re-challenge patients with atezolizumab should be based on investigator's assessment of benefitrisk and 
documented by the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as needed.


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm
Table 5
Guidelines for Management of Patients Who Experience Adverse Events in AtezoRegorafenibAB928 
(cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
298/Protocol CO39612, Version 11
e Atezolizumab may be continued at the discretion of the investigator in consultation with the Medical Monitor, and both atezolizumab and 
regorafenib treatment may resume if the patient is thought to be deriving benefit.
f For Grade 3 events, regorafenib may be continued at the discretion of the investigator per medical judgment.
g Resumption of regorafenib may be considered in patients who are deriving benefit and have fully recovered from the toxicity.  The decision 
to re-challenge patients with regorafenib should be based on investigator's assessment of benefitrisk and documented by the 
investigator (or an appropriate delegate).  The Medical Monitor is available to advise as needed.
h The dose of AB928 can be reduced from 150 mg to 100 mg (i.e., one dose level), and then from 100 mg to 75 mg for management of 
drug-related toxicities.  Additional dose reductions are not allowed.  If a dose reduction is indicated for a patient receiving the 75-mg dose 
of AB928, then that patient should discontinue AB928.  Upon adverse event resolution, a dose re-escalation of AB928 is allowed at the 
investigator’s discretion.  The Medical Monitor is available to advise as needed.
i Resumption of AB928 may be considered in patients who are deriving benefit and have fully recovered from the toxicity.  The decision to 
re-challenge patients with AB928 should be based on investigator's assessment of benefitrisk and documented by the investigator (or an 
appropriate delegate).  The Medical Monitor is available to advise as needed.
j Regorafenib may be withheld for a longer period of time (i.e. >42 days after event onset).  The acceptable length of the extended period of 
time must be based on an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to advise as needed.
k AB928 may be withheld for a longer period of time (i.e. >42 days after event onset).  The acceptable length of the extended period of time 
must be based on an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the duration of 
treatment and documented by the investigator.  The Medical Monitor is available to advise as needed.


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
299/Protocol CO39612, Version 11
A135.2
ADVERSE EVENTS OF SPECIAL INTEREST FOR 
ATEZOREGORAFENIBAB928 ARM (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 in the protocol body for reporting instructions).  Adverse events of special 
interest for the AtezoRegorafenib+AB928 arm are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7 in the protocol body) 

Suspected transmission of an infectious agent by the study treatment, as defined 
below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of study treatment is suspected.

Pneumonitis

Colitis

Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis

Hepatitis, including AST or ALT 10 upper limit of normal

Systemic lupus erythematosus

Neurologic disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis

Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, influenza-like illness, HLH, and MAS

Nephritis

Ocular toxicities (e.g., uveitis, retinitis, and optic neuritis)

Myositis

Myopathies, including rhabdomyolysis

Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Vasculitis

Autoimmune hemolytic anemia

Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis)


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
300/Protocol CO39612, Version 11
A135.3
REPORTING REQUIREMENTS FOR PREGNANCIES IN 
ATEZOREGORAFENIBAB928 ARM
A135.3.1 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 atezolizumab, 2 months after the last dose of regorafenib, or 30 days after the 
last dose of AB928.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study treatment and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
A135.3.2 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 
2 months after the last dose of regorafenib or 30 days after the last dose of AB928.  A 
paper Clinical Trial Pregnancy Reporting Form should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study treatment.  When permitted by the site, the pregnant partner 
will need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  If the authorization has been signed, 
the investigator should submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  An 
investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the investigator and/or obstetrician.
A135.3.3 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, 


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
301/Protocol CO39612, Version 11
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2 in the protocol body).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
A135.3.4 Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment should be classified as a serious adverse event, recorded on the Adverse 
Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2 in the protocol body).


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
302/Protocol CO39612, Version 11
A136. SCHEDULE OF ACTIVITIES AND SAMPLE COLLECTION FOR ATEZOREGORAFENIBAB928 ARM
Table 6:
Schedule of Activities for AtezoRegorafenibAB928 Arm
Assessment/Procedure
Screening
Days
–28 to –1
Treatment Cycles (28-Day Cycles) a
Stage 2 
Screen. c
or Treat. 
Discon. d
Follow-Up
Every 
3 Months
(7 days)
Cycle 1 b
Cycle 2
Cycles 3
Days 
Days 
Days 
1
2
8
(1 d)
15
(1 d)
22
(1 d)
1
8
(1 d)
15
(1 d)
1
(2 d)
15
(2 d)
Molecular profile of CRC 
(if available)
See
Appendix 15
Whenever updated information becomes available
Vital signs e
x
x
x
x
x
x
x
x
x
x
x
Weight 
x f
x f
x f
x
Complete physical examination g
x
Limited physical examination h
x f
x f
x f
x f
x f
x f
x f
x f
x f
ECOG Performance Status
x f
x f
x f
x
ECG i
As clinically indicated f
x o
Hematology j
x k, l
x k
x k
x k
x k
x k
x k
x k
x
Chemistry m
x k, l
x k
x k
x k
x k
x k
x k
x k
x
Coagulation (INR and aPTT) n
x k, l
x k
x k
x o
TSH, free T3 (or total T3), and 
free T4 p
x k, l, p
x
Viral serology q
x o, q
C-reactive protein
x o
Plasma CEA r
x k
x k, r


Appendix 13:  Study Details Specific to Atezo RegorafenibAB928 Arm
Table 6:
Schedule of Activities for AtezoRegorafenibAB928 Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
303/Protocol CO39612, Version 11
Assessment/Procedure
Screening
Days
–28 to –1
Treatment Cycles (28-Day Cycles) a
Stage 2 
Screen. c
or Treat. 
Discon. d
Follow-Up
Every 
3 Months
(7 days)
Cycle 1 b
Cycle 2
Cycles 3
Days 
Days 
Days 
1
2
8
(1 d)
15
(1 d)
22
(1 d)
1
8
(1 d)
15
(1 d)
1
(2 d)
15
(2 d)
LDH
See
Appendix 15
x o
Pregnancy test s
x k, l
x k
x k
x t
x s
Urinalysis u
x
x
x
x o, t
Serum autoantibody sample v
Perform if patients experience suspected immune-mediated adverse event
xo
Blood sample for RBR (optional) w
x
Biomarker samples 
Refer to Table 7 below
Serum ADA sample
Refer to Table 7 below
Serum and plasma PK sample
Refer to Table 7 below
Tumor biopsy
x x
Tumor biopsy (optional)
x y
Tumor response assessments
x z, aa, bb
Concomitant medications cc
x
x
x
x
x
x
x
x
x
x
x
Adverse events dd
x
x
x
x
x
x
x
x
x
x
x dd
x dd
Administer atezolizumab ee, ff
x
x
x
x
x
x
Dispense regorafenib ff, gg
x
x
x
Dispense AB928 ff, hh
x
x
x
Study drug accountability ii
x
x
x
x
x
Survival follow-up and anti-cancer 
treatment
x jj


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm
Table 6:
Schedule of Activities for AtezoRegorafenibAB928 Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
304/Protocol CO39612, Version 11
ADAanti-drug antibody; CTcomputed tomography; dday; Discondiscontinuation; ECOG Eastern Cooperative Oncology Group; 
eCRFelectronic Case Report Form; HBcAbhepatitis B core antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; HCVhepatitis C 
virus; MRImagnetic resonance imaging; PKpharmacokinetic; RBRResearch Biosample Repository; RECIST v1.1Response Evaluation Criteria in 
Solid Tumors, Version 1.1; Screenscreening; T3triiodothyronine; T4thyroxine; Treat.treatment; TSHthyroid-stimulating hormone.
Note:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified
a If a visit is precluded because of a holiday, vacation, or other circumstance, it may occur outside of the specified window.
b It is recommended that treatment be initiated no later than 7 days after randomization; however the first dose of study treatment should not occur 
within 7 days after a core biopsy or other surgical procedure. 
c Patients who experience loss of clinical benefit defined as (1) confirmed disease progression or (2) lack of continued benefit as determined by the 
investigator (see Section 3.1.1 in the protocol body for details) or unacceptable toxicity may be given the option of receiving a different treatment 
combination during Stage 2 of the study (as outlined in Section 3.1.2 in the protocol body provided Stage 2 is open for enrollment) and will undergo 
screening assessments to determine eligibility.  Study details specific to the Stage 2 treatment regimens are provided in the appropriate appendix.  
Written informed consent must be obtained before performing screening evaluations for Stage 2.
d Patients will return to the clinic for a Stage 2 screening or treatment discontinuation visit not more than 30 days after the last dose of study treatment.  
The visit at which loss of clinical benefit is confirmed may be used as the Stage 2 screening or treatment discontinuation visit.  Treatment 
discontinuation assessments must be performed for all patients, regardless of whether they enter Stage 2.  Patients who do not enter Stage 2 will 
undergo follow-up assessments after completing the treatment discontinuation visit.
e Vital signs include respiratory rate, pulse rate, pulse oximetry, systolic and diastolic blood pressure while the patient is in a seated position, and 
temperature.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  Refer to 
Section A134.1.2 for details related to vital signs monitoring during atezolizumab infusions.
f
Assessment may be performed within 24 hours prior to dosing during the treatment period.
g Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
h Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  Record abnormalities 
observed at baseline on the General Medical History and Baseline Conditions eCRF.administered.  The skin examination should be extended 
according to medical need.
i
ECG recordings will be obtained during screening and as clinically indicated at other timepoints.  It is recommended that patients be resting in a 
supine position for at least 10 minutes prior to ECG recording.
j
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).
k Laboratory tests must be performed within 96 hours prior to dosing during the treatment period.
l
If screening laboratory assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated.
m Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (per standard of care for the region), sodium, potassium, 
magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, and AST.  CPK will be


Appendix 13:  Study Details Specific to Atezo RegorafenibAB928 Arm
Table 6:
Schedule of Activities for AtezoRegorafenibAB928 Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
305/Protocol CO39612, Version 11
performed only on Day 1 of each cycle and at treatment discontinuation.
n Monitoring of INR/aPTT should be performed more frequently if clinically indicated.
o Assessments to be performed only for patients undergoing Stage 2 screening.
p TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed at screening and on Day 1 of Cycle 1 and every third 
cycle thereafter (i.e., Cycles 4, 7, 10, etc.).
q At Stage 2, patients without a prior positive HIV test result will undergo an HIV test, unless not permitted per local regulations.  Patients will also be 
tested for HBsAg, total HBcAb, and HCV antibody.  If a patient has a negative HBsAg test and a positive total HBcAb test at screening, an HBV DNA 
test must also be performed to determine if the patient has an HBV infection.  If a patient has a positive HCV antibody test at screening, an HCV RNA 
test must also be performed to determine if the patient has an active HCV infection. 
r
CEA will be assessed on Day 1 of Cycle 1 and every 2 cycles thereafter (i.e., Cycles 3, 5, 7, etc.) until disease progression.
s All women of childbearing potential will have a serum pregnancy test at screening.  Urine or serum pregnancy tests will be performed at specified 
subsequent visits and at 3 months and 6 months after treatment discontinuation.  If a urine pregnancy test is positive, it must be confirmed by a 
serum pregnancy test.
t
Screening laboratory test results must be obtained within 14 days prior to initiation of study treatment.
u Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted.  Patients with 2+ protein on dipstick urinalysis must undergo a 
24-hour urine collection and demonstrate 3.5 g of protein in 24 hours. Urinalysis may be performed up to 72 hours prior to Day 1 of each cycle, as 
results must be available prior to treatment administration.
v Autoantibody analysis includes anti-nuclear antibody, antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear 
anti-neutrophil cytoplasmic antibody.
w Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have provided 
written informed consent to participate.  RBR sample should be collected prior to study treatment.
x Patients will undergo tumor biopsy sample collection at the time of unacceptable toxicity or loss of clinical benefit as determined by the investigator 
(see Section 3.1.1 for details), if deemed clinically feasible by the investigator.  Biopsies should be performed within 40 days after determination of 
unacceptable toxicity or loss of clinical benefit, or prior to the next anti-cancer therapy, whichever is sooner.  Patients enrolled in the mandatory 
serial-biopsy arm (see Section 3.1.1.2 in the protocol body) will undergo tumor biopsy sample collection 4 weeks (7 days) after treatment initiation (if 
deemed clinically feasible by the investigator).  See Section 4.5.7 in the protocol body for tissue sample requirements.
y Patients who consent to optional biopsies will undergo tumor biopsy sample collection 4 weeks (7 days) after treatment initiation, if deemed 
clinically feasible and may undergo additional on-treatment biopsies at any other time during Stage 1 or Stage 2 at the investigator's discretion.
z Patients will undergo tumor assessments at baseline, every 6 weeks (1 week) for the first 48 weeks following treatment initiation, and every 
12 weeks (2 weeks) thereafter, regardless of dose delays, until loss of clinical benefit defined as (1) confirmed disease progression or (2) lack of 
continued benefit as determined by the investigator (see Section 3.1.1 in the protocol body for details).  Thus, tumor assessments are to continue 
according to schedule in patients who discontinue treatment for reasons other than loss of clinical benefit, even if they start new 
nonprotocol-specified anti-cancer therapy.


Appendix 13:  Study Details Specific to Atezo RegorafenibAB928 Arm
Table 6:
Schedule of Activities for AtezoRegorafenibAB928 Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
306/Protocol CO39612, Version 11
aa All measurable and/or evaluable lesions identified at baseline should be re-assessed at subsequent tumor evaluations according to the schedule 
described above.  Brain metastases identified at baseline that have been treated with radiotherapy or surgery will not be considered measurable or 
evaluable unless there is suspected disease progression in the brain (i.e., the patient becomes symptomatic).  Thus, subsequent head CT scans are 
not required unless clinically indicated.  The same radiographic procedures used to assess disease sites at screening should be used for subsequent 
tumor assessments (e.g., the same contrast protocol for CT scans).  
bb For patients who undergo screening for Stage 2, tumor assessments performed prior to or at the time of loss of clinical benefit during Stage 1 may 
serve as baseline assessments for Stage 2, provided the tumor assessments are performed within 28 days prior to initiation of Stage 2 treatment 
(i.e., Day 1 of Cycle 1).
cc Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated study treatment from 7 days prior to initiation of study treatment until the treatment discontinuation visit.
dd After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first.  Serious adverse events and adverse events of special 
interest will continue to be reported until 135 days after the last dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first.  After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6 in the 
protocol body).  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as 
stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse 
events considered to be related to study treatment or trial-related procedures until a final outcome can be reported.
ee Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Days 1 and 15 of each 28-day cycle.  The initial dose of atezolizumab 
will be delivered over 60 (15) minutes.  Subsequent infusions will be delivered over 30 (10) minutes if the previous infusion was tolerated without 
infusion-associated adverse events, or 60 (15) minutes if the patient experienced an infusion-associated adverse event with the previous infusion.  
ff Treatment will continue until unacceptable toxicity or loss of clinical benefit defined as (1) confirmed disease progression or (2) lack of continued 
benefit as determined by the investigator (see Section 3.1.1 in the protocol body for details).
gg Patients will receive regorafenib orally on Days 121 of each cycle. At least 7 days off regorafenib are required prior to starting a new treatment cycle
(see Section A134.1.2.2 for details).  On clinic visit days when PK samples are collected, patients should take their regorafenib dose in the clinic.
hh Patients will receive AB928 orally on Days 128 of each cycle (see Section A134.1.2.3 for details).  On clinic visit days when PK samples are 
collected, patients should take their AB928 dose in the clinic.
ii Medication diaries should be collected and reviewed, and unused medications should be collected for assessment of compliance
jj After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) will be 
collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months until death (unless the patient withdraws 
consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this request must be documented in the source 
documents and signed by the investigator.  If the patient withdraws from the study, the study staff may use a public information source (e.g., county 


Appendix 13:  Study Details Specific to Atezo RegorafenibAB928 Arm
Table 6:
Schedule of Activities for AtezoRegorafenibAB928 Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
307/Protocol CO39612, Version 11
records) to obtain information about survival status only. For an experimental arm in which all patients discontinued treatment and passed the safety 
follow-up window, as well as approximately 80% of patients discontinued the study, the Sponsor may conclude the arm (the remaining ~20% of 
patients will be discontinued from the study).


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
308/Protocol CO39612, Version 11
Table 7
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker 
Samples for AtezoRegorafenibAB928 Arm:  Preliminary and 
Expansion Phases
Visit
Time
Sample Type
Day 1 of Cycle 1
Prior to study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Regorafenib PK (plasma) a

AB928 PK (plasma) b

Biomarkers (plasma, serum, PBMC)
30 (10) minutes after atezolizumab 
infusion

Atezolizumab PK (serum)
30 (5) minutes after AB928 dose

AB928 PK (plasma) b
1 hour (5 minutes) after AB928 dose 
AB928 PK (plasma) b
2 hours (10 minutes) after AB928 
dose

AB928 PK (plasma) b
4 hours (10 minutes) after AB928 
dose

AB928 PK (plasma) b
6 hours (10 minutes) after AB928 
dose

AB928 PK (plasma) b
Day 2 of Cycle 1
24 hours (1 hour) after AB928 dose
on Cycle 1 Day 1

AB928 PK (plasma) b
Day 8 of Cycle 1
Prior to study treatment

Regorafenib PK (plasma) a

AB928 PK (plasma) b
Day 15 of Cycle 1
Prior to study treatment

Regorafenib PK (plasma) a

AB928 PK (plasma) b

Biomarkers (plasma, serum)
Day 22 of Cycle 1
Prior to study treatment
Regorafenib PK (plasma) a

AB928 PK (plasma) b
Atezoatezolizumab; ADAanti-drug antibody; PBMCperipheral blood mononuclear cell; 
PKpharmacokinetic.
Note:  Based on emerging safety/efficacy data the number of PK/ADA and/or biomarker samples 
may be reduced/removed and/or the timing of samples may be modified.
a
Regorafenib PK includes regorafenib, regorafenib M-2, and regorafenib M-5.
b
AB928 PK includes AB928, AB928 glucuronide, and AB928 N-dealkylated.


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
309/Protocol CO39612, Version 11
Table 7
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker 
Samples for AtezoRegorafenibAB928 Arm:  Preliminary and 
Expansion Phases (cont.)
Visit
Time
Sample Type
Day 1 of Cycle 2
Prior to study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

AB928 PK (plasma) b

Biomarkers (plasma, serum, PBMC)
30 (5) minutes after AB928 dose

AB928 PK (plasma) b
1 hour (5 minutes) after AB928 dose 
AB928 PK (plasma) b
3 hours (10 minutes) after AB928 
dose

AB928 PK (plasma) b
Day 1 of Cycle 3
Prior to study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

AB928 PK (plasma) b
Day 1 of Cycles 4 
and 8
Prior to study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

AB928 PK (plasma) b

Biomarkers (plasma, serum)
Day 1 of Cycles 12 
and 16
Prior to study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

AB928 PK (plasma) b
Treatment 
discontinuation visit 
(30 days after 
last dose)
At visit

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Biomarkers (plasma, serum)
Atezoatezolizumab; ADAanti-drug antibody; PBMCperipheral blood mononuclear cell; 
PKpharmacokinetic.
Note:  Based on emerging safety/efficacy data the number of PK/ADA and/or biomarker samples 
may be reduced/removed and/or the timing of samples may be modified.
a
Regorafenib PK includes regorafenib, regorafenib M-2, and regorafenib M-5.
b
AB928 PK includes AB928, AB928 glucuronide, and AB928 N-dealkylated.


Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
310/Protocol CO39612, Version 11
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Appendix 13:  Study Details Specific to AtezoRegorafenibAB928 Arm
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312/Protocol CO39612, Version 11
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Hoff S, Grünewald S, Röse L, et al. Immunomodulation by regorafenib alone and in 
combination with anti PD1 anbitody on murine models of colorectal cancer. Annals 
of Oncology 2017;28(Issue suppl_5).
Kroemer G, Galluzzi L, Kepp O, et al. Immunogenic cell death in cancer therapy. Annu 
Rev Immunol 2013;31:5172.
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair 
deficiency. N Engl J Med 2015;372:250920.
Le Mercier I, Lines JL, Noelle RJ. Beyond CTLA-4 and PD-1, the generation Z of 
negative checkpoint regulators. Front Immunol 2015;6:418.
Legitimo A, Consolini R, Failli A, et al. Dendritic cell defects in colorectal cancer. Hum 
Vaccin Immunother 2014;10:322435.
Li J, Qin S, Xu R, et al. Regorafenib plus best supportive care versus placebo plus best 
supportive are in Asian patients with previously treated metastatic colorectal 
cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. 
Lancet Oncol 2015;16:61929.
Maj T, Wang W, Crespo J, et al. Oxidative stress controls regulatory T cell apoptosis and 
suppressor activity and PD-L1blockade resistance in tumor. Nat Immunol 
2017;18:133241.
Marin-Acevedo JA, Dholaria B, Soyano AE, et al. Next generation of immune checkpoint 
therapy in cancer: new developments and challenges. J Hematol Oncol 
2018;11:39.
Mittal D, Young A, Stannard K, et al. Antimetastatic effects of blocking PD-1 and the 
adenosine A2A receptor. Cancer Res 2014;74:36528.
Olah ME and Caldwell CC. Adenosine receptors and mammalian toll-like receptors: 
synergism in macrophages. Mol Interv 2003;3:3704.
Overman MJ, LoRusso P, Strickler JH, et al. Safety, efficacy and pharmacodynamics 
(PD) of MEDI9447 (oleculmab) alone or in combination with durvalumab in 
advanced colorectal cancer (CRC) or pancreatic cancer (panc). J Clin Oncol 
2018;36(suppl_15):4123.
Perrot I, Michaud HA, Giraudon-Paoli M, et al. Blocking antibodies targeting the 
CD39/CD73 immunosuppressive pathway unleash immune responses in 
combination cancer therapies. Cell Rep 2019;27:241125.
Ribas and Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 
2018;359:135055.


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Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following 
treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 
trial. Lancet 2016;387:190920.
Serra S, Horenstein AL, Vaisitti T, et al. CD73-generated extracellular adenosine in 
chronic lymphocytic leukemia creates local conditions counteracting drug-induced 
cell death. Blood 2011;118:614152.
Sundström P, Stenstad H, Langeses V, et al. Regulatory T cells from colon cancer 
patients inhibit effector T-cell migration through an adenosine-dependent 
mechanism. Cancer Immunol Res 2016;4:18393.
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Tecentriq(atezolizumab) U.S. Package Insert, Genentech.
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Appendix 14
Study Details Specific to AtezoLOAd703 Arm 
TABLE OF CONTENTS
A141.
Background on AtezoLOAd703 Arm
A141.1 Background on Atezolizumab
A141.2 Background on LOAd703
A142.
Rationale for AtezoLOAd703 Arm
A142.1 The PD-L1 Pathway
A142.2 LoAd703 Mechanism of Action
A142.3 Rationale for Combining LOAd703 with Immune Checkpoint 
Inhibition
A142.4 BenefitRisk Assessment
A143.
Rationale for Dose and Schedule for AtezoLOAd703 
A143.1 Rationale for Atezolizumab Dose and Schedule
A143.2 Rationale for LOAd703 Dose and Schedule
A144.
Materials and Methods Specific to AtezoLOAd703 Arm 
A144.1 Treatment in AtezoLOAd703 Arm 
A144.1.1 Formulation, Packaging, and Handling
A144.1.2 Dosage, Administration, and Compliance
A144.1.3 Stage 2 Treatment
A144.2 Concomitant Therapy for AtezoLOAd703 Arm 
A144.2.1 Permitted Therapy for AtezoLOAd703 Arm 
A144.2.2 Cautionary Therapy for AtezoLOAd703 Arm 
A144.2.3 Prohibited Therapy for AtezoLOAd703 Arm 
A144.3 Contraception Requirements for AtezoLOAd703 Arm  
A145.
Assessment of Safety for AtezoLOAd703 Arm 
A145.1 Safety Plan for AtezoLOAd703 Arm 
A145.1.1 Risks Associated with Atezolizumab
A145.1.2 Risks Associated with LOAd703 
A145.1.3 Risks Associated with Combination Use of Atezolizumab 
and LOAd703 
A145.1.4 Management of Patients Who Experience Adverse 
Events in AtezoLOAd703 Arm
A145.2 Adverse Events of Special Interest for AtezoLOAd703 Arm 
(Immediately Reportable to the Sponsor)
A145.3 Reporting Requirements for Pregnancies in Atezo LOAd703 Arm 
A145.3.1 Pregnancies in Female Patients
A145.3.2 Pregnancies in Female Partners of Male Patients 
A145.3.3 Abortions
A145.3.4 Congenital Anomalies/Birth Defects 
A146.
Schedule of Activities and Sample Collection for AtezoLOAd703 Arm 


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A141 BACKGROUND ON ATEZO LOAD703 ARM
A141.1
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated antibody 
mediated clearance of activated effector T cells.
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy.
Atezolizumab has been generally well tolerated.  Adverse events with potentially 
immune-mediated causes consistent with an immunotherapeutic agent, including rash, 
influenza like illness, endocrinopathies, hepatitis or transaminitis, pneumonitis, colitis, 
and myasthenia gravis, have been observed (see the Atezolizumab Investigator's 
Brochure for detailed safety results).  To date, these events have been manageable with 
treatment. 
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer (NSCLC), small-cell lung cancer, triple-negative breast cancer, hepatocellular 
carcinoma, and melanoma.
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies.
A141.2
BACKGROUND ON LOAD703
LOAd703 is an oncolytic virus (OV) administered by intratumoral injection that is 
currently being evaluated in clinical trials for the treatment of melanoma and pancreatic, 
biliary, colorectal, and ovarian cancer.  LOAd703 is armed with two immunostimulatory 
transgenes (TMZ-CD40L and 4-1BBL) that can activate dendritic cells (DCs) and 
stimulate anti-tumor T cells.  Because of specific deletions in the viral genome, the 
replication of oncolysis by LOAd703 is restricted to malignant cells with a dysfunctional 
retinoblastoma pathway, a common mutation found in a wide spectrum of tumors.  
LOAd703 does not replicate in, and is not toxic to, healthy cells.  However, transgene 
expression can occur in all cells infected with LOAd703, regardless of the cell's ability to 
replicate, including cells in the tumor microenvironment (Eriksson et al. 2017a).  In 


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murine models, LOAd703 treatment has been shown to improve infiltration of T cells, 
natural killer (NK) cells, and DCs, in both tumors injected with OVs and tumors not 
injected with OVs.
Refer to the LOAd703 Investigator's Brochure for details on nonclinical and clinical 
studies.
A142 RATIONALE FOR ATEZO LOAD703 ARM
A142.1
THE PD-L1 PATHWAY 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies (Hodi et al. 
2010; Kantoff et al. 2010; Chen et al. 2012).
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that downregulates immune responses through binding 
to its two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor expressed on T cells 
following T-cell activation, and expression is sustained in states of chronic stimulation 
(Blank et al. 2005; Keir et al. 2008).  B7-1 is a molecule expressed on 
antigen-presenting cells and activated T cells.  Binding of PD-L1 to PD-1 and B7-1 
inhibits T-cell proliferation and activation, cytokine production, and cytolytic activity, 
leading to the functional inactivation or exhaustion of T cells (Butte et al. 2007; Yang et 
al. 2011).  Overexpression 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 pathway represents an attractive strategy for 
restoring tumor-specific T-cell immunity.
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed standard of care therapies.  Objective 
responses have been observed across a broad range of malignancies, including NSCLC, 
urothelial carcinoma, renal cell carcinoma, melanoma, CRC, head and neck cancer, 
gastric cancer, breast cancer, and sarcoma (see the Atezolizumab Investigator's 
Brochure for detailed efficacy results).  
Early clinical data had shown encouraging results with the antiPD-1 checkpoint inhibitor 
pembrolizumab as a single agent in patients with metastatic CRC (mCRC) assessed as 
having high microsatellite instability (MSI-H) status, but not with microsatellite-stable 
(MSS) status (Le et al. 2015).  These data resulted in the May 2017 approval of 
pembrolizumab in adult and pediatric patients with tumors characterized as MSI-H or 
deficient for mismatch repair genes based on objective response rate (ORR) and 


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durability of the response.  ORR was similar irrespective of whether patients were 
diagnosed with CRC (36%) or a different cancer type (46% across the 14 other MSI-H 
cancer types).  Similar response rates were observed in patients with second-line or 
later mCRC enrolled in a Phase Ia study investigating atezolizumab as single agent 
(Roche Study PCD4989g) and a Phase Ib study investigating the combination of 
atezolizumab plus bevacizumab (Roche Study GP28328, Arm A).  In Study PCD4989g, 
there was 1 responder reported in 14 patients with MSS status per Response Evaluation 
Criteria in Solid Tumors, Version 1.1 (RECIST v1.1).  In the 10 patients with MSI-H 
status enrolled in Study GP28328, the investigator assessed confirmed ORR per 
RECIST v1.1 was 40% (95% CI: 12.2, 73.8), with all 4 responders having partial 
responses.  No objective responses were seen in the 14 patients with MSS tumors.
A142.2
LOAD703 MECHANISM OF ACTION
OVs have the ability to infect and kill cancer cells through excessive viral replication.  As 
such, many different OVs are currently being evaluated in both the nonclinical and 
clinical setting (Vacchelli et al. 2013).  Some OVs are armed with immunostimulatory 
transgenes that can induce a systemic anti-tumor response. In addition, some OVs 
encode granulocyte macrophagecolony stimulating factor (GM-CSF), which can 
stimulate DCs.  However, GM-CSF may also lead to induction of immunosuppressive 
cells (Tähtinen et al. 2015). 
LOAd703 is an OV armed with the immunostimulatory transgenes TMZ-CD40L and 
4-1BBL and is engineered to target the human receptor CD46, which is expressed by 
most tumors.  LOAd703 has several modes of action that support anti-tumor activity.  
Induction of cell death by oncolysis is expected to enhance anti-tumor T-cell responses 
by releasing tumor antigens, which can be phagocytosed and processed by DCs.  These 
antigen-presenting cells are activated by viral danger signals (such as TLR9) and can 
effectively cross-prime effector and memory CD8+ T cells that migrate to the tumor 
and exert specific lytic activity towards cancer cells.  Additionally, all infected cells, 
including tumor, stromal, and immune cells, can express TMZ-CD40L and 4-1BBL 
on their cell membrane.  In addition to viral-mediated oncolysis, the translated 
TMZ-CD40L itself can bind to CD40 expressed on tumor cells to induce apoptosis.  
Following the death of tumor cells via these two different pathways, tumor antigens are 
released into the surrounding tumor microenvironment, where tumor-residing DCs can 
engulf the released tumor antigens.  Maturation, differentiation, and activation of DCs is 
induced following ligation of CD40 and 4-1BB, leading to priming and expansion of 
cytotoxic tumor-specific T and NK cells.  Stimulation of 4-1BB further promotes T- and 
NK-cell proliferation and prolonged survival.  Moreover, engagement of CD40 on tumor-
associated macrophages stimulates their polarization towards M1 phenotype, whereas 
CD40 ligation on endothelial cells induces upregulation of adhesion molecules to 
facilitate lymphocyte transmigration into the tissue (Eriksson 2017b).  LOAd703-encoded 


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transgenes TMZ-CD40L and 4-1BBL, together with oncolysis and activation of antigen-
presenting cells by viral danger signals, can induce and sustain Th1-type of immunity 
while favorably altering the tumor microenvironment to support T-cell activity.
A142.3
RATIONALE FOR COMBINING LOAD703 WITH IMMUNE 
CHECKPOINT INHIBITION 
Recently, single-agent immune checkpoint inhibitors have demonstrated clinical efficacy 
and long term disease control for some patients (typically 15%-30%) in a select set of 
tumor types (e.g., NSCLC, bladder cancer, MSI-H CRC).  However, the majority of 
patients are either refractory to treatment or become resistant after an initial response.  
Resistance is likely due to the patient’s immune status, (e.g., having an 
immunosuppressive tumor microenvironment with very few activated antitumor reactive 
T cells). 
Treatment with intratumoral OVs not only induces tumor cell-restricted lysis but can 
prime the tumor microenvironment by influx of a variety of immune cells and cytokines.  
These modifications to the tumor microenvironment can set the stage for subsequent 
treatment with an immune checkpoint inhibitor, which is more effective in the presence of 
high lymphocytic infiltration.  Tumors with low lymphocytic infiltration commonly do not 
respond at all to immune checkpoint inhibition.  Since this type of treatment is dependent 
on preexisting tumor-reactive T cells, an appealing way to enhance the effect of immune 
checkpoint inhibitors is to sensitize patients’ tumors with immune-activating therapy such 
as an immunostimulatory OV.  Indeed, in a study combining the first approved OV, 
talimogene laherparepvec, with pembrolizumab (anti-PD1), preliminary efficacy data on 
21 patients with melanoma demonstrated a 62% response rate, with 33% complete 
responders, which is almost double the response rate with PD-L1 blockade 
monotherapy (Ribas et al. 2017).  An increase in CD8+ T-cell infiltration, PD-L1 protein 
expression, and IFN-γ gene expression was observed in tumors of patients who 
responded to this combination therapy.  Interestingly, responses were seen in patients 
whose baseline biopsies had very low CD8+ T-cell infiltrate or negative IFNsignature.  
Overall, the study suggests that oncolytic virotherapy can improve the efficacy of 
immune checkpoint inhibitors.
LOAd703 is engineered to target the human receptor CD46, which can be a major 
advantage, especially in the treatment of CRC, in which the prevalence of CD46 
expression has been shown to be up to 80%.  Because only negligible activity has been 
reported with single-agent immune checkpoint inhibitors in patients with mCRC who 
have MSS tumors, there is a strong rationale for combining antiPD-L1 therapy with 
LOAd703 for the treatment of mCRC.
Combination therapy with LOAd703 and antiPD-L1 has not been evaluated in 
nonclinical animal models of CRC, because of a lack of appropriate models that would 


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support both viral entry and replication in mouse tissues.  However, the effect of the 
immunostimulatory transgenes has been evaluated in immunocompetent mice implanted 
with murine melanoma tumors expressing human CD46.  This tumor model enables viral 
uptake but is non-permissive for viral replication and oncolysis, thus allowing simple 
assessment of the immunostimulatory capacity of LOAd703.  Following intratumoral 
treatment with LOAd703 and systemic treatment with anti-PD-L1, robust stimulation of 
DCs, T cells, and NK cells was observed.  While LOAd703 was able to control tumor 
growth as monotherapy, superior anti-tumor efficacy was observed when LOAd703 was 
combined with immune checkpoint inhibitors targeting either PD1 or PD-L1.  
Furthermore, biopsies demonstrated that combination therapy with LOAd703 and 
antiPD-L1 increased tumor infiltration of cytotoxic T lymphocytes, NK cells, and CD103+
DCs over single-agent therapies.  Similarly, the combination of LOAd703 and 
antiPD-L1 was found to control tumor growth and increase the frequency of tumor-
infiltrating T cells in both injected and non-injected lesions, suggesting that combination 
therapy was able to induce systemic anti-tumor immunity.
In summary, additive and synergistic mechanisms of action of an armed oncolytic 
adenovirus such as LOAd703 and an antiPD-L1 therapy such as atezolizumab could 
ultimately translate into clinical benefit when this treatment combination is administered 
to patients with mCRC. 
A142.4
BENEFITRISK ASSESSMENT
This study will enroll patients with mCRC who have become refractory to first- and 
second-line standard therapies.  The patient population for this study has a median 
overall survival (OS) of less than 9 months with currently available treatments.  In 
addition, available standard of care treatments are often poorly tolerated.  Despite the 
success of single-agent immune checkpoint inhibitors in the MSI-H patient population, 
the vast majority of patients with CRC have MSS tumors and do not respond to 
single-agent immune checkpoint inhibitors, highlighting the need for safe and effective 
combination treatments.  Therefore, there remains a great need for investigating new 
cancer immunotherapy combinations to improve the outcome for this difficult-to-treat 
patient population.
Preliminary data from Phase I and II trials of other oncolytic adenoviruses have 
demonstrated the feasibility and the potential to combine them  with immune checkpoint 
inhibitors.
In a Phase I dose-escalation study of DNX-2401, an unarmed intratumorally 
administered OV, in 37 patients with recurrent glioma, no dose-limiting toxicities (DLTs) 
occurred, and only 2 patients experienced adverse events related to DNX-2401, 
including Grade 1 to 2 headache, nausea, confusion, vomiting, and pyrexia (Lang, JCO 
2018).  In a Phase II study of DNX-2401 combined with pembrolizumab in 48 patients 


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with recurrent glioblastoma, no DLTs or unexpected safety issues were reported.  The 
majority of adverse events were mild to moderate and unrelated to DNX-2401.  The 
combination showed promising activity, with a median OS of 12 months and a 6-month 
OS rate of 91% (Aiken et al. 2019). 
In the SPICE study (ColoAd1-1003), the combination of enadenotucirev (EnAd), an 
unarmed OV administered intravenously, was investigated in combination with 
nivoloumab in patients with solid tumors who had primary or secondary resistance to 
checkpoint inhibitors (n40, Fakih et al. 2019). The combination had a manageable 
safety profile   with the majority of patients reporting flu-like symptoms.  Adverse events 
of infusion reactions and hypoxia met DLT criteria on Day 1 of Cycle 2 of EnAd, requiring 
increased prophylaxis.  Cases of renal injury and lung injury led to the addition of 
mitigation measures in the ongoing protocol.  Among the 34 mCRC patients enrolled in 
the study, 4 patients (21%) achieved stable disease for 4 months.  One confirmed 
partial response (PR) of 15 weeks was seen in a patient who had mCRC with low-MSI 
status, low tumor mutation burden, and a BRAF mutation, a feature typically associated 
with a poor prognosis.  Remarkably, a median OS of 14 months was reported, which is 
greater than the OS observed with regorafenib or TAS-102 treatment in this patient 
population. 
In the Phase I portion of a study of ONCOS-10, an armed intraperitoneally administered 
OV encoding for GM-CSF, combined with the antiPD-L1 antibody durvalumab in 
patients with refractory ovarian cancer or mCRC with intraperitoneal disease (n17), 1 
patient had durable confirmed PR and remains on treatment (for 1 year) and 4 patients 
had stable disease as best overall response (Zamarin 2020).  No DLTs were reported.
Safety data are available for single-agent atezolizumab in patients with advanced 
solid tumors including CRC.  Atezolizumab was generally well tolerated among the 
14 patients with MSS mCRC who received single-agent atezolizumab in Study 
PCD4989g.  Grade 3 or 4 adverse events, treatment-related adverse events, and 
serious adverse events were reported at a similar rate as for patients with other solid 
tumors.  The most commonly reported treatment-related adverse events in this 
population (25%, 4 patients) were constipation, nausea, fatigue, diarrhea, dyspnea, 
pruritus, night sweats, and chills.  Three patients (21.4%) reported Grade 3 or 4 adverse 
events related to atezolizumab:  2 cases of Grade 3 asthenia, which led to study drug 
withdrawal in one case, and 1 case of Grade 3 abnormal liver function tests.
Preliminary data from an ongoing Phase Ib trial in patients with metastatic triple-negative 
breast cancer (TNBC) or CRC with liver metastases (NCT03256344) suggest that 
atezolizumab can be safely combined with T-Vec, an OV administered by intrahepatic 
injection that expresses GM-CSF (Pascual et al 2020).  The most common treatment-


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related adverse events among the first 7 patients (all with TNBC) were pyrexia (85.7%) 
and chills (71.4%).  No DLTs have been reported, and there was one confirmed PR. 
Although LOAd703 has not been investigated as a single agent, it is being evaluated at 
doses of 5 1010 VP to 5 1011 VP, Q2W or Q3W, in combination with chemotherapy 
and/or atezolizumab in three ongoing Phase I/II studies.  Study LOKON001 is evaluating 
LOAd703 in combination with gemcitabine plus nab-paclitaxel (Arm 1) and in 
combination with gemcitabine, nab-paclitaxel and atezolizumab (Arm 2) in pancreatic 
ductal adenocarcinoma.  Study LOKON002 is evaluating LOAd703 in combination with 
chemotherapy in different solid tumor indications.  Study LOKON003 is evaluating
LOAd703 in combination with atezolizumab in patients with advanced melanoma.
As of the Development Safety Update Report cutoff date (31 May 2020), among the 
21 patients treated in Arm 1 of Study LOKON001, 1 patient (5%) dosed at 5 1011 VP 
experienced a transient Grade 3 ALT elevation post- virus injection that led to a dose 
reduction to 1 1011 VP (this has been the only DLT reported to date).  In the same 
study, 2 patients (9.5%) experienced LOAd703-related serious adverse events of 
Grade 1 fever.  Among the 16 patients treated in Study LOKON002, 4 patients (25%) 
experienced a total of eight LOAd703-related serious adverse events that were Grade 1 
or 2 fever (in 3 patients dosed at 5 1011 VP) and Grade 1 or 2 cytokine-release 
syndrome (CRS) (in 1 patient dosed at 1 1011 VP and 1 patient dosed at 5 1011 VP).  
For all reported serious adverse event cases, the criterion for seriousness was the 
requirement for a brief hospitalization.
In Arm 2 of Study LOKON001, 3 patients have been treated with LOAd703 at a dose of 
1 1011 and 4 patients at 5 1011 VP in combination with gemcitabine, nab-paclitaxel 
and atezolizumab.  In Study LOKON003, 2 patients have been treated with LOAd703 at 
a dose of 1 1011 VP in combination with atezolizumab.  As of the data cutoff date of 
9 November 2020, no DLT or LOAd703-related serious adverse events were reported 
across these two atezolizumab combination studies (Lokon data on file).
Across the three studies and range of dose levels, the most common adverse events 
have been fever, nausea, vomiting, chills, and ALT increase, with most events being 
mild or moderate. There have been no fatal adverse events related to LOAd703 or 
LOAd703-related adverse events leading to discontinuation of study treatment (Lokon
data on file). 
There is a theoretical risk of a nontargeted-organ expression of the immunostimulatory 
transgenes resulting from unintentional spreading of LOAd703 into adjacent normal 
tissue or blood vessels, which could lead to CRS.  However, CRS would be expected to 
be transient, because the virus will not replicate in normal cells, and the immune system 


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will rapidly clear both OV and OV-infected cells.  This rapid immune response will also 
make late immune-mediated events unlikely.
Biodistribution and shedding was investigated for various types of oncolytic adenovirus 
(i.e., replication deficient, or replication competent with tumor cell selectivity) 
administered either systemically, locally or directly into the tumor. Shedding of viral DNA 
was detected in serum, urine, stool and saliva, as well as in physiologic components 
related to the route of administration, such as in the ascites fluid following intraperitoneal 
injections and in the bronchoalveolar lavage following intrabronchial injections. In these 
studies, viral shedding is largely dose dependent, with the highest frequency, 
concentrations and durations of shedding reported in patients receiving the highest 
doses of virus (Dummer et al. 2000, Griscelli et al.2003, Makower et al. 2003, Small et al. 
2006, Kawahira et al. 2010, Kimball et al. 2010, Kim et al. 2012, Kim et al. 2013, 
Garcia et al. 2019, Machiels et al. 2019).  Data on shedding of live oncolytic 
adenoviruses virus is more limited with a few studies that reported live virus mostly in 
sputum samples in a dose dependent manner after both intravenous or intra tumoral 
administration. However, virus detection was limited to the first few days after virus 
administration, suggesting that shedding of the live virus is short lasting 
(Griscelli et al. 2003, Makower et al. 2003, Small et al. 2006). Due to the differences in 
the type of adenovirus tested, route of administration and shedding assays across 
studies, it is not possible to draw conclusions on any potential differences in shedding 
activity between different types of adenoviruses and/or route of administration. Of note, 
none of these studies have reported any transmission of oncolytic adenovirus to 
household contacts or healthcare providers.
LOAd703 is administered intra-tumorally which is expected to limit systemic exposure. 
In addition, the pre-existing and induced anti-adenovirus immune response will likely 
result in a rapid clearance of LOAd703 from the patient’s body. These factors are likely 
to reduce the duration and extend LOAd703 shedding as a viable virus. In addition, 
should the virus be transmitted to another person, LOAd703 is designed to selectively 
replicate within, and lyse the tumor cells and as such is expected to result in minimal 
pathogenicity to the host normal cells/tissues compared to the parental adenovirus strain.
Notwithstanding the low risk of infectivity of LOAd703, the protocol includes 
precautionary measures to minimize exposure of healthcare providers and close 
contacts, including contraception requirements for both females and male study subjects 
(Section A144.3), precautionary instructions to study staff during preparation and 
administration of LOAd703 and precautionary instructions to patients and close contacts 
(Section A144.1.2.2). In addition, shedding analyses will be performed to evaluate the 
biodistribution and shedding potential of LOAd703 (A14Table 9).


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
323/Protocol CO39612, Version 11
Given the mechanism of action for atezolizumab and LOAd703, immune-mediated 
adverse events and CRS are potential overlapping toxicities associated with the 
combination use of these two agents.  Therefore, there may be a potential for an 
increased risk of enhanced inflammatory response if a patient develops SARS-CoV-2 
infection while receiving atezolizumab and LOAd703.  If a patient develops severe CRS 
during the study, a differential diagnosis including COVID-19 testing should be 
considered.
Because LOAd703 is currently under evaluation in cancer patients and sufficient efficacy 
data are not yet available, its benefits are unknown at this time. 
In summary, preliminary data of the combination of OVs with immune checkpoint 
inhibitors support further investigation of OVs with an anti-PD-L1 in patients with 
refractory mCRC.
Safety data from ongoing investigations of LOAd703 have not revealed findings that 
would prohibit the investigation of LOAd703 combined with atezolizumab in the setting of 
a Phase Ib/II study.  The benefit-risk profile is considered positive, given the high unmet 
need  for well tolerated and effective treatments for patients with refractory mCRC, the 
scientific rationale for the combination of atezolizumab and LOAd703, and the 
anticipated safety profile for this combination.
A143 RATIONALE FOR DOSE AND SCHEDULE FOR ATEZO LOAD703
A143.1
RATIONALE FOR ATEZOLIZUMAB DOSE AND SCHEDULE
Atezolizumab will be administered at a fixed dose of 1200 mg Q3W (1200 mg on Day 1 
of each 21 day cycle), which is an approved dosage for atezolizumab, as outlined in the 
prescribing information.  Anti-tumor activity has been observed across doses ranging 
from 1 mg/kg to 20 mg/kg Q3W.  In Study PCD4989g, the maximum tolerated dose of 
atezolizumab was not reached, and no DLTs were observed at any dose.  The fixed 
dose of 1200 mg Q3W (equivalent to an average body weightbased dose of 15 mg/kg 
Q3W) was selected on the basis of both nonclinical studies (Deng et al. 2016) and 
available clinical pharmacokinetic, efficacy, and safety data (refer to the Atezolizumab 
Investigator's Brochure for details).
A143.2
RATIONALE FOR LOAD703 DOSE AND SCHEDULE
The intended target dose and schedule for LOAd703 is 5 1011 VP Q3W.  However, to 
account for potential overlapping toxicities, special caution will be taken by starting 
LOAd703 at the lower dose of 1 1011 VP. The safety and tolerability of LOAd703 at a 
dose level of 1 1011 VP in combination with atezolizumab will be evaluated in 
approximately 3 to 6 patients. If the dose of LOAd703 is determined to be safe and well 
tolerated, the Sponsor may decide to escalate the dose to 5 1011 VP in the subsequent 
patients according to the considerations described in Section A14-4.1.2.2.


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
324/Protocol CO39612, Version 11
The doses and schedule were selected on the basis of previous experience with the 
predecessor OV AdCD40L and results from the ongoing LOAd703 studies LOKON001 
and LOKON002.  AdCD40L has been safely injected repeatedly (48 weekly injections) 
at 2.5 1011 VP in a 500 l suspension in combination with cyclophosphamide 
preconditioning (Loskog et al. 2016).  Furthermore, another oncolytic adenovirus 
expressing CD40L has been safely tested at doses ranging from 3 1010 to 2 1012
VP/dose (35 injections) in patients with or without metronomic cyclophosphamide 
combination (Pesonen et al. 2012).  In Studies LOKON001 and LOKON002, the tested 
LOAd703 dose ranged from 5 1010 VP to the highest target dose of 5 1011 VP.  In 
these studies, LOAd703 administered at a dose of 5 1011 VP Q2W did not significantly 
increase the rate of severe toxicities induced by the chemotherapy regimen or the 
combination of chemotherapy plus atezolizumab.  Based on these results, 5 1011 VP 
Q2W  has been selected as the recommended Phase II dose and schedule in 
combination with chemotherapy. The 5 1011 VP  dose will continue to be evaluated in 
combination with chemotherapy plus atezolizumab as a Q2W regimen in Arm 2 of Study 
LOKON001 and is planned to be investigated in combination with atezolizumab as a 
Q3W regimen in Study LOKON003.  The Q3W schedule of administration for LoAD703 
aligns with the approved atezolizumab dosing schedule (1200 mg Q3W) and is expected 
to result in an acceptable safety profile, while reducing the procedure and visit burden to 
patients as compared with a Q2W regimen.  Refer to the LOAD703 Investigator’s 
Brochure for additional details.
A144 MATERIALS AND METHODS SPECIFIC TO ATEZO LOAD703 ARM
A144.1
TREATMENT IN ATEZO LOAD703 ARM
A144.1.1 Formulation, Packaging, and Handling
A144.1.1.1
Atezolizumab
The atezolizumab drug product will be supplied by the Sponsor as a sterile liquid in a 
single-use, 20-mL glass vial.  The vial contains approximately 20 mL (1200 mg) of 
atezolizumab solution.
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure.
A144.1.1.2
LOAd703
The LOAd703 drug product will be supplied by the Sponsor as sterile frozen liquid in a 
single-use vial. Each vial contains 650l LOAd703 adenoviral particles in suspension at 
a concentration of 1 1012 virus particles (VP)/ml. 
For information on the formulation and handling of LOAd703, see the pharmacy manual 
and the LOAd703 Investigator's Brochure.


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
325/Protocol CO39612, Version 11
A144.1.2 Dosage, Administration, and Compliance
Patients in the AtezoLOAd703 arm will receive treatment as outlined in Table 1 until 
unacceptable toxicity or loss of clinical benefit defined as (1) confirmed disease 
progression or (2) lack of continued benefit as determined by the investigator, after an 
integrated assessment of radiographic and biochemical data, local biopsy results (if 
available), and clinical status (e.g., symptomatic deterioration such as pain secondary to 
disease) (see Section 3.1.1 in the protocol body for details).  It is recommended that 
treatment be initiated no later than 7 days after randomization. 
Table 1
Treatment Regimen for AtezoLOAd703 Arm
Cycle 
Length
Dose, Route, and Regimen
(Drugs Listed in Order of Administration)
21 days

Atezolizumab 1200 mg IV on Day 1 of each cycle a

LOAd703 11011 VP or 51011 VP b intratumoral injection on Day 1 of 
each cycle c
a Atezolizumab will be administered preferably prior to LOAd703 injection.  If LOAd703 
cannot be administered the day of atezolizumab infusion, LOAd703 can be given on 
another day during the treatment week, after prior consultation with the Medical Monitor.  
If atezolizumab is administered after LOAd703, it should not be administered until the 
LOAd703 observation period has ended. 
b Initially, approximatively 3 to 6 patients will be treated at the dose of 1 1011 VP. If this 
dose is determined to be safe and well tolerated in these first 36 patients, the dose 
may be increased to 5 1011VP in the next enrolled patients according to the 
considerations described in Section A144.1.2.2.
c After the initial six injections of LOAd703 (Cyles 16), there is an option to continue 
treatment with LOAd703 for an additional 6 administrations (Cycles 712) for a 
maximum total number of 12 injections for patients who are deriving clinical benefit as 
determined by the investigator.  In the absence of confirmed PD, (as described in 
Section 3.1.1), atezolizumab treatment can continue after LOAd703 treatment has 
ended or has been discontinued for reasons other than toxicity, provided the patient is 
tolerating atezolizumab and is receiving clinical benefit in the opinion of the investigator. 
The Medical Monitor is available to advise as needed.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Guidelines for dose modification and treatment interruption or discontinuation because of 
toxicities are provided in Section A145.1.4.  Atezolizumab or LOAd703 treatment 
interruptions for reasons other than toxicity (e.g., surgical procedures) may be allowed.  
The acceptable length of treatment interruption must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator. The Medical Monitor is 
available to advise as needed.


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
326/Protocol CO39612, Version 11
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 5.3.5.12.  No safety data related to atezolizumab or LOAd703 overdose are 
available.  
A144.1.2.1
Atezolizumab
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle.  Atezolizumab will be administered preferably prior to LOAd703 
injection. If, for any reason, the investigator judges that LOAd703 should not be 
administered the day of atezolizumab infusion, LOAd703 can be given on another day 
during the treatment week after prior consultation with the Medical Monitor. If 
atezolizumab is administered after LOAd703, it should not be administered until the 
LOAd703 observation period has ended. 
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 5.  
Atezolizumab infusions will be administered per the instructions outlined in Table 2.
Table 2
Administration of First and Subsequent Atezolizumab Infusions
First Infusion
Subsequent Infusions

No premedication is permitted prior to the 
atezolizumab infusion.

Vital signs (pulse rate, respiratory rate, 
pulse oximetry, blood pressure, and 
temperature) should be recorded within 
60 minutes prior to the infusion.

Atezolizumab should be infused over 
60 (15) minutes.

If clinically indicated, vital signs should be 
recorded every 15 (5) minutes during the 
infusion and 30 (10) minutes after the 
infusion.

Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms.

If the patient experienced an 
infusion-related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator.

Vital signs should be recorded within 
60 minutes prior to the infusion.

Atezolizumab should be infused over 
30 (10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion.

If the patient experienced an infusion-
related reaction with the previous infusion 
or if clinically indicated, vital signs should 
be recorded during the infusion and at 
30 (10) minutes after the infusion.
Guidelines for medical management of infusion-related reactions (IRRs) for 
atezolizumab are provided in Appendix 6.


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
327/Protocol CO39612, Version 11
No dose modification for atezolizumab is allowed.  Guidelines for atezolizumab 
treatment interruption or discontinuation because of toxicities are provided in 
Section A145.1.4.  
A144.1.2.2
LOAd703
LOAd703 will be administered by intratumoral injection at a dose level of 1 1011 VP or 
5 1011 VP on Day 1 of each 21-day cycle during Cycles 16.  
Administration of LOAd703 will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.
LOAd703 injections will be administered per the instructions outlined in Table 3.
Dose Selection for LOAd703
Consideration for dose-escalation to 5 1011 VP will be based on a review of data from 
individual patients that have received at least one dose of the study treatment 
combination (i.e., LOAd703 and atezolizumab) and completed at least one treatment 
cycle (21 days).  The dose-escalation decision will be based on the occurrence (or 
absence) of Grade 3 or higher toxicity (per CTCAE Version 4.0) related to LOAd703
and/or atezolizumab in the safety-evaluable patients, with the following exceptions:

Grade 3 increase in liver function tests that resolves to Grade 1 or to baseline 
within 3 weeks  

Grade 3 fever and/or chills that improves to Grade 2 within 48 hours or fully 
resolves within 1 week

Grade 3 arthralgia and/or myalgia that can be adequately managed with supportive 
care or that resolves to Grade 2 within 1 week

Grade 3 nausea or vomiting that resolves to Grade 1 within 72 hours with or 
without appropriate supportive therapy

Grade 3 headache that can be adequately managed with supportive care or that 
resolves to Grade 2 within 1 week

Grade 3 fatigue/asthenia that resolves to Grade 2 within 1 week

Grade 3 tumor flare defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor
Evaluation of the LOAd703 1 1011 VP dose level will proceed as follows:

Initially, a minimum of 3 patients will be treated with the 1 1011 VP dose in 
combination with atezolizumab 1200 mg Q3W. 


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
328/Protocol CO39612, Version 11

If the 1 1011 VP dose is determined to be safe and well tolerated in all 3 patients, 
the Sponsor may proceed to evaluate the 5 1011 VP dose in the next enrolled 
patients.

If the 1 1011 VP dose is determined to be safe and well tolerated in only 2 out of 
3 patients, this dose will be evaluated in 3 additional patients. 

If the 1 1011 VP dose is determined to be safe and well tolerated in a minimum of
5 out of 6 patients, the Sponsor may proceed to evaluate the 5 1011 VP dose in the 
next enrolled patients. Otherwise, the Sponsor may decide to maintain the 
LOAd703 dose at 1 1011 VP.

If 2 or more of the first 36 patients dosed at 5 1011 VP experience a Grade 3 or 
higher toxicity related to LOAd703, enrollment into the AtezoLOAd703 arm will be 
halted. If enrollment of this arm is halted, the available safety data will be reviewed 
by the Internal Monitoring Committee (IMC; see Section 3.1.4).  Enrollment may 
continue if the IMC determines there is a positive benefit-risk assessment for 
patients entering the arm and there is a high likelihood that the underlying rate of 
Grade 3 or higher toxicity related to LOAd703 is not 30%.
Evaluation of the LOAd703 5 1011 VP dose level will proceed as follows:

Initially, a minimum of 3 patients will be treated with the 5 1011 VP dose in 
combination with atezolizumab 1200 mg Q3W. 

If the 5 1011 VP dose is determined to be safe and well tolerated in a minimum of 
2 out of 3 patients, the Sponsor may proceed to evaluate the 5 1011 VP dose in 
3 additional patients. 

If the 5 1011 VP dose is determined to be safe and well tolerated in a minimum of
5 out of 6 patients, this dose will be selected for evaluation in the remaining patients.

If 2 or more of the first 36 patients dosed at 5 1011 VP experiences a Grade 3 or 
higher toxicity related to LOAd703, the dose of 1 1011 VP will be selected for 
evaluation in the remaining patients.  
During the dose-escalation phase, patients who withdraw for any reason other than a 
high-grade toxicity and who have completed 1 cycle of the treatment regimen will be 
replaced. Also, the patients treated at the selected dose during the dose-escalation 
phase will contribute to the overall safety and efficacy analysis of the preliminary phase 
of this arm (see Section 3.1.1). 
The Sponsor may also decide to maintain or de-escalate the dose of LOAd703 to 
1 1011 VP if warranted by the emerging safety, pharmacokinetic, pharmacodynamic, 
biomarker, or efficacy data from the current study as well as data from ongoing studies 
with LOAd703.


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
329/Protocol CO39612, Version 11
Additionally, enrollment in the AtezoLOAd703 arm will be halted if Grade 3 or higher 
study treatment-related adverse events that are unmanageable and lead to 
discontinuation of all study drugs occur in at least one-third of patients in a given 
LOAd703 dose level during the dose-escalation phase.  If enrollment of this arm is 
halted, the available safety data will be reviewed by the IMC (see Section 3.1.4). 
Enrollment may continue if the IMC determines there is a positive benefitrisk 
assessment for patients entering that arm and there is a high likelihood that the 
underlying discontinuation rate due to adverse events is not 30%.
No intra-patient dose escalation is allowed.
In patients who are deriving clinical benefit as determined by the investigator and the 
Medical Monitor, there is the option to continue LOAd703 administrations for up to 
6 additional administrations Q3W for a maximum total number of 12 injections.
Guidelines for LOAd703 Administration
The investigator will assess which lesion is deemed clinically feasible for injection.  In 
general, preference should be given to injectable and measurable lesions (as per 
RECIST v1.1) over injectable and non-measurable lesions.  The following criteria should 
be considered when selecting injectable lesion(s).

Lesions selected for injection should meet at least one of the following size criteria:
–
Non-nodal lesions should measure 1 cm in the longest diameter
–
Nodal lesions should measure 1.5 cm in the shortest diameter
–
For non-nodal lesions with necrosis, the longest diameter of the necrotic region 
subtracted from the longest diameter of the lesion should measure 1 cm 

Lesions with any of the following characteristics should not be injected:
–
Lung lesions
–
Tumor lesions encasing or invading major blood vessels 
–
Lesions with risks to bowel penetration 
–
Lesions that have received lesion-directed therapy (eg, radiation, ablation, 
embolization) within 4 weeks prior to the start of study treatment
–
Predominantly necrotic lesions (the LOAd703 virus requires viable cells for 
efficacy.
–
For liver lesions:
-
Lesions located where any potential tumor swelling after injection may 
lead to biliary tract obstruction (e.g., 1 cm adjacent to the left main, right 
main, or common biliary ducts) 


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
330/Protocol CO39612, Version 11
-
Lesions that are  at risk of bleeding, including, but not limited to, the 
following:  
Lesions located 1 cm from the hepatic capsule
Lesions with tumor infiltration into the main portal vein, hepatic 
vein or vena cava
-
Approximately more than one-third of the liver is estimated to be involved 
with metastases
Five hundred microliters (500 l) LOAd703 at a total dose level of 1 1011 VP or 
5 1011 VP will be administered by image guided injection (either ultrasound or 
computed tomography) into one measurable (as per RECIST v1.1) and injectable lesion. 
The same lesion should preferably be used for all injections.  However, if over the 
course of treatment the injected lesion no longer fullfills the criteria for injection as 
outlined above, the injected lesion is not responding over time, or the patient may benefit 
from injection into another lesion as assessed by the investigator, a new lesion may be 
selected for further injections.
If any of the above occurs and another lesion is selected for injection, an explanation 
describing why the lesion was changed should be documented in the eCRF.
Tumor biopsy sample collection following treatment initiation
In consenting patients, and if deemed clinically feasible by the investigator, a tumor 
biopsy sample will be collected from the injected lesion immediately before the third 
LOAd703 administration on Day 1 of Cycle 3.  Local anesthesia is commonly not needed 
prior to LOAd703 injection but is recommended when this biopsy is taken. 
Instructions to study staff involved in the preparation and administration of 
LOAd703
The LOAd703 virus will be handled only by study staff trained to handle genetically 
modified microorganisms. All study staff involved in the viral administration and the 
collection of excretion samples should wear personal protective equipment that are
disposed of immediately after use. Pregnant or severely immunocompromised (e.g., 
bone marrow transplant) healthcare providers should be prohibited from preparing
and/or dosing LOAd703 or caring for LOAd703-treated patients. For details on 
precautions during preparation and administration of LOAd703, see the Pharmacy 
Manual.
Action plan in case of accidental exposure

Always inform the Supervisor (the principal investigator at the clinical trial site) and 
the IRB, if applicable, according to local institutional policy, as well as the Sponsor 


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
331/Protocol CO39612, Version 11
about accidental exposure/contamination with LOAd703. The accident form should 
be completed to document types of accident and actions taken.

Virus spillage: vacate the spill area for approximately 30 minutes to allow any 
potential aerosols to settle. Inactivate the LOAd703 virus with Virkonor equivalent 
disinfectant by gently pouring Virkon/disinfectant on the contaminated area. Allow
it to inactivate for at least 10 minutes before cleaning with absorbent paper using 
gloves. Dispose of the paper and gloves in a biohazard box.

Clothes contamination: Place the clothing item(s) in a trashbag and pour Virkon  
disinfectant over it. Close the trashbag properly and discard it in the hazardous 
waste.

Accidental needle stick injury: Allow the puncture wound to bleed before 
thoroughly flushing it with water, cleaning with soap and water and/or disinfectant
and covering the site with sterile gauze dressing that is discarded in an appropriate 
waste container when removed.

Exposure of intact or broken skin to virus: Flush with running water. Next wash 
with soap and rinse with water. Repeat washing. Soak the skin in disinfectant and 
allow air-dry. Seek medical care if inflammation or irritation develops.

Accidental exposure of mucous area (eyes, nose or mouth): Irrigate these 
areas with clean water or physiological saline solution (NaCL 0.9%). Eyes can also 
be rinsed with eyewash. Seek medical care if inflammation or irritation develops.
Guidance to patients and close contacts

Patients should avoid touching or scratching injection sites or the occlusive 
dressings.

When the dressing is removed at home, dressing should be handled with gloves or 
hands should be washed with soap and warm water immediately after the handling 
of the dressing. Used dressing should be placed in sealed plastic bags before 
disposal in the household trash.

Avoid kissing and common usage of cutlery, crockery, drinking vessels, and tooth 
brushes for the duration of LOAd703 treatment and until 30 days after the last dose 
of LOAd703.

Caregivers and family members should observe personal hygiene 
(i.e., handwashing) after contact with treated participants.

Close contacts that are pregnant, newborn or immunocompromised should avoid 
exposure to the injection site and the patient’s body fluids.


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm 
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332/Protocol CO39612, Version 11
Table 3
Administration of First Two and Subsequent LOAd703 Injections
First Two Injections a
Subsequent Injections

Patients should be monitored overnight.

Premedication or post-dose prophylaxis 
with paracetamol (1 g, oral) or nonsteroidal 
anti-inflammatory drug (e.g., Ibuprofen, 
400 mg, oral) is recommended to reduce 
the risk of systemic injection reactions and 
CRS.

If the patient experienced a CRS with any 
previous injection, premedication with low-
dose corticosteroids may be administered 
for subsequent doses at the discretion of 
the investigator.  

Patients receiving LOAd703 as a 
percutaneous injection may receive an 
anxiolytic drug such as a benzodiazepine 
prior to the procedure.  

Prophylactic antibiotics such as 
IV-administered fluroquinolone is 
recommended if there is a risk of 
penetrating bowels or other circumstances 
that increase risk of infections, in the 
opinion of the investigator.

Vital signs (pulse rate, respiratory rate, 
pulse oximetry, blood pressure, and 
temperature) should be recorded within 
60 minutes prior to the injection.

LOAd703 should be administered by 
intratumoral injection as outlined in Section 
A144.1.2.2.

After the injection, vital signs should be 
recorded every 30 (5) minutes for the first 
2 hours and at 3h, 4h, 5h, 6h, and 8h (10 
minutes).

If clinically indicated, vital signs should be 
recorded every 4 hours (30 minutes) 
thereafter until discharge.

Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms.

Patients should be monitored for a minimum 
of 6 hours.

Premedication or post-dose prophylaxis with 
paracetamol (1 g, oral) or nonsteroidal anti-
inflammatory drug (e.g., Ibuprofen, 400 mg, 
oral) is recommended to reduce the risk of 
systemic injection reactions and CRS.

If the patient experienced a CRS with any 
previous injection, premedication with low-
dose corticosteroids may be administered for 
subsequent doses at the discretion of the 
investigator.  

Patients receiving LOAd703 as a 
percutaneous injection may receive an 
anxiolytic drug such as a benzodiazepine 
prior to the procedure.  

Prophylactic antibiotics such as 
IV-administered fluroquinolone is 
recommended if there is a risk of penetrating 
bowels or other circumstances that increase 
risk of infections, in the opinion of the 
investigator.

Vital signs should be recorded within 
60 minutes prior to the injection.

LOAd703 should be administered by 
intratumoral injection as outlined in Section 
A144.1.2.2.

After the injection, vital signs should be 
recorded every 30 (5) minutes for the first 
2 hours and hourly  until the end of the 6-
hour observation period if the previous 
injection was tolerated without an injection-
related reaction

If the patient experienced any injection-
related reaction with the previous injection or 
if clinically indicated, the patient should be 
monitored overnight.  After the injection, vital 
signs should be recorded every 30 (5)  
minutes for the first 2 hours and hourly (10 
minutes) until the end of the 6-hour 
observation period.  If clinically indicated, 
vital signs should be recorded every 4 hours 
(30 minutes) thereafter until discharge.
a Day 1 of Cycles 1 and 2.


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
333/Protocol CO39612, Version 11
Note that provisions should be made for overnight monitoring; patients may be released 
early according to the requirements outlined in Table 3 above at the discretion of the 
investigator.
Guidelines for LOAd703 dose modification and treatment interruption or discontinuation 
because of toxicities are provided in Section A145.1.4.
A144.1.3 Stage 2 Treatment
Patients in Stage 1 who experience loss of clinical benefit as determined by the 
investigator (as described in Section 3.1.1 in the protocol body) or unacceptable toxicity 
may be eligible to receive a different treatment combination during during Stage 2, 
provided a Stage 2 treatment is available for enrollment and they meet the eligibility 
criteria of that treatment regimen.  Stage 2 treatment must begin within 3 months after 
the patient has experienced loss of clinical benefit or unacceptable toxicity.  However, it 
is recommended that patients begin Stage 2 treatment as soon as possible, but no 
earlier than 2 weeks after the last dose of treatment in Stage 1. 
Tumor assessments performed prior to or at the time of loss of clinical benefit or 
unacceptable toxicity during Stage 1 may serve as baseline assessments for Stage 2, 
provided the tumor assessments are performed within 28 days prior to initiation of 
Stage 2 treatment (i.e., Day 1 of Cycle 1).  Stage 2 treatment will continue until 
unacceptable toxicity or loss of clinical benefit as determined by the investigator.
Table 4
Stage 2 Treatment Regimens Available for the Atezo LOAd703 
Arm
Study Treatment
Appendix
No Stage 2 treatment currently available 



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A144.2
CONCOMITANT THERAPY FOR ATEZO LOAD703 ARM
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated study treatment from 
7 days prior to initiation of study treatment to the treatment discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.
A144.2.1 Permitted Therapy for AtezoLOAd703 Arm
Patients are permitted to use the following therapies during the study:

Oral contraceptives

Hormone-replacement therapy

Prophylactic anticoagulation 
Prophylactic anticoagulation for the patency of venous access devices is 
allowed provided the activity of the agent results in an INR 1.5upper limit of 
normal (ULN) and aPTT is within normal limits within 14 days prior to Day 1.

Prophylactic antibiotic or antiviral treatment administered according to institutional 
standards

Vaccinations (such as influenza, COVID-19; please see Section A144.2.3)
Live, attenuated vaccines are not permitted.

Prophylactic standard anti-emetic therapy

Megestrol acetate administered as an appetite stimulant after initiation of study 
treatment

Mineralocorticoids (e.g., fludrocortisone)

Inhaled corticosteroids administered for chronic obstructive pulmonary disease or 
asthma

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency

Hormonal therapy with gonadotropin releasinghormone agonists or antagonists for 
prostate cancer

Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below:
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  
Treatment with atezolizumab and LOAd703 may be continued during palliative 
radiotherapy.  It is recommended not to irradiate a lesion that has been injected 
or will be injected with LOAd703.  


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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.
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).
A144.2.2 Cautionary Therapy for Atezo LOAd703 Arm
A144.2.2.1
Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis FactorInhibitors
Systemic corticosteroids, immunosuppressive medications, and tumor necrosis factor
(TNF) inhibitors may attenuate potential beneficial immunologic effects of treatment 
with atezolizumab and LOAd703.  Therefore, in situations in which systemic 
corticosteroids, immunosuppressive medications, or TNFinhibitors would be routinely 
administered, alternatives, including antihistamines, should be considered.  If the 
alternatives are not feasible, systemic corticosteroids, immunosuppressive medications,
and TNF-inhibitors may be administered at the discretion of the investigator.
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy (refer to Appendix 6 for details).


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm 
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A144.2.2.2
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer (see 
Section A144.2.3) may be used during the study at the discretion of the investigator.
A144.2.2.3
Anti-Platelet Agents and Low Molecular Weight Heparin
The following guidelines should be followed for procedures with moderate or significant 
risk of bleeding (deep lesions and/or organs):

Long-acting agents such as aspirin or clopidogrel should be discussed on a case-
by-case basis with the Sponsor and may need to be discontinued before the start of 
study treatment.

Use of preventive doses of low molecular weight heparin (LMWH) or direct anti-oral 
coagulant (DOAC) is allowed  but should be withheld 24 hours for LMWH or 48 h for 
DOAC prior to intratumoral injection and resumed 24 hours after the injection.
A144.2.3 Prohibited Therapy for AtezoLOAd703 Arm
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, may be prohibited 
prior to starting study treatment, depending on the agent, and is prohibited during 
study treatment until disease progression is documented and the patient has 
discontinued study treatment, with the exception of palliative radiotherapy and local 
therapy under certain circumstances outlined above in Section A144.2.1.

Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 28 days prior to initiation of study treatment and during study treatment.

Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with atezolizumab and LOAd703, for 
5 months after the final dose of atezolizumab, and for 90 days after the final 
administration of LOAd703.

Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin 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 and LOAd703.

For procedures with moderate or significant risk of bleeding (deep lesions and/or 
organs), use of therapeutic doses of anticoagulants is prohibited.

Adenovirus-based vaccines (e.g., ChAdOx1 nCoV-19, Ad26.COV2.S) are prohibited
for up to 6 months prior to initiation of study treatment, during treatment with 


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atezolizumab and LOAd703, and up to 6 months after the final administration of 
LOAd703.
A144.3
CONTRACEPTION REQUIREMENTS FOR ATEZO LOAD703 
ARM
Contraception requirements for women and men in the Atezo LOAd703 arm are 
outlined below:

For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse), or use contraceptive methods with a failure rate of 
1% per year during the treatment period and for 5 months after the last dose of 
atezolizumab and for 6 months after the last dose of LOAd703.  Women must refrain 
from breastfeeding during this same period of time.  During treatment with LOAd703 
and for 6 months after the last dose, women must refrain from egg donation.
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, hormonal contraceptives that inhibit 
ovulation, hormone releasing intrauterine devices, 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 a condom, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for 
6 months after the last dose of LOAd703 and to avoid exposing the embryo.  
Men must refrain from donating sperm during this same period. The female 
sexual partner must also agree to remain abstinent (refrain from heterosexual 
intercourse and from donating eggs) or use contraceptive methods with a 
failure rate of 1% per year during treatment with LOAd703 and for 6 months 
after the last dose.  Women must refrain from breastfeeding during this same 
period of time.  
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.


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm 
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A145 ASSESSMENT OF SAFETY FOR ATEZO LOAD703 ARM
A145.1
SAFETY PLAN FOR ATEZO LOAD703 ARM
The safety plan for patients in this study is based on clinical experience with 
atezolizumab and LOAd703 in completed and ongoing studies.  The anticipated 
important safety risks are outlined below (see Sections A145.1.1, A145.1.2, and 
A145.1.3).  Guidelines for the management of patients who experience specific 
adverse events are provided in Section A145.1.4.
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria, close monitoring of 
patients during the study, and reporting serious adverse events and adverse events of 
special interest until 180 days after the last administration of LOAd703 
(see Section 5.3.1).  Because of the potential for overlapping toxicities identified for 
atezolizumab and LOAd703, special caution will be taken by performing a planned 
safety evaluation for patients randomized to this arm (see Section 3.1.1.1). 
Administration of all agents 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 in the protocol body.
A145.1.1 Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, hypophysitis, adrenal insufficiency, Guillain-Barré
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
myocarditis, nephritis, myositis, and severe cutaneous adverse reactions.  
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), 
which are considered to be potential risks for atezolizumab.  Refer to Appendix 6 of the 
protocol and Section 6 of the Atezolizumab Investigator's Brochure for a detailed 
description of anticipated safety risks for atezolizumab.  
A145.1.2 Risks Associated with LOAd703
The overall safety profile of LOAd703 is based on data from 44 patients with advanced 
cancer.  The most common adverse reactions include fever, chills, nausea, vomiting and 
transient increased ALT.  These adverse events occur a few hours after LOAd703 
injection, when virus particles leak from the tumor to the blood stream where 
anti-adenovirus antibodies react to and clear the virus particles.  The symptoms are 
transient and manageable with symptomatic medication.  Grades 12 fever and 
Grades 12 CRS have been reported as serious adverse events related to LOAd703.  


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Local inflammation and swelling of the injected tumor may occur at the injected tumor 
site as part of the mechanism of action of LOAd703.  Tumor inflammation can be 
associated with pain at the tumor site or affect the function of the organ in which the 
lesion is injected (e.g., increased level of liver function enzymes and bilirubin).  Pain and 
erythema at the injection site related to the injection procedure may be observed as well.  
One patient in Study LOKON001 developed sepsis with splenic infection after 
completing 6 LOAd703 doses at 51010 VP.  The sepsis was reported as unrelated to 
LOAd703 and likely due to penetration of the bowel by the tumor. However, it is possible 
that the route of drug administration, via endoscopic ultrasound-guided injection of 
pancreatic lesions, may have contributed to the event.  Therefore, the Study LOKON001 
protocol was amended to include prophylactic administration of IV antibiotics on the day 
of LOAd703 administration if the injections are performed via an endoscopic procedure 
or if the percutaneous injection is of risk to penetrate bowels, depending on the location 
of the tumor. 
Refer to the LOAd703 Investigator’s Brochure and Section A14-2.4 for detailed safety 
information from ongoing clinical studies of LOAd703.
A145.1.3 Risks Associated with Combination Use of Atezolizumab, and 
LOAd703
Potential overlapping toxicities for the combination of atezolizumab and LOAd703 
include immune-mediated adverse events, injection-related reactions, IRRs, and CRS. 
A145.1.4 Management of Patients Who Experience Adverse Events in 
AtezoLOAd703 arm
A145.1.4.1
Dose Modifications
There will be no dose modifications for atezolizumab in this study.
For management of drug-related toxicities, the dose of LOAd703 may be reduced up to 
two times as outlined in Table 5 and Table 6.  If further dose reduction below 51010 is 
indicated, LOAd703 should be discontinued.  After dose reduction, the dose may not be 
escalated during subsequent administrations.
Table 5
Recommended Dose Reductions for the
LOAd703 1 1011 VP Dose Level 
Initial Dose
First Dose Reduction
LOAd703
11011VP
51010VP


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm 
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340/Protocol CO39612, Version 11
Table 6
Recommended Dose Reductions for the
LOAd703 5 1011 VP Dose Level 
Initial Dose
First Dose Reduction
Second Dose Reduction
LOAd703
51011VP
11011VP
51010VP
A145.1.4.2
Treatment Interruption for Toxicities
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 more 
than 12 weeks, the patient will be discontinued from the study.  However, atezolizumab 
may be withheld for more than 12 weeks to allow for patients to taper off corticosteroids 
prior to resuming treatment.  Atezolizumab can be resumed after being withheld for more 
than 12 weeks if the patient is likely to derive clinical benefit. The decision to re-
challenge patients with atezolizumab should be based on investigator’s assessment of 
benefitrisk and documented by the investigator.  The Medical Monitor is available to 
advise as needed.
LOAd703 may be temporarily suspended in patients experiencing toxicity related to 
study treatment.  If LOAd703 has been withheld for more than 12 weeks because of 
toxicity, the patient should be discontinued from LOAd703.  However, LOAd703 can be 
resumed after being withheld for more than 12 weeks if the patient is likely to derive 
clinical benefit. The Medical Monitor is available to advise as needed.
If atezolizumab or LOAd703 are permanently discontinued, the other agent should also 
be discontinued unless the patient is likely to derive clinical benefit from single-agent use, 
as determined by the investigator. The Medical Monitor is available to advise as needed.
Refer to Section A14-4.1.2 for information on dose interruptions for reasons other than 
toxicity.
A145.1.4.3
Management Guidelines for Adverse Events
Guidelines for the management of patients who experience specific adverse events are 
provided below in Table 7 for events related to overlapping toxicities or LOAd703 
treatment.
For cases in which management guidelines are not covered in Appendix 6 or Table 7, 
patients should be managed and treatments should be withheld or discontinued as 
deemed appropriate by the investigator according to best medical judgment.  


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Table 7
Guidelines for Management of Patients Who Experience Adverse Events in AtezoLOAd703 Arm
Event
Action to Be Taken
Anaphylaxis, and 
hypersensitivity reactions

Guidelines for management for atezolizumab are provided in Appendix 6.

For anaphylaxis precautions, see Appendix 5.
Tumor inflammation and 
injection-site reaction

Consider treatment with anti-inflammatory medication and symptomatic pain control as needed. 
NSAID should be preferred over corticosteroids. 
Systemic injection-related reactions, IRR, CRS
General guidance

Because systemic injection reactions and CRS related to LOAd703 maybe indistinguishable from IRR 
and CRS related to atezolizumab, the same supportive care and treatment with corticosteroids and/or 
anti-cytokine therapy is recommended for both as described in the IRR/CRS management guidelines 
in Appendix 6. 
Grade 1a
Including fever b with or without 
constitutional symptoms

Follow guidelines for atezolizumab in Appendix 6.

Administer next injection of LOAd703 at the same dose level.
Grade 2
Fever b with hypotension not 
requiring vasopressors
and/or
Hypoxia requiring low-flow oxygen 
d by nasal cannula or blow-by

Follow guidelines for atezolizumab in Appendix 6.

Collect sample for cytokine measurements (e.g. IL-6) at time of event and before releasing patient 
from hospital.

If symptoms resolve to Grade 1 or better for 3 consecutive days, the next dose of LOAd703 may be 
administered at the same dose level.  


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm
Table 7
Guidelines for Management of Patients Who Experience Adverse Events in AtezoLOAd703 (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
342/Protocol CO39612, Version 11
Event
Action to Be Taken
Grade 3
Fever b with hypotension requiring 
a vasopressor (with or without 
vasopressin)
and/or
Hypoxia requiring high-flow 
oxygen d by nasal cannula, face 
mask, non-rebreather mask, or 
venturi mask

Follow guidelines for atezolizumab in Appendix 6.

Collect sample for cytokine measurements (e,g. IL-6) at time of event and before releasing patient 
from hospital

Permanently discontinue LOAd703 and contact Medical Monitor. g
Grade 4
Fever b with hypotension requiring 
multiple vasopressors (excluding 
vasopressin)
and/or
Hypoxia requiring oxygen by 
positive pressure (e.g., CPAP, 
BiPAP, intubation and mechanical 
ventilation)

Follow guidelines for atezolizumab in Appendix 6.

Permanently discontinue LOAd703 and contact Medical Monitor. g

Collect sample for cytokine measurements (e,g. IL-6) at time of event and before releasing patient 
from hospital


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm
Table 7
Guidelines for Management of Patients Who Experience Adverse Events in AtezoLOAd703 (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
343/Protocol CO39612, Version 11
Hepatic event (elevations in ALT, AST, and/or bilirubin) 
General guidance

For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate.

If elevated, LFTs should be monitored closely to determine whether this is a transient or persistent 
elevation.

Patients with right upper quadrant abdominal pain and/or unexplained nausea or vomiting should have 
liver function tests performed immediately and reviewed before the next administration of study drug(s).

If immune-mediated hepatitis is suspected, refer to guidance in Appendix 6.
Grade 1: 3ULN elevations in 
ALT or AST;  
1.5ULN total bilirubin 
elevation;
2.5ULN elevation ALP. 

Continue atezolizumab and LOAd703 at the same dose level.


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm
Table 7
Guidelines for Management of Patients Who Experience Adverse Events in AtezoLOAd703 (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
344/Protocol CO39612, Version 11
Grade 2: 
ALT 3ULN and 5ULN;
AST 3ULN and 5ULN;
Total bilirubin 1.5ULN and  
3ULN;
ALP 2.5ULN and 5ULN
OR
For patients with documented liver 
metastases AND:
Baseline AST/ALT is ULN to 
5ULN and increase to
5ULN to 10ULN.

Continue atezolizumab and LOAd703 at the same dose level.

Monitor LFTs at least weekly for a minimum of 4 weeks until transaminases return to 3ULN (Grade 
1), baseline, or 5 ULN for patients with liver metastases and elevated LFTs at baseline. Check LFTs 
prior to next dose.

If event does not improve within 5 days:
–
Withhold LOAd703 and atezolizumab for up to 12 weeks after event onset. h
–
Initiate treatment with 1-2 mg/kg/day oral prednisone or equivalent.
–
If event resolves to Grade 1 or better within 12 weeks (or 2-fold increase in baseline values for 
patients with liver metastases and elevated LFTs at baseline), resume atezolizumab and 
LOAd703 at the same dose level. i
–
If event does not resolve to Grade 1 or better (or2 fold increase in baseline values for patients 
with liver metastases and elevated LFTs at baseline) while withholding LOAd703 and 
atezolizumab, permanently discontinue atezolizumab and contact Medical Monitor. f, j


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm
Table 7
Guidelines for Management of Patients Who Experience Adverse Events in AtezoLOAd703 (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
345/Protocol CO39612, Version 11
Grade 3 or 4:
ALT 5ULN;
AST 5ULN;
Total bilirubin 3ULN;
ALP 5ULN.
OR
For patients with documented liver 
metastases AND Baseline 
AST/ALT is ULN to 5ULN 
and 
AST/ALT increases to 10 ULN 
or total bilirubin increases to
3ULN.

Permanently discontinue atezolizumab and LOAd703 and contact Medical Monitor. f, j

Consider patient referral to GI specialist for evaluation and liver biopsy to establish etiology of hepatic 
injury. 

Initiate treatment with 1-2 mg/kg/day oral prednisone or equivalent.

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.
Immune-mediated adverse events or atezolizumab-related toxicities not described above
Grade 1
Follow guidelines for atezolizumab in Appendix 6.
Continue LOAd703.
Grade 2
Follow guidelines for atezolizumab in Appendix 6.
LOAd703 may be continued at the investigator’s discretion
Grade 3 or 4

Follow guidelines for atezolizumab in Appendix 6.

Permanently discontinue LOAd703. g
LOAd703-related toxicities not described above
Grade 1 or 2
Initiate symptom-directed supportive care.
Continue atezolizumab.
Consider LOAd703 dose modification as clinically indicated; otherwise continue LOAd703 at the same 
dose.


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm
Table 7
Guidelines for Management of Patients Who Experience Adverse Events in AtezoLOAd703 (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
346/Protocol CO39612, Version 11
Grade 3
Withhold LOAd703.  Atezolizumab may be continued at the investigator’s discretion.
If event resolves to Grade 1 or better within 8 weeks, resume LOAd703 with a one-level dose reduction.  
If not, permanently discontinue LOAd703. g
Dose re-escalation of LOAd703 is not permitted.
Grade 4
Permanently discontinue LOAd703. g  Withhold atezolizumab.
If event improves and Medical Monitor agrees that atezolizumab should be continued, resume 
atezolizumab.  If not, permanently discontinue atezolizumab. f
ASTCT American Society for Transplantation and Cellular Therapy; BiPAPbi-level positive airway pressure; CPAPcontinuous positive 
airway pressure; CRScytokine-release syndrome; CTCAECommon Terminology Criteria for Adverse Events; eCRF electronic Case Report 
Form; GIgastrointestinal; HLHhemophagocytic lymphohistiocytosis; ICUintensive care unit; IRRinfusion-related reaction; LFT liver 
function test; MASmacrophage activation syndrome; NCINational Cancer Institute; NSAIDnonsteroidal anti-inflammatory drug;
ULNupper limit of normal;
a Grading system for management guidelines is based on ASTCT consensus grading for CRS.  NCI CTCAE (version as specified in the 
protocol) should be used when reporting severity of IRRs, CRS, or organ toxicities associated with CRS on the Adverse Event eCRF.  Organ 
toxicities associated with CRS should not influence overall CRS grading.
b Fever is defined as temperature ≥ 38C not attributable to any other cause.  In patients who develop CRS and then receive anti-pyretic, anti-
cytokine, or corticosteroid therapy, fever is no longer required when subsequently determining event severity (grade).  In this case, the grade 
is driven by the presence of hypotension and/or hypoxia
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, bronchodilators, and/or oxygen.  For bronchospasm, 
urticaria, or dyspnea, additional treatment may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as oxygen delivered at 6 L/min.
e There are case reports where anti-cytokine therapy has been used for treatment of CRS with immune checkpoint inhibitors (Rotz et al. 2017; 
Adashek and Feldman 2019), but data are limited, and the role of such treatment in the setting of antibody-associated CRS has not been 
established.
f Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the event.  The decision to
re-challenge patients with atezolizumab should be based on investigator's assessment of benefitrisk and documented by the investigator (or 
an appropriate delegate).  The Medical Monitor is available to advise as needed.


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm
Table 7
Guidelines for Management of Patients Who Experience Adverse Events in AtezoLOAd703 (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
347/Protocol CO39612, Version 11
g Resumption of LOAd703 at a lower dose level may be considered in patients who are deriving benefit and have fully recovered from the 
toxicity.  The decision to re-challenge patients with LOAd703 should be based on investigator's assessment of benefitrisk and documented 
by the investigator (or an appropriate delegate).  The Medical Monitor is available to advise as needed.
h 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 based on an assessment 
of benefitrisk by the investigator and in alignment with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.
i
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.
j
Rechallenge with a lower dose level of LOAd703 may be considered if an alternative cause for impaired liver tests is discovered and/or the 
laboratory abnormalities resolve to normal/baseline within 7 days. If signs/symptoms recur with rechallenge, permanently discontinue 
LOAd703.


Appendix 14:  Study Details Specific to AtezoLOAd703Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
348/Protocol CO39612, Version 11
A145.2
ADVERSE EVENTS OF SPECIAL INTEREST FOR 
ATEZO LOAD703 ARM (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 in the protocol body for reporting instructions).  Adverse events of special 
interest for the AtezoLOAd703 arm are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7 in the protocol body) 

Suspected transmission of an infectious agent by the study treatment, as defined 
below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of study treatment is suspected.

Pneumonitis

Colitis

Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis

Hepatitis, including AST or ALT 10 ULN

Systemic lupus erythematosus

Neurologic disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis

Events suggestive of hypersensitivity, IRRs, systemic injection-related reactions, 
CRS, influenza-like illness, HLH, and MAS 

Nephritis

Ocular toxicities (e.g., uveitis, retinitis, and optic neuritis)

Myositis

Myopathies, including rhabdomyolysis

Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Vasculitis

Autoimmune hemolytic anemia

Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis)


Appendix 14:  Study Details Specific to AtezoLOAd703Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
349/Protocol CO39612, Version 11
A145.3
REPORTING REQUIREMENTS FOR PREGNANCIES IN 
ATEZOLOAD703 ARM
A145.3.1 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 6 months after the last 
dose of atezolizumab and LOAd703.  A paper Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.  
Pregnancy should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study treatment and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
A145.3.2 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 
6 months after the last dose of LOAd703.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study treatment.  
When permitted by the site, the pregnant partner will need to sign an Authorization for 
Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy.  If the authorization has been signed, the investigator should submit a 
Clinical Trial Pregnancy Reporting Form when updated information on the course and 
outcome of the pregnancy becomes available.  An investigator who is contacted by the 
male patient or his pregnant partner may provide information on the risks of the 
pregnancy and the possible effects on the fetus, to support an informed decision in 
cooperation with the investigator and/or obstetrician.
A145.3.3 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, 


Appendix 14:  Study Details Specific to AtezoLOAd703Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
350/Protocol CO39612, Version 11
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2 in the protocol body).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
A145.3.4 Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment should be classified as a serious adverse event, recorded on the Adverse 
Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2 in the protocol body).


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
351/Protocol CO39612, Version 11
A146. SCHEDULE OF ACTIVITIES AND SAMPLE COLLECTION FOR ATEZOLOAD703 ARM
Table 8:
Schedule of Activities for Atezo LOAd703 Arm
Assessment/Procedure
Screening
Days
–28 to –1
Treatment (21-Day Cycles) a
Stage 2
Screening d
or Treatment
Discon e
Follow-Up
Every 
3 Months
(7 days)
Cycle 1 b
Cycle 2
Cycles 3
Days 
Days 
Days 
1
2 jj
8
(3 days)
1
(3 days)
2 jj
8
(3 days)
1
(3 days)
Molecular profile of CRC
(if available)
See
Appendix
15
Whenever updated information becomes available
Vital signs f
x c
x
x
x c
x
x
x
x
Weight
x g
x g
x g
x
Complete physical examination h
x
Limited physical examination i
x g
x g
x g
x g
x g
x g
x g
x
ECOG Performance Status
x g
x g
x g
x
ECG j
As clinically indicated g
x k
Hematology l
x m, n
x m
x m
x m
x m
x
Chemistry o
x m, n
x m
x m
x m
x m
x
Coagulation (INR and aPTT) p
x m, n
x m
x m
x k
TSH, free T3 (or total T3), and
free T4 q
x m, n, q
x
Viral serology r
x k, r
C-reactive protein
x k
Plasma CEA s
x m
x m, s


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm
Table 8:
Schedule of Activities for Atezo LOAd703 Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
352/Protocol CO39612, Version 11
Assessment/Procedure
Screening
Days
–28 to –1
Treatment (21-Day Cycles) a
Stage 2
Screening d
or Treatment
Discon e
Follow-Up
Every 
3 Months
(7 days)
Cycle 1 b
Cycle 2
Cycles 3
Days 
Days 
Days 
1
2 jj
8
(3 days)
1
(3 days)
2 jj
8
(3 days)
1
(3 days)
LDH
x k
Pregnancy test t
x m, n
x m
x m
x u
x t
Urinalysis v
See
Appendix
15
Perform as clinically indicated
x k, u
Serum autoantibody sample w
Perform if patients experience suspected immune-mediated adverse 
event
x k
Blood sample for RBR 
(optional) x
x
Biomarker samples 
Refer to Table 9 below
Virus shedding samples
Refer to Table 9 below
Serum ADA sample
Refer to Table 9 below
Serum PK sample
Refer to Table 9 below
Serum anti-adenovirus antibody 
sample
Refer to Table 9 below
Tumor biopsy
x y
Tumor biopsy (optional)
x z
Tumor response assessments
x aa, bb, cc
Concomitant medications dd
x
x
x
x
x
x
x
x
Adverse events ee
x
x
x
x
x
x
x
x ee
x ee


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm
Table 8:
Schedule of Activities for Atezo LOAd703 Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
353/Protocol CO39612, Version 11
Assessment/Procedure
Screening
Days
–28 to –1
Treatment (21-Day Cycles) a
Stage 2
Screening d
or Treatment
Discon e
Follow-Up
Every 
3 Months
(7 days)
Cycle 1 b
Cycle 2
Cycles 3
Days 
Days 
Days 
1
2 jj
8
(3 days)
1
(3 days)
2 jj
8
(3 days)
1
(3 days)
Administer atezolizumab ff, hh
x
x
x
Administer LOAd703 gg, hh
x
x
x
Survival follow-up and 
anti-cancer treatment
x ii
ADAanti-drug antibody; CEAcarcinoembryonic antigen; CRCcolorectal cancer; CT computed tomography; dday; Discondiscontinuation; 
ECOGEastern Cooperative Oncology Group; eCRF electronic Case Report Form; HBcAbhepatitis B core antibody; HBsAghepatitis B 
surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; LDHlactate dehydrogenase; MRImagnetic resonance imaging; 
PKpharmacokinetic; RBR Research Biosample Repository; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; 
T3triiodothyronine; T4thyroxine; TSHthyroid-stimulating hormone.
Note:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.
a If a visit is precluded because of a holiday, vacation, or other circumstance, it may occur outside of the specified window.
b It is recommended that treatment be initiated no later than 7 days after randomization; however the first dose of study treatment should not occur 
within 7 days after a core biopsy or other surgical procedure. 
c Vital signs will be recorded through 8 hours post-injection for the first two injections (Day 1 of Cycles 1 and 2) as outlined in Section A144.1.2.2, 
Table 3.  Provisions should be made for overnight monitoring.
d Patients who experience loss of clinical benefit defined as (1) confirmed disease progression or (2) lack of continued benefit as determined by 
the investigator (see Section 3.1.1 for details) or unacceptable toxicity may be given the option of receiving a different treatment combination 
during Stage 2 of the study (as outlined in Section 3.1.2 provided Stage 2 is open for enrollment) and will undergo screening assessments to 
determine eligibility.  Study details specific to the Stage 2 treatment regimens are provided in the appropriate appendix.  Written informed 
consent must be obtained before performing screening evaluations for Stage 2.
e Patients will return to the clinic for a Stage 2 screening or treatment discontinuation visit not more than 30 days after the last dose of study 
treatment.  The visit at which loss of clinical benefit is confirmed may be used as the Stage 2 screening or treatment discontinuation visit.  


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm
Table 8:
Schedule of Activities for Atezo LOAd703 Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
354/Protocol CO39612, Version 11
Treatment discontinuation assessments must be performed for all patients, regardless of whether they enter Stage 2.  Patients who do not enter 
Stage 2 will undergo follow-up assessments after completing the treatment discontinuation visit.
f
Vital signs include respiratory rate, pulse rate, pulse oximetry, systolic and diastolic blood pressure while the patient is in a seated position, and 
temperature.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  Refer to 
Section A144.1.2.2, Table 3 for details related to vital signs monitoring during study treatment administration.
g Assessment may be performed within 24 hours prior to dosing during the treatment period.
h Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
i
Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  Record abnormalities 
observed at baseline on the General Medical History and Baseline Conditions eCRF.  The skin examination should be extended according to 
medical need.  During visits when a patient will undergo a tumor assessment, the physical examination should include an evaluation of the 
presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly.
j
ECG recordings will be obtained during screening and as clinically indicated at other timepoints.  It is recommended that patients be resting in a 
supine position for at least 10 minutes prior to ECG recording.
k Assessments to be performed only for patients undergoing Stage 2 screening.
l
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).
m Laboratory tests must be performed within 96 hours prior to dosing during the treatment period.
n If screening laboratory assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated.
o Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (per standard of care for the region), sodium, potassium, 
magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, and AST.
p Monitoring of INR/aPTT should be performed more frequently if clinically indicated.
q TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed at screening and on Day 1 of Cycle 1 and every 
third cycle thereafter (i.e., Cycles 4, 7, 10, etc.).
r
At Stage 2, patients without a prior positive HIV test result will undergo an HIV test, unless not permitted per local regulations.  Patients will also 
be tested for HBsAg, total HBcAb, and HCV antibody.  If a patient has a negative HBsAg test and a positive total HBcAb test at screening, an 
HBV DNA test must also be performed to determine if the patient has an HBV infection.  If a patient has a positive HCV antibody test at 
screening, an HCV RNA test must also be performed to determine if the patient has an active HCV infection. 
s CEA will be assessed on Day 1 of Cycle 1 and every 2 cycles thereafter (i.e., Cycles 3, 5, 7, etc.) until disease progression.


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm
Table 8:
Schedule of Activities for Atezo LOAd703 Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
355/Protocol CO39612, Version 11
t
All women of childbearing potential will have a serum pregnancy test at screening.  Urine or serum pregnancy tests will be performed at specified 
subsequent visits and at 3 months and 6 months after treatment discontinuation.  If a urine pregnancy test is positive, it must be confirmed by a 
serum pregnancy test.
u Screening laboratory test results must be obtained within 14 days prior to initiation of study treatment.
v Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted. 
w Autoantibody analysis includes anti-nuclear antibody, antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and 
perinuclear anti-neutrophil cytoplasmic antibody.
x Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate.  RBR sample should be collected prior to study treatment.
y Patients will undergo tumor biopsy sample collection at the time of unacceptable toxicity or loss of clinical benefit as determined by the 
investigator (see Section 3.1.1 for details), if deemed clinically feasible by the investigator.  Biopsies should be performed within 40 days after 
determination of unacceptable toxicity or loss of clinical benefit, or prior to the next anti-cancer therapy, whichever is sooner.  
Patients enrolled in the mandatory serial-biopsy arm (see Section 3.1.1.2) will undergo tumor biopsy sample collection 4 weeks (7 days) after 
treatment initiation (if deemed clinically feasible by the investigator).  See Section 4.5.7 for tissue sample requirements.
z Patients who consent to optional biopsies will undergo tumor biopsy sample collection immediately before the third LOAd703 administration on 
Day 1 of Cycle 3, if deemed clinically feasible and may undergo additional on-treatment biopsies at any other time during Stage 1 or Stage 2 at 
the investigator's discretion.
aa Patients will undergo tumor assessments at baseline, every 6 weeks (1 week) for the first 48 weeks following treatment initiation, and every 
12 weeks (2 weeks) thereafter, regardless of dose delays, until loss of clinical benefit defined as (1) confirmed disease progression or (2) lack 
of continued benefit as determined by the investigator (see Section 3.1.1 for details).  Thus, tumor assessments are to continue according to 
schedule in patients who discontinue treatment for reasons other than loss of clinical benefit, even if they start new nonprotocol-specified 
anti-cancer therapy.
bb All measurable and/or evaluable lesions identified at baseline should be reassessed at subsequent tumor evaluations according to the schedule 
described above.  Brain metastases identified at baseline that have been treated with radiotherapy or surgery will not be considered measurable 
or evaluable unless there is suspected disease progression in the brain (i.e., the patient becomes symptomatic).  Thus, subsequent head CT 
scans are not required unless clinically indicated.  The same radiographic procedures used to assess disease sites at screening should be used 
for subsequent tumor assessments (e.g., the same contrast protocol for CT scans).  
cc For patients who undergo screening for Stage 2, tumor assessments performed prior to or at the time of loss of clinical benefit during Stage 1 
may serve as baseline assessments for Stage 2, provided the tumor assessments are performed within 28 days prior to initiation of Stage 2 
treatment (i.e., Day 1 of Cycle 1).


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm
Table 8:
Schedule of Activities for Atezo LOAd703 Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
356/Protocol CO39612, Version 11
dd Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by a patient in addition to protocol-mandated study treatment from 7 days prior to initiation of study treatment until the treatment 
discontinuation visit.
ee After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first.  Serious adverse events and adverse events of special 
interest will continue to be reported until 180 days after the last dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first.  After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6 in 
the protocol body).  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is 
assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  
Every effort should be made to follow all serious adverse events considered to be related to study treatment or trial-related procedures until a 
final outcome can be reported.
ff Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle.  Atezolizumab will be administered 
preferably prior to LOAd703 injection.  The initial dose of atezolizumab will be delivered over 60 (15) minutes.  Subsequent infusions will be 
delivered over 30 (10) minutes if the previous infusion was tolerated without infusion-associated adverse events, or 60 (15) minutes if the 
patient experienced an infusion-associated adverse event with the previous infusion.  
gg LOAd703 will be administered by intratumoral injection at a dose level of 1 1011 VP or 5 1011 VP on Day 1 of each 21-day cycle (Q3W) during 
Cycles 16.  LOAd703 will be administered preferably after atezolizumab.  Premedication or postdose prophylaxis with paracetamol (1 g, oral) or 
nonsteroidal anti-inflammatory drug (e.g., ibuprofen, 400 mg, oral) is recommended.  Refer to Section A144.1.2.2 and
Table 3 for details.
hh Treatment will continue until unacceptable toxicity or loss of clinical benefit defined as (1) confirmed disease progression or (2) lack of continued 
benefit as determined by the investigator (see Section 3.1.1 for details).  In the absence of confirmed disease progression, atezolizumab 
treatment can continue after LOAd703 treatment has ended provided patient is tolerating atezolizumab and receiving clinical benefit in the 
opinion of the investigator in consultation with the Medical Monitor.
ii After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) 
will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months until death (unless the patient 
withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this request must be documented 
in the source documents and signed by the investigator.  If the patient withdraws from the study, the study staff may use a public information 
source (e.g., county records) to obtain information about survival status only. For an experimental arm in which all patients discontinued 
treatment and passed the safety follow-up window, as well as approximately 80% of patients discontinued the study, the Sponsor may conclude 
the arm (the remaining ~20% of patients will be discontinued from the study).


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm
Table 8:
Schedule of Activities for Atezo LOAd703 Arm (cont.)
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
357/Protocol CO39612, Version 11
jj If LOAd703 is administered on Day 2, assessments will be performed on Day 3. 


Appendix 14:  Study Details Specific to AtezoLOAd703Arm 
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
358/Protocol CO39612, Version 11
Table 9
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker 
Samples for AtezoLOAd703 Arm:  Preliminary and Expansion 
Phases
Visit
Time
Sample Type
Day 1 of Cycle 1
Prior to any study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

LOAd703 Shedding a

LOAd703 ADA (serum)

Biomarkers (plasma, serum, PBMC)
30 (10) minutes after atezolizumab 
infusion b

Atezolizumab PK (serum)
Day 2 of Cycle 1
24 hours (4 hours) after LOAd703 
injection on Day 1 c

LOAd703 Shedding a
Day 8 of Cycle 1
At visit

LOAd703 Shedding a

LOAd703 ADA (serum)

Biomarkers (plasma and serum)
Day 1 of Cycle 2
Prior to any study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

LOAd703 Shedding a

LOAd703 ADA (serum)

Biomarkers (plasma, serum, PBMC)
Day 2 of Cycle 2
24 hours (4 hours) after LOAd703 
injection on Day 1 d

LOAd703 Shedding a
Day 8 of Cycle 2
At visit

LOAd703 Shedding a

LOAd703 ADA (serum)
Day 1 of Cycle 3
Prior to any study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

LOAd703 Shedding a

LOAd703 ADA (serum)
Day 1 of Cycle 4
Prior to any study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

LOAd703 Shedding a

LOAd703 ADA (serum)

Biomarkers (plasma and serum)
Day 1 of Cycle 6
Prior to any study treatment

LOAd703 Shedding a

LOAd703 ADA (serum)
30 days after last dose 
of LOAd703 e
At visit

LOAd703 Shedding a

LOAd703 ADA (serum)
Day 1 of Cycle 8
Prior to any study treatment

Biomarkers (plasma and serum)

Atezolizumab PK (serum)

Atezolizumab ADA (serum)
3 months14 days after 
last dose of LOAd703 e, f
At visit

LOAd703 Shedding a

LOAd703 ADA (serum)
Day 1 of Cycle 12
Prior to any study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
359/Protocol CO39612, Version 11
Visit
Time
Sample Type
6 months14 days after 
last dose of LOAd703 e, f
At visit

LOAd703 Shedding a

LOAd703 ADA (serum)
Day 1 of Cycle 16
Prior to study treatment

Atezolizumab PK (serum)

Atezolizumab ADA (serum)
Treatment discontinuation 
visit (30 days after 
last study dose)
At visit

Biomarkers (plasma and serum)
Atezo atezolizumab; ADA anti-drug antibody; PBMC peripheral blood mononuclear cell; PK pharmacokinetic.
Note:  On the basis of emerging safety or efficacy data, the number of PK,ADA, anti-adenovirus antibody, shedding, 
and/or biomarker samples may be reduced or sample collection may cease altogether.  Additionally, collected 
samples may not be analyzed if not warranted. 
LOAd703 Shedding and ADA sample collections may align with atezolizumab infusion visits as appropriate per 
protocol specifications. 
Viral shedding will be assessed by PCR.
a
Shedding collection for LOAd703 includes:  blood (serum), urine sample, oral swab, and a rectal swab. 
b
If Atezolizumab is administered on Day 2 of Cycle 1, collection visit will be on Day 2 of Cycle 1.
c
If LOAd703 is administered on Day 2 of Cycle 1, collection visit will be on Day 3 of Cycle 1.
d
If LOAd703 is administered on Day 2 of Cycle 2, collection visit will be on Day 3 of Cycle 2.
e
LOAd703 shedding and ADA sample collections will be obtained at 30 days after the last dose of LOAd703, and
at 3 and 6 months14 days after the last dose of LOAd703, regardless of whether patients will have received 6 or 
12 doses. 
f
LOAd703 shedding and ADA sample collections at 3 months and 6 months for patients who continue atezolizumab 
monotherapy for 6 months after discontinuation of LOAd703 treatment are optional. 


Appendix 14:  Study Details Specific to AtezoLOAd703 Arm
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
360/Protocol CO39612, Version 11
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CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
363/Protocol CO39612, Version 11
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CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
364/Protocol CO39612, Version 11
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Appendix 15
Schedules of Activities for Screening
Table 1
Schedule of Activities for Stage 1 Screening 
Assessment/Procedure
Stage 1 Screening a
(Day –28 to –1)
Informed consent
x b
Demographic data
x
Medical history and baseline conditions
x
Molecular profile of colorectal cancer (if available)
x
MSI and BRAF status
x
Vital signs c
x
Weight
x
Height
x
Complete physical examination d
x
ECOG Performance Status
x
ECG (12-Lead) e
x
Hematology f
x g
Chemistry h
x g
Coagulation (INR, aPTT)
x g
TSH, free T3 (or total T3), free T4 i
x g
Viral serology j
x g
Pregnancy test k
x g
Urinalysis l, m
x g
C-reactive protein
x g
LDH
x g
Serum autoantibody sample n
x g
Tumor biopsy o
x g
Baseline tumor assessments p
x
Concomitant medications q
x
Adverse events r
x
TP53 mutation status
x s
ECOGEastern Cooperative Oncology Group; ECHOechocardiogram; eCRFelectronic 
Case Report Form; HBcAb hepatitis B core antibody; HBsAghepatitis B surface antigen; 
HBVhepatitis B virus; HCVhepatitis C virus; IVintravenous; MSImicrosatellite instability; 
T3triiodothyronine; T4thyroxine; TSHthyroid-stimulating hormone.


Appendix 15:  Schedule of Activities for Screening
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
367/Protocol CO39612, Version 11
Table 1
Schedule of Activities for Stage 1 Screening (cont.)
a Patients who fail their first screening for study eligibility may qualify for two re-screening 
opportunities (for a total of three screenings per patient) at the investigator’s discretion.  
Patients must re-sign the consent form prior to re-screening.  Results of standard-of-care
tests or examinations performed prior to obtaining informed consent and within 28 days 
prior to Day 1 (within 14 days prior to Day 1 for laboratory tests) may be used; such tests 
do not need to be repeated for screening or re-screening.
b Informed consent must be documented before any study-specific screening procedure is 
performed and may be obtained more than 28 days before initiation of study treatment.
c Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the 
patient is in a seated position, pulse oximetry, and temperature.  Record abnormalities 
observed at baseline on the General Medical History and Baseline Conditions eCRF. 
d Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic 
systems.  Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions eCRF.
e It is recommended that patients be resting in a supine position for at least 10 minutes prior 
to ECG recording.
f
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells).
g Screening laboratory test results must be obtained within 14 days prior to initiation of study 
treatment (Cycle 1, Day 1).  Exception:  Serum autoantibody samples must be collected 
within this window, but results will not be available before initiation of study treatment.
h Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (per 
standard of care for the region), CPK, sodium, potassium, magnesium, chloride, glucose, 
BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, 
ALT, and AST. 
i
Total T3 may be performed for sites where free T3 is not performed.
j
At screening, patients without a prior positive HIV test result will undergo an HIV test, 
unless not permitted per local regulations.  Patients will also be tested for HBsAg, total 
HBcAb, and HCV antibody.  If a patient has a negative HBsAg test and a positive total 
HBcAb test at screening, an HBV DNA test must also be performed to determine if the 
patient has an HBV infection.  If a patient has a positive HCV antibody test at screening, 
an HCV RNA test must also be performed to determine if the patient has an HCV infection.
k All women of childbearing potential will have a serum pregnancy test at screening.
l
Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted.
m Patients with 2protein on dipstick urinalysis at screening must undergo a 24-hour urine 
collection for protein, but only if a regorafenib-containing arm is open for enrollment.
n Autoantibody analysis includes anti-nuclear antibody, antidouble-stranded DNA, 
circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil 
cytoplasmic antibody.
o Baseline tumor tissue samples will be collected 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, provided that the tissue was obtained from a 
biopsy performed within 6 months prior to enrollment and that the patient has not received 
any anti-cancer therapy since the time of the biopsy.  Refer to Section 4.5.7 for tissue 
sample requirements.


Appendix 15:  Schedule of Activities for Screening
CRC Immunotherapy Combinations—F. Hoffmann-La Roche Ltd
368/Protocol CO39612, Version 11
Table 1
Schedule of Activities for Stage 1 Screening (cont.)
p All measurable and evaluable lesions should be assessed and documented at screening.  
Tumor assessments performed as standard of care prior to obtaining informed consent 
and within 28 days prior to initiation of study treatment do not have to be repeated at 
screening.  Screening assessments must include CT scans (with IV contrast; with or 
without oral contrast) or MRI scans (with IV contrast) of the chest, abdomen, pelvis, and 
head.  A spiral CT scan of the chest may be obtained but is not a requirement.  If a CT 
scan with contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal 
clearance), a non-contrast CT scan of the chest may be performed and MRI scans (with IV 
contrast, if feasible) of the abdomen, pelvis, and head should be performed.  A CT scan 
with contrast or MRI scan with contrast of the head must be done at screening to evaluate 
CNS metastasis in all patients (MRI scan must be performed if contrast is contraindicated).  
Bone scans and CT scans of the neck should also be performed if clinically indicated.  At 
the investigator’s discretion, other methods of assessment of measurable disease as per 
RECIST v1.1 may be used.  Refer to Section 4.5.6 for further details on tumor 
assessments.
q Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal 
or homeopathic remedies, nutritional supplements) used by a patient within 7 days prior to 
initiation of study treatment.
r
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study treatment or trial-related 
procedures until a final outcome can be reported.
s TP53 mutation status testing will only be required during screening for patients who did not 
undergo prescreen testing.