An Open Label, Non-Randomized Multisite Phase II Trial Combining Bevacizumab, Atezolizumab and Rucaparib for the Treatment of Previously Treated Recurrent and Progressive Endometrial Carcinoma
Phase: PHASE2
Conditions: Endometrial Cancer, Uterine Carcinosarcoma
Sponsor: Medical College of Wisconsin

MCW Protocol No: EndoBARR 
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CLINICAL STUDY PROTOCOL 
 
An Open Label, Non-Randomized Multisite Phase II 
Trial Combining Bevacizumab, Atezolizumab and 
Rucaparib for the Treatment of Previously Treated 
Recurrent and Progressive Endometrial Carcinoma 
 
Short Title 
The EndoBARR Trial 
(Endometrial Bevacizumab, Atezolizumab, Rucaparib) 
 
 
 
William H. Bradley, MD  
                                                   
Version 5.0; November 22, 2022 
 
 
 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential, 
and may not be disclosed to others except to the extent necessary to obtain Institutional Review 
Board approval and informed consent, or as required by federal and state laws. Persons to 
whom this information is disclosed should be informed that this information is privileged and 
confidential and that it should not be further disclosed. 

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Protocol Signature Page 
 
Protocol No.: 5.0 
Version Date: 11/22/2022/2020 
➢ I agree to follow this protocol version as approved by the MCW Scientific Review Committee 
(SRC), Institutional Review Board (IRB) and Data Safety Monitoring Committee (DSMC). 
 
➢ I will conduct the study in accordance with applicable IRB requirements, federal regulations, and 
state and local laws to maintain the protection of the rights and welfare of study participants. 
 
➢ I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol. 
 
 
➢ I agree to maintain adequate and accurate records in accordance with IRB policies, Federal, state 
and local laws and regulations. 
 
 
 
 
 
 
 
MCW Principal Investigator / Study 
Chair 
WILLIAM H. BRADLEY, MD 
Printed Name 
Signature 
Date 

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Title: An Open Label, Non-Randomized Multisite Phase II Trial Combining Bevacizumab, 
Atezolizumab and Rucaparib for the Treatment of Previously Treated Recurrent and Progressive 
Endometrial Carcinoma 
 MCW Protocol No.: PRO 34127 
 
 
Principal Investigator 
William H. Bradley, MD 
Associate Professor 
Division of Gynecology Oncology Department 
of Obstetrics and Gynecology Medical College 
of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, Wis. 53226 
Telephone: 414-805-6600 
Fax: 414-805-6622 
Email: wbradley@mcw.edu 
Sub-Investigator 
Janet S. Rader, MD 
Jack A. and Elaine D. Klieger Professor and Chair 
Division of Gynecology Oncology 
Department of Obstetrics and Gynecology 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, Wis. 53226 
Telephone: 414-805-6600 
Fax: 414-805-6622 
Email: jrader@mcw.edu 
Sub-Investigator 
Erin Bishop, MD 
Assistant Professor  
Division of Gynecologic 
Oncology 
Department of Obstetrics and Gynecology 
8701 Watertown Plank Road 
Milwaukee, Wis. 53226 
Telephone: 414-805-6600 
Fax: 414-805-6622 
 Email: erbishop@mcw.edu 
Sub-Investigator 
Denise Uyar, MD 
Associate Professor 
Division of Gynecologic Oncology 
Department of Obstetrics and Gynecology 
8701 Watertown Plank Road 
Milwaukee, Wis. 53226 
Telephone: 414-805-6600 
Fax: 414-805-6622 
Email: duyar@mcw.edu 
 
Biostatistician: 
Pippa Simpson 
Professor, Director 
Division of Quantitative Health Sciences 
Department of Pediatrics 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, Wis. 53226 
Telephone: 414-955-4521 
Fax: 414-955-6331 
Email: psimpson@mcw.edu 
Sub-Investigator 
Elizabeth Hopp, MD 
Assistant Professor 
Division of Gynecologic Oncology 
Department of Obstetrics and Gynecology 
8701 Watertown Plank Road 
Milwaukee, Wis. 53226 
Telephone: 414-805-6600 
Fax: 414-805-6622 
Email: ehopp@mcw.edu 
 

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Participating Sites Principal Investigators 
Pathologist  
Monica Prasad Hayes, MD 
Associate Professor 
Division of Gynecologic Oncology 
The Mount Sinai Medical Center 
1176 5th Avenue 
New York, NY 10028 
Telephone: 212-427-9898 
Email: monica.prasad@mssm.edu 
Nicholas Taylor, MD 
St Luke’s University Health Network 
701 Ostrum Street, Suite 502 
Bethlehem, PA 18015 
Tel: 484-526-7555 
Fax:484-526-3583 
Nicholas.Taylor@sluhn.org 
Juan Felix, MD  
Professor 
Department of Pathology 8701 
Watertown Plank Road 
Milwaukee, Wis. 53226 
Telephone: 414-805-6966 
Fax: 414-805-6980 
Email: jfelix@mcw.edu 
Radiologist 
Michael Holt, MD 
Assistant Professor 
 Department of Radiology 
9200 West Wisconsin Avenue 
Milwaukee, WI 53226 
Telephone: 414-805-3750 
Email: miholt@mcw.edu 
Funding Sponsor: 
Clovis Oncology 
Genentech 
Cardiologist 
Christopher Muller, MD FAC 
Assistant Professor of Medicine 
Division of Cardiovascular Medicine 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
Telephone: 414-805-3666 
E-mail: crmueller@mcw.edu 
Commercial Products: 
Rucaparib – Supplied by Clovis Oncology 
Atezolizumab – Supplied by Genentech 
Bevacizumab – Supplied by Genentech 

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REVISION HISTORY 
Revision history is presented in reverse order so that the information pertaining to the most 
current version of the protocol is presented first in this section. 
 
Version 5.0, Version Date 11/22/2022 
 
Version 4.0, Version Date 02/03/2020 
 
Version 3.0, Version Date 12/02/2019 
 
Version 2.1, Version Date 06/24/2019 
 
Version 2, Version Date 03/05/2019 
 
Version 1, Version Date 10/08/2018 
 
Initial submission of the protocol. 

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PROTOCOL SUMMARY 
 
Title 
An Open Label, Non-Randomized Multisite Phase II Trial Combining 
Bevacizumab, Atezolizumab and Rucaparib for the Treatment of Previously 
Treated Recurrent and Progressive Endometrial Carcinoma 
Protocol Number 
  EndoBARR 
Principal Investigator 
William H. Bradley, MD 
Study Sites 
Froedtert Hospital & the Medical College of Wisconsin 
Clinical Trial Phase 
Phase II 
Study Disease 
Recurrent Endometrial Carcinoma 
Main Eligibility Criteria 
Women with recurrent endometrial carcinoma, having progressed after or on 
primary or secondary anti-neoplastic therapy. 
Study Rationale 
To demonstrate the efficacy and safety of the combination of rucaparib, 
bevacizumab and atezolizumab in recurrent, progressive endometrial 
carcinoma. 
Primary Objectives 
To estimate the overall response of patients with progressive/persistent or 
recurrent endometrial cancer on study- directed therapy using RECIST 1.1. 
Secondary Objectives 
To estimate the progression free and overall survival and duration of response 
of patients with progressive/persistent or recurrent endometrial cancer, when 
treated with the combination of rucaparib, bevacizumab and atezolizumab. 
To determine the nature and degree of toxicity of treatment with this 
combination in this cohort of patients. 
Exploratory Objectives 
To explore best overall response and progression-free survival by patient and 
tumor factors: 
1. Microsatellite instability — both genetic and epigenetic. 
2. Homologous recombination deficiency. 
3. TIL population and PD-L1 expression in the tumor. 
4. Tumor mutational burden. 
5. Loss of heterozygosity 
6. Circulating tumor DNA 
7. Stool Microbiome 

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8. Cardiac toxicity by echo derived measurements of cardiac strain and assess 
the ability of this technique to predict development of toxicity for 
subjects under treatment 
Study Design 
Non-blinded, open-label, single-arm phase II protocol with safety lead- in. 
Study Agent/ 
Intervention 
Description 
Rucaparib, bevacizumab and atezolizumab in recurrent, progressive 
endometrial carcinoma. 
Number of Subjects 
30 
Subject Participation 
Duration 
Patients may continue on study directed treatment until disease progression, 
beyond progression with clinical benefit, removal for toxicity, or death from 
disease from the time of study entry. Subjects may continue on trial after 
progression if, in the opinion of the treating physician, the subject is obtaining 
clinical benefit from study directed treatment. 
Duration of Follow-up 
Until death. 
Estimated Time to 
Complete Enrollment: 
Two years. 
Statistical 
Methodology: 
The primary outcome is overall response rate (ORR). If the ORR is 27% 
(Castonguay et al., 2014) the one sided lower 95% CI bound is 14%. If the 
ORR is 23% the one sided lower 95% CI bound is 11%. 
Safety Assessments 
All information on AEs and SAEs will be listed by patient, and will be 
summarized. The SAE report will include event term(s), serious criteria, and 
the sponsor-investigator’s or sub-investigator’s determination of both the 
intensity of the event(s) and the relationship of the event(s) to study drug 
administration. Intensity for each SAE, including any lab abnormalities, will 
be determined by using the NCI CTCAE v.5 as a guideline whenever possible. 
Frequencies will be presented for the categorical variables (e.g., race) and 
descriptive statistics will be presented for continuous variables (e.g., weight, 
age). 
Efficacy Assessments 
Cross-sectional imaging with either CT scan or MRI (consistent modality for 
each subject). Imaging to be obtained every six weeks for the first 6 months 
on study, and then every 9 weeks while on study directed treatment. 
Unique Aspects of this 
Study 
This is the first trial to test the combination of a PARPi (rucaparib), PD- L1 
blockade (atezolizumab) and anti-VEGF therapy (bevacizumab) in this 
population. 

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SCHEMA 
 
 
 
Patients with 
recurrent or 
persistent 
endometrial 
carcinoma treated 
with one or two 
prior lines of 
therapy 
Atezolizumab 
1200mg IV Day 1, 
every 21 days 
Bevacizumab 15 
mg/kg IV Day 1, 
every 21 days 
Rucaparib 600 mg 
PO bid continuous 
Treatment until 
disease progression, 
beyond progression 
with clinical benefit, 
removal for toxicity, 
or death 

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Table 1. Study Calendar 
Period/ 
Procedure 
Within 0- 
28 
days 
prior 
to 
treatment 
Cycle 1 & 2 
 (+/-3 days) 
Cycle 1 & 
2, Days 8 
& 15 
  (+/-1 day) 
 
Cycle 3 and 
beyond 
(+/-3 days) 
 
End of 
treatment16 
Visit 
Follow-up (30 
and 9014 days 
+/- 7 after end 
of 
treatment 
visit) 
Informed consent 
X 
Inclusion and Exclusion Criteria 
X1 
AE assessment 
X 
X 
X7 
X 
X 
X 
Demographics and Medical History 
X 
X2 
X2 
X2 
X2 
X2 
Prior and Concomitant Medication 
Review 
X 
X 
X7 
X 
X 
X 
Archival or Newly Obtained 
Tissue Collection 
X 
 
X18 
Survival Status 
X 
X3 
Treatment/Drug Administration 
Atezolizumab 
Every 21 
Days 
 
Every 21 
Days 
Bevacizumab 
Every 21 
Days 
 
Every 21 
Days 
Rucaparib 
Twice 
daily4 
 
Twice 
daily4 
Clinical procedures 
Physical exam 
X 
X 
 
X 
X 
Vital signs, height5 and weight 
X 
X 
X7 
X 
X 
ECOG Performance status 
X 
X 
 
X 
X 
Laboratory procedures 
Study Day/Visit Day 
CBC w/ Differentials6 
X 
X7 
X7 
X 
X 
Blood chemistry: CMP, Mg+, Phos6 
X 
X7 
X7 
X 
X 
Non-fasting cholesterol6 
X 
X 
 
X 
X 
Thyroid Function Tests: TSH, T3 
Total, Free T46 
X 
X 
X 
Blood for Correlative Studies6/8 
 
X 
 
X 
X 
Urinalysis6 
X 
X9 
 
X9 
Urine Protein/Creatinine (UPC) ratio6 
X 
X9 
 
X9 
Prothrombin time/PTT/INR6 
X 
X10 
 
X10 
Pregnancy test (urine or serum hCG)11 
X 
X 
 
X 
Amylase, Lipase6 
X 
X 
 
X 
Stool sample12 
 
X 
 
X 
 
X 

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Table 1. Study Calendar 
Period/ 
Procedure 
Within 0- 
28 
days 
prior 
to 
treatment 
Cycle 1 & 
2 
(+/-3 days) 
 
Cycle 1 & 
2, Days 8 
& 15 
  (+/-1 day) 
Cycle 3 and 
beyond 
(+/-3 days) 
 
End of Treatment 
Visit16 
Follow-up (30 
and 9014 days 
+/- 7 after End 
of 
Treatment 
Visit) 
Imaging procedures 
Imaging: CT Chest, abdomen, 
pelvis preferred 
X 
X13 
 
X15 
2-D Echocardiography17 
X 
X 
 
X 
X 
ECG/EKG17 
X 
X 
 
X 
X 
1. 
Signed by the treating physician and confirmed by sponsor site prior to study entry (please see appendix 3 for 
enrollment worksheet) 
2. 
If any changes from screening. 
3. 
Survival to be re-assessed every three months (i.e. 90 days) +/- 7 days after end of treatment visit. 
4. 
Compliance to be assessed by pill count. 
5. 
Height should be recorded at screening and then once every 12 months from Cycle 1 Day 1 (i.e. 360 days +/- 7 days). 
6. 
If CBC with differential and Blood Chemistry labs are collected within 14 days before Cycle 1 Day 1, they do 
not need to be repeated on Cycle 1 Day 1. If Cholesterol, Thyroid Function Tests, PT/INR/PTT, Urine protein 
creatine (UPC) Ratio, Amylase, Lipase, and Urinalysis are collected within 28 days before Cycle 1 Day 1, they 
do not need to be repeated on Cycle 1 Day 1. 
7. 
CBC, CMP will be drawn weekly along with vital signs, AE and concomitant medication assessment (+/- 1 day) for 
the first two cycles. 
8. 
Correlative blood draws collected only if consented and while on treatment per study directed therapy. Cycle 1 Day 
1 correlative blood can be drawn any time within 0 to 28 days prior to treatment (blood should be collected before 
first cycle dose). Correlative draw will be collected pre-dose for the first 8 cycles, then stopped.  One draw will be 
collected at end of treatment visit. 
9. 
Urine protein creatine (UPC) Ratio to be collected within 28 days of Cycle 1 Day 1 and then on the first day of every 
odd cycle while on study (i.e. cycles 3, 5, 7, 9 and so on while subject is on study directed therapy). Urine protein via 
dipstick or urinalysis (either method is acceptable) to be collected within 28 days of Cycle 1 Day 1 and then on the 
first day of every even cycle while on study (i.e. cycles 2, 4, 6, 8 and so on while subject is on study directed 
therapy). 
10. PTT/PT/INR will be drawn with each cycle if the subject is on anticoagulation therapy and PTT/PT/INR is the 
method indicated to monitor therapy. 
11. If subject has child bearing capacity.  
12. First stool sample to be collected by patient within 7 days before Cycle 1 Day 1. Second stool sample to be 
collected by patient within 7 days before Cycle 4 Day 1, if on study directed therapy. Third stool sample to be 
collected by patient within 7 days before 30-day follow up visit, after treatment has ended. 
13. CT Chest/Abdomen/ Pelvis will be done every 6 weeks +/- 7 days from Cycle 1 Day 1 for the first 24 weeks, 
then every 9 weeks +/- 7 days while on treatment. If subject has chest CT negative for disease on screening, 
Chest X-ray may be substituted in subsequent imaging per investigator’s discretion. 
14. 90 day follow up may be done via phone to assess Adverse Events.  Resolution or continuation of AE’s will be 
documented.  
15. Subjects removed from active treatment for reasons other than progression should be imaged every 3 months 

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(i.e. 90 days) +/- 7 days or as indicated until consent is withdrawn. 
16. End of treatment visit should occur up to but no more than +7 days after last exposure to rucaparib or, if 
rucaparib is discontinued, no more than +21 days after last exposure to bevacizumab and/or atezolizumab. 
17. ECG/ Echocardiogram should be completed every 3 months (i.e. 90 days) +/- 7 days from Cycle 1 Day 1 while 
on treatment. End of treatment ECG/ Echocardiogram should be completed within +/- 7 days of the end of 
treatment visit. 
18. Newly-obtained tissue at end of treatment to be provided if consented and available. Tissue can be 
collected at any time after discontinuation of study treatment prior to the start of any new treatment 
regimens. 

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Table of Contents 
PROTOCOL SUMMARY ................................................................................................ 6 
SCHEMA ........................................................................................................................... 8 
LIST OF ABBREVIATIONS ......................................................................................... 14 
1 BACKGROUND .......................................................................................................... 17 
2 HYPOTHESIS AND OBJECTIVES ......................................................................... 20 
2.1 PRIMARY OBJECTIVES .................................................................................................................. 20 
2.2 SECONDARY OBJECTIVES ............................................................................................................ 21 
2.3 EXPLORATORY OBJECTIVES ....................................................................................................... 21 
3 STUDY DESIGN ......................................................................................................... 21 
3.1 GENERAL DESCRIPTION ............................................................................................................... 21 
3.2 RANDOMIZATION ............................................................................................................................ 22 
3.3 PRIMARY COMPLETION ............................................................................................................... 22 
3.4 STUDY COMPLETION ..................................................................................................................... 22 
4 PATIENT SELECTION ............................................................................................. 22 
4.1 INCLUSION CRITERIA .................................................................................................................... 22 
4.2 EXCLUSION CRITERIA ................................................................................................................... 24 
5 STUDY ENTRY AND WITHDRAWAL: STUDY PROCEDURES ...................... 26 
5.1 STUDY ENTRY PROCEDURES ...................................................................................................... 26 
5.2 END OF TREATMENT ...................................................................................................................... 29 
5.3 POST-TREATMENT .......................................................................................................................... 29 
5.4 STUDY WITHDRAWAL PROCEDURES ....................................................................................... 30 
6 TREATMENT PLAN .................................................................................................. 31 
6.1 INVESTIGATIONAL AGENT ADMINISTRATION ..................................................................... 31 
6.2 DOSE ESCALATION/DE-ESCALATION SCHEDULE ............................................................... 31 
6.3 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES .... 31 
6.4 MONITORING SUBJECT COMPLIANCE .................................................................................... 33 

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7 PHARMACEUTICAL INFORMATION .................................................................. 33 
7.1 BEVACIZUMAB ................................................................................................................................. 33 
7.2 RUCAPARIB (RUBRACA®) ......................................................................................... 34 
7.3 ATEZOLIZUMAB ............................................................................................................................... 36 
8 DOSING DELAYS/DOSE MODIFICATIONS ........................................................ 38 
8.1 MONITORING AND TOXICITY MANAGEMENT ...................................................................... 38 
8.2 RUCAPARIB ........................................................................................................................................ 38 
8.3 ATEZOLIZUMAB ............................................................................................................................... 41 
8.4 BEVACIZUMAB ................................................................................................................................. 52 
9 ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS .. 55 
9.1 DEFINITIONS OF ADVERSE EVENTS ......................................................................................... 55 
9.2 RECORDING OF EVENTS ............................................................................................................... 61 
10 REPORTING AND DOCUMENTING RESULTS (MEASUREMENT OF EFFECT) 
65 
10.1 EVALUATION OF EFFICACY (OR ACTIVITY) ........................................................... 65 
10.2 ANTITUMOR EFFECT – SOLID TUMORS ............................................................................... 65 
10.2.1 DEFINITIONS ............................................................................................................................... 65 
10.2.2 DISEASE PARAMETERS ........................................................................................................... 66 
10.2.3 METHODS FOR EVALUATION OF MEASURABLE DISEASE ......................................... 67 
10.2.4 RESPONSE CRITERIA ............................................................................................................... 68 
11 CORRELATIVE STUDIES/SPECIAL STUDIES .................................................. 69 
SHIPPING INSTRUCTIONS FOR MICROBIOME............................................................................... 72 
12 STATISTICAL CONSIDERATIONS ...................................................................... 73 
12.1 STUDY ENDPOINTS ........................................................................................................................ 73 
12.2 STUDY DESIGN ................................................................................................................................ 73 
12.3 RANDOMIZATION .......................................................................................................................... 74 
12.4 EXPLORATORY ANALYSIS .......................................................................................................... 74 
12.5 DETERMINATION OF SAMPLE SIZE AND ACCRUAL RATE ............................................. 74 
12.6 SAMPLE SIZE JUSTIFICATION AND FUTILITY ANALYSIS ................................................ 75 
12.7 REPLACEMENT POLICY .............................................................................................................. 75 
12.8 ACCRUAL ESTIMATES .................................................................................................................. 75 
12.9 INTERIM ANALYSES AND STOPPING RULES ........................................................................ 75 
12.10 ANALYSES PLANS ........................................................................................................................ 77 
12.10.1 PRIMARY ANALYSIS (OR ANALYSIS OF PRIMARY ENDPOINTS) ........................ 77 
12.10.2 SECONDARY ANALYSIS (OR ANALYSIS OF SECONDARY ENDPOINTS) .............. 77 

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12.10.3 OTHER ANALYSES/ASSESSMENTS .................................................................................... 78 
12.11 EVALUATION OF SAFETY ......................................................................................................... 78 
13 DATA AND SAFETY MONITORING PLAN (DSMP) ......................................... 80 
13.1 STUDY TEAM ................................................................................................................................... 80 
13.2 QUALITY ASSURANCE .................................................................................................................. 80 
13.3 CLINICAL TRIALS OFFICE.......................................................................................................... 80 
13.4 DSMC ....................................................................................................................... 81 
14 REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT ..... 81 
14.1 ETHICAL STANDARD .................................................................................................................... 81 
14.2 REGULATORY COMPLIANCE ..................................................................................................... 81 
14.3 PRESTUDY DOCUMENTATION ................................................................................................... 82 
14.4 INSTITUTIONAL REVIEW BOARD ............................................................................................. 82 
14.5 SUBJECT CONFIDENTIALITY AND ACCESS TO SOURCE DOCUMENTS/DATA .......... 83 
14.6 PROTECTION OF HUMAN SUBJECTS ....................................................................................... 84 
14.7 CHANGES IN THE PROTOCOL .................................................................................................... 84 
14.8 INVESTIGATOR COMPLIANCE .................................................................................................... 84 
14.9 PRODUCT COMPLAINTS ................................................................................................................ 86 
 
15 DATA HANDLING AND RECORD KEEPING ..................................................... 85 
15.1 OVERVIEW ....................................................................................................................................... 85 
15.2 DATA MANAGEMENT RESPONSIBILITIES............................................................................. 85 
15.3 HANDLING AND DOCUMENTATION OF CLINICAL SUPPLIES ........................................ 86 
15.4 SOURCE DOCUMENTS ................................................................................................................. 86 
15.5 CASE REPORT FORMS ................................................................................................................. 87 
15.6 STUDY RECORD RETENTION .................................................................................................... 87 
REFERENCES ................................................................................................................ 89 
APPENDIX 1. PERFORMANCE STATUS CRITERIA ............................................... 94 
APPENDIX 2. PREGNANCY FORM ............................................................................. 95 
APPENDIX 3. ENROLLMENT WORKSHEET ............................................................ 99 
APPENDIX 4. SAE REPORTING ................................................................................ 101 

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List of Abbreviations 
 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
CBC 
complete blood cell (count) 
CR 
complete response 
CRC 
clinical research coordinator 
CRF 
case report form 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
DC 
dendritic cell 
DFS 
disease-free survival 
DLT 
dose-limiting toxicity 
DSMB 
Data and Safety Monitoring Board 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECOG 
Eastern Cooperative Oncology Group 
FCBP 
female of childbearing potential 
FDA 
FFPE 
Food and Drug Administration 
Formalin Fixed, Paraffin Embedded 

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GCP 
Good Clinical Practice 
HBeAg 
hepatitis B “e” antigen 
HBV 
hepatitis B virus 
HCT 
hematocrit 
HCV 
hepatitis C virus 
HGB 
hemoglobin 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
IND 
investigational new drug application 
IP 
investigational product 
IRB 
Institutional Review Board 
IRR 
Infusion Related Reactions 
iwCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LOH 
loss of heterozygosity 
MCWCC 
Medical College of Wisconsin Cancer Center 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin lymphoma 
ORR 
overall response rate 

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PARP 
poly (ADP-ribose) polymerase 
PD 
disease progression 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PO 
per os (by mouth, orally) 
PR 
partial response 
QOL 
Quality of Life 
RBC 
red blood cell (count) 
SAE 
serious adverse event 
SD 
stable disease 
SD 
standard deviation 
SRC 
Scientific Review Committee 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
ULN 
upper limit of normal 
UP 
unanticipated problem 
UPIRSO 
unanticipated problems involving risks to subjects or others 
VEGF 
vascular endothelial growth factor 
WBC 
white blood cell (count) 

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1 BACKGROUND 
1.1 Endometrial Carcinoma 
 
Endometrial cancer is diagnosed in more than 50,000 women annually in the United States and is the 
cause of more than 10,000 deaths, making it the sixth most common cause of female cancer death (Siegel 
et al., 2017). Although the majority of cases are cured with surgical interventions, chemotherapy 
regimens of carboplatin and paclitaxel are often used for advanced or metastatic disease. Endometrial 
cancer that recurs or progresses after initial chemotherapy has no standard of care treatment agent(s), 
with median overall survival under two years (Fleming et al., 2004). 
Multiple second line agents are utilized, but response rates are limited, with single-agent chemotherapy 
response rarely greater than 10% (Fleming, 2015). Hormonal therapies have been used with limited 
response duration (typically <12 months). Furthermore, this approach relies on an estrogen or 
progesterone receptor positive tumor, which may not be the case in non- endometrioid sub-types (Carlson 
et al., 2014). Newer approaches, including anti-vascular endothelial growth factor (VEGF/anti-
angiogenic) and immunotherapy, are being utilized. 
Approximately 25–35% of the cases of endometrial cancer will have microsatellite instability (MSI) 
(Goodfellow et al., 2015; McMeekin et al., 2016), supporting the use of immunotherapy. 
 
1.1.1 Rationale for Antiangiogenic Therapy 
 
Antiangiogenic agents have shown activity in treating endometrial cancer progression after treatment 
with chemotherapy. When used as a single agent, bevacizumab demonstrated a response rate of 13.5% 
with a 40% progression-free survival (PFS) at six months (Aghajanian et al., 2011). Other 
antiangiogenic agents, including aflibercept, brivanib and sunitinib, have all shown similar progression-
free survival (PFS) at six months (Castonguay et al., 2014; Coleman et al., 2012; Powell et al., 2014). 
When combined with carboplatin and paclitaxel, the addition of bevacizumab improved overall survival 
in a chemotherapy naïve population and increased overall survival when compared with combination 
therapy with temsirolimus (Aghajanian et al., 2015). 
 
1.1.2 Rationale for Anti-PD-L1 Therapy and PARPi 
 
The use of immunotherapy in solid tumors offers a number of salient points in this disease site. In the 
Keynote Trial, treatment of endometrial cancer using pembrolizumab showed a response rate of 13% in 
a cohort of 24 patients. The median PFS for stable disease was 25 weeks. A hypermutated patient with 
a POLE mutation (without MSI) was noted to have strong response (Ott et al., 2017). Patients with 
colon cancer that demonstrates microsatellite instability have shown increased rates of response to PD-
L1 blockade, with response rates of up to 40% and PFS of 78% (median not reached) (Le et al., 2015). 
 
The Cancer Genome Atlas (TCGA) Research Network classified endometrial cancers into four 
subgroups based on genomic characteristics. The tumor groups are classified as 1) tumors with mutations 
in the DNA polymerase epsilon catalytic subunit (POLE), 2) endometrioid carcinomas with 
microsatellite instability (MSI), 3) endometrioid carcinomas with low copy number and 4) serous-like 
tumors with TP53 mutations. The POLE and MSI groups carry a higher mutationa burden and have an 
upregulation of immune checkpoint proteins, including PD-1 and PD-L1, and thus, contribute to the 
adaptive immune resistance of such tumors (Cancer Genome Atlas Research et al., 2013). 
 
PTEN mutations are common in endometrioid endometrial cancers, leading to an increase in DNA 
damage and genomic instability. Heeke et al reported high rates of homologous recombination (HR) 
deficiency in endometrial cancers with 38% (1956/5137) showing HR mutations (ASCO, 2017. 
Abstract #1502). These findings suggest susceptibility of these tumors to both immunotherapy and 
PARPi, such as Rucaparib. 

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Jiao et al measured PD-L1 expression in breast cancer cell lines before and after PARPi therapy. 
Inactivation of GSK2β by PARPi lead to enhanced expression of PD-L1. Subsequent blockade by PD-
L1 therapy led to T-cell mediated cell death. There was a significant increase in response in vivo to 
combination therapy compared to single-agent treatment (Jiao et al., 2017). Higuchi et al demonstrated 
CTLA-4 blockade could synergize with PARPi in a BRCA1-deficient mouse model, supporting an 
enhanced immune effect in combination therapy (Higuchi et al., 2015). 
 
1.1.3 Rationale for Combination of Anti-PD-L1 and Antiangiogenic Therapy 
 
Increasing evidence has described a link between (pro)angiogenesis and immunosuppression (Ott et 
al., 2015). Preclinical work by Shrimalia et al revealed that antiangiogenic therapy, in combination 
with adoptive T-cell transfer, yielded enhanced anti-tumor activity of T-cells compared with little 
tumor response to treatment when antiangiogenic was utilized alone. Initial work in understanding the 
angiogenic impact on dendritic cells (DCs) revealed that the normal DC population shifts to more 
immature precursors in the presence of antiangiogenic treatment (Gabrilovich et al., 1996). The 
significance of DCs on tumor immunity and prognosis has also been described. Almand et al noted 
that in 44 cancer patients with head and neck cancer, NSC lung cancer and breast cancer, the majority 
of DCs identified were immature and that the blood samples demonstrated decreased T-cell 
stimulation. Saito et al noted that DC infiltration and density correlated with an improved prognosis 
and that DC density is inversely correlated with angiogenic expression in gastric carcinoma. The 
combination of angiogenic inhibition with checkpoint inhibition offers a synergistic technique to 
enhance immune therapy. Early clinical studies have demonstrated the safety of this combination as 
well. Dudek et al presented their preliminary data with a combination of pembrolizumab (200 mg IV 
every three weeks) and bevacizumab (both 10 mg and 15 mg IV every three weeks). They reported 
that the combination therapy produced a greater reduction in circulating tumor cells and that in this 
cohort of 20 patients combination therapy was well tolerated with no dose-limiting toxicities, serious 
adverse events or Grade 3 or 4 drug-related toxicities. 
 
1.1.4 Rationale for Combination of PARPi and Antiangiogenic Therapy 
 
The combination of angiogenic inhibition and PARP inhibition is being used in serous ovarian 
carcinoma, with combination activity showing improvements over single-agent treatment (Liu et al., 
2014). The combination of cediranib and olaparib appears to reduce invasion and microvascular 
formation to a greater degree than either alone. This potentially offers both a direct cytotoxic effect, as 
well as potentially enhances the effect of immunotherapy. The molecular make up of serous ovarian 
cancer mimics serous endometrial cancer in a number of important fashions, including frequent P53 
mutations. The likelihood of cross-response in the endometrial disease site is supported by this 
commonality. 
 
1.1.5 Rationale for Combination of PARPi, Anti-PD-L1 and Antiangiogenic Therapy. 
 
The combination of the three proposed agents offers the opportunity to explore synergistic relationships 
between antiangiogenic and immunotherapy and antiangiogenic and PARPi. Increasing genetic 
instability by PARPi and double-strand breaks may lead to a proinflammatory state that would enhance 
the activity of immunotherapy, leading to synergistic response in a category of solid tumors that lack 
active therapy. It is expected that increased double-strand breaks may lead to increased expression of 
immunogenic antigens, increasing the effect of anti- PD-L1 therapy. Phase I data combining the PD-L1 
inhibitor durvalumab with either olaparib or cediranib showed good tolerability and evidence of 
response (Lee et al., 2017). Although there is not PK data for the combination of these agents, there is 
no clear rationale to suspect significant interaction, or cross-toxicities. 

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1.2 Cardiac Assessment 
 
Newer findings in cancer immunotherapy have included cardiotoxicity, with cardiomyopathy, 
symptomatic heart failure, myocarditis and fibrosis being noted (Heinzerling et al., 2016; Varricchi et 
al., 2017). Bevacizumab is also associated with arterial thromboembolic events in roughly 2% of 
patients (Totzeck et al., 2017), hypertension (5-18% incidence of Grade 3 or 4 hypertension) (FDA 
package insert, accessed February 24, 2018), and CHF (1.7-3%)(Choueiri et al., 2011). Given that 
cardiotoxicity may be an adverse event of this combination, routine monitoring with echocardiography 
will be undertaken. Technology, such as strain monitoring, will be used to predict and identify those 
at higher risk for development of these complications (Herrmann et al., 2014). 
 
1.3 Correlative/Exploratory studies 
 
1. Microsatellite instability (MSI) — both genetic and epigenetic 
2. Homologous recombination deficiency gene alterations 
3. PD-L1 expression in the tumor 
4. Tumor mutational burden 
5. Circulating tumor DNA 
6. Stool microbiome 
 
1.3.1 MSI 
 
The identification of microsatellite instability in endometrial carcinoma has become a routine 
assessment in standard of care. The use of either immunohistochemistry or qtPCR or both on either a 
biopsy specimen or final specimen has been shown to demonstrate MSI in up to 30% of cases 
(Goodfellow et al., 2015). These changes in tumor mismatch repair have been shown to affect tumor 
type as well as response to therapy (Cosgrove et al., 2017; Makker et al., 2017). 
 
1.3.2 Homologous recombination deficiency 
 
The rate of homologous recombination deficiency (HRD) in endometrial cancers has recently been 
demonstrated to be high among solid tumors (Arielle Lutterman Heeke, 2017). The effect of PARPi is 
modulated by synthetic lethality and alterations in HRD genes may associate with increased response. 
 
1.3.3 PD-L1 Expression 
 
Tumor samples (from initial diagnosis) will have PD-L1 assessed by IHC. Although the association 
between response to PD-1/PD-L1 blockade is not directly associated with expression, the correlation 
between PD-L1 and the monocyte population in the tumor is exploratory in this solid tumor. 
 
1.3.4 Tumor Mutational Burden 
 
Tumor response to immune checkpoint blockade has been associated with higher levels of mutational 
burden (Rizvi et al., 2015). This level will be assessed in primary patient specimens using formalin fixed, 
paraffin-embedded samples. 
 
1.3.5 Circulating Tumor DNA 
 
One of the challenges of immunotherapy-based solid tumor treatments is the timing of response to 
therapy. Solid tumors may enlarge and then later respond to treatment. The use of circulating DNA from 

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the tumor may provide a biomarker offering an earlier assessment of the likelihood of response 
(Goldberg et al., 2018). 
 
1.3.6 Stool Microbiome 
 
The microbiome is increasingly being noted to affect the response of malignancies to immunotherapy 
(Gopalakrishnan et al., 2018; Matson et al., 2018). Samples collected prior to therapy, after the third cycle, 
and after conclusion will allow longitudinal assessments of variations of the microbiome from patient to 
patient, and changes within a single patient. 
 
2 HYPOTHESIS AND OBJECTIVES 
2.1 Primary Objectives 
 
2.1.1 To estimate the overall response rate (ORR) of patients with progressive/persistent or 
recurrent endometrial cancer on study-directed therapy, using the combination of rucaparib, 
bevacizumab and atezolizumab. 
 
2.2 Secondary Objectives 
2.2.1 To estimate the progression free survival (PFS) and overall survival (OS) of patients with 
progressive/persistent or recurrent endometrial cancer when treated with the combination of rucaparib, 
bevacizumab and atezolizumab. 
 
2.2.2 To determine the nature and degree of toxicity of treatment with this combination in this cohort 
of patients. 
2.3 Exploratory Objectives 
 
2.3.1 To explore best overall response and progression-free survival stratified by patient and 
tumor factors: 
 
1. Microsatellite instability (MSI) — both genetic and epigenetic 
2. Homologous recombination deficiency gene alterations 
3. PD-L1 expression in the tumor 
4. Tumor mutational burden 
5. Loss of Heterozygosity 
6. Circulating tumor DNA 
7. Stool Microbiome 
8. To evaluate cardiac toxicity by echo derived measurements of cardiac strain and assess the ability 
of this technique to predict development of toxicity for subjects under treatment 
 
3 STUDY DESIGN 
3.1 General Description 
 
This is a phase II, open-label trial estimating primarily the ORR, secondarily PFS and OS of patients 
with persistent/progressive or recurrent endometrial cancer on bevacizumab, atezolizumab, and 
rucaparib. A safety lead-in of six-plus patients for toxicity will confirm tolerability. Patients will have 
recurrent or persistent/progressive endometrial carcinoma and have undergone one to two lines of prior 
therapy. Patients who have undergone two prior lines must have an ECOG performance status of 0 or 
1. Patients will be treated with an every three- week cycle of atezolizumab and bevacizumab. Rucaparib 
will be provided daily. Cross-sectional imaging will be undertaken every six weeks to assess disease 
status during the first six months on therapy, then imaging will be taken every nine weeks unless 
clinically indicated. 

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As stated above, there will be a planned six-subject safety lead in. After the first six subjects are enrolled 
and have received one cycle of study directed treatment, the DSMB/sponsors/PI will assess for 
associated DLTs attributed to the study medications. If there are three DLTs attributable to the study 
medication (in a cohort of either six or nine) the study enrollment will be stopped and dosing and 
schedule re-considered.  The trial may be continued with lower doses of the agent(s) considered to be 
the attributed source or sources of the DLT. The decision to continue the trial will be addressed at this 
point. If the trial is continued after the safety lead-in, the subjects enrolled during the lead-in will be 
considered assessable for primary, secondary and translational outcomes, regardless of whether one had 
had a DLT. 
 
3.1.1 Number of Subjects 
 
Thirty subjects will be enrolled. The planned enrollment is two years. 
 
3.2 Randomization 
 
This is a nonrandomized, open label, single-arm trial. 
 
3.3 Primary Completion 
 
The study will reach primary completion 30 months from the time the study opens to accrual. This is 
based on an expected enrollment time of two years to accrue 30 patients, and follow-up of 
approximately six months to complete treatment of subjects. 
 
Patients who progress on study-directed therapy may remain on study if, in the opinion of the treating 
physician, the subject is receiving clinical benefit. 
 
3.4 Study Completion 
 
The study will follow patients until death or close out of study. This is anticipated to be less than five 
years from enrollment at recurrent disease. 
 
4 PATIENT SELECTION 
4.1 Inclusion Criteria 
1. Patients must have recurrent or persistent/progressive endometrial carcinoma, which is refractory 
to curative therapy or established treatments. Histologic confirmation of the original primary tumor 
is required. Stained slides of either the primary or recurrent tumor are required. If primary FFPE 
samples are not available, a biopsy demonstrating recurrent disease must be obtained. Pathologic 
Slides/Blocks will be reviewed at the primary site for confirmation. 
 
2. Patients with the following histologic epithelial cell types are eligible: Endometrioid 
adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, 
mixed epithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.), mucinous 
adenocarcinoma, squamous cell carcinoma, transitional cell carcinoma and uterine carcinosarcoma 
(MMT). 
 
3. Patients must have had one prior chemotherapeutic regimen for management of endometrial 
carcinoma. Chemotherapy administered in conjunction with primary radiation as a radio-sensitizer 
WILL be counted as a chemotherapy regimen. Patients may have had, but are not required to have 
received, a second chemotherapeutic regimen for recurrent disease. 

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4. All patients must have either measurable disease or non-measurable but evaluable disease, as 
defined by RECIST 1.1. Measurable disease is defined as at least one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded). For disease to be measurable, 
each target lesion should be ≥ 10 mm when measured by CT or MRI and lymph nodes must be > 
15 mm in short axis when measured by CT or MRI. 
 
5. Patients may be enrolled if they do not have a target lesion (i.e. ≥ 10 mm lesion or ≥15 mm lymph 
node), if they have evaluable disease. This is defined by RECIST 1.1 as a suspicious lesion <10 
mm or a lymph node ≥10 mm but <15 mm. 
 
6. Patients must have an EGOG Performance Status of 0, 1. 
 
7. Recovery from effects of recent surgery, radiotherapy, or chemotherapy. 
 
8. Patients should be free of active infection requiring antibiotics (with the exception of 
uncomplicated UTI). 
 
9. Any hormonal therapy directed at the malignant tumor must be discontinued at least one week 
prior to registration. 
 
10. Any other prior therapy directed at the malignant tumor, including chemotherapy and 
immunologic agents, must be discontinued at least three weeks prior to first cycle of 
treatment. 
 
11. Any prior radiation therapy must be completed at least four weeks prior to first cycle of 
treatment. 
 
12. Prior hormonal therapy is allowed. There is no limit on the number of prior hormonal therapies 
allowed. Hormonal therapy will not be counted as a line of therapy for purposes of this trial. 
 
13. Patients must have a urine protein of ≤ 2+ on dipstick and urine protein creatinine ratio < 3.5. If 
urine protein dipstick is >2+, 24-hour urine protein must be obtained and should be < 1g for patient 
to be eligible. 
 
14. Patients must have signed an approved informed consent and authorization permitting release 
of personal health information for study purposes. 
 
15. Patients must meet pre-entry requirements, as specified in section 5. 
 
16. Patients of childbearing potential must agree to use an accepted and effective nonhormonal method 
of contraception i.e., double-barrier method (e.g., condom plus diaphragm) from the time of signing 
the informed consent through six months after last dose of study drug. 
 
17. Patients 18 years of age or greater. 
 
18. Be willing to provide tissue from the primary surgical resection or recurrent disease (paraffin block or 
slides). 
 
19. Must have laboratory values in the below ranges: 
 

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System 
Laboratory Value 
Endocrine 
Thyroid function testing (TSH) 
0.350 – 5.500 ulU/mL (Or within institutional laboratory range). 
Free T4/Total T3 
If TSH is outside of laboratory range and subject is clinically 
euthyroid, enrollment may occur if Free T4/Total T3 are in normal 
range by local lab values 
Hematological 
System 
Laboratory Value 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
Serum creatinine OR 
Measured or calculateda creatinine clearance 
(GFR can also be used in place of creatinine 
or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
≥60 mL/min for subject with creatinine levels > 1.5 X institutional 
ULN 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 
ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy as 
long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy as 
long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
4.2 Exclusion Criteria 
1. Patients with a history of other invasive malignancies, with the exception of non-
melanoma skin cancer, are excluded if there is any evidence of the other malignancy being 
present within the last two years. Patients with Ductal Carcinoma in situ (DCIS) of the 
breast in the prior two years may be enrolled on study if the treatment required no 
chemotherapy or radiation. Patients are also excluded if their previous cancer treatment 
contraindicates this protocol therapy. 
 
2. Patients must not have had exposure to Bevacizumab, PARPi, or immunotherapy. Patients 
may have had exposure to anti-angiogenic therapy provided it was not Bevacizumab. 
 
3. Patients who have received prior radiotherapy to any portion of the abdominal cavity or 
pelvis OTHER THAN for the treatment of endometrial cancer within the last three years 
are excluded. Prior radiation for localized cancer of the breast, head and neck or skin is 
permitted, provided that it was completed more than three years prior to registration, and 
the patient remains free of recurrent or metastatic disease. 

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4. Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER 
THAN for the treatment of endometrial cancer within the last three years are excluded. 
Patients may have received prior adjuvant chemotherapy for localized breast cancer, 
provided that it was completed more than two years prior to registration, and that the patient 
remains free of recurrent or metastatic disease. 
 
5. Inability to tolerate an oral medication or keep pills down. 
6. Patients who are pregnant or nursing. 
 
7. Patients with a complete bowel obstruction; recent (within six months) history of fistula, 
intraabdominal abscess or bowel perforation; subjects requiring total parenteral nutrition 
or parenteral hydration. 
 
8. Has a current diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within seven days prior to the first dose of 
trial treatment. 
 
9. Patients with history or evidence upon physical examination of CNS disease, including 
brain tumor, seizures not controlled with standard medical therapy or any brain metastases. 
 
10. Patients with clinically significant cardiovascular disease. This includes: 
 
o Myocardial infarction or unstable angina within 12 months of the first date of 
study treatment. 
 
o New York Heart Association (NYHA) Class II or greater congestive heart 
failure (Appendix I). 
 
o History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular 
fibrillation) or cardiac arrhythmias requiring antiarrhythmic medications (except for 
atrial fibrillation that is well controlled with antiarrhythmic medication). 
 
o Grade 2 or greater peripheral vascular disease. 
 
o Cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or 
subarachnoid hemorrhage within six months of the first date of study treatment. 
 
o History of arterial ischemia or thrombus. 
11. Patients with uncontrolled hypertension defined as systolic > 150 mm Hg or diastolic > 
90 mm Hg. The use of antihypertensive medications to control hypertension is permitted. 
 
12. Patients who have undergone major surgical procedure, open biopsy or significant traumatic 
injury within 28 days prior to the first date of study treatment or who have a major surgical 
procedure anticipated during the course of the study. Laparoscopic biopsy is acceptable and 

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will not require a delay in study treatment. 
 
13. Patients with serious nonhealing wound, ulcer (including gastrointestinal) or bone fracture. 
 
14. Patients with any condition, which in the investigator’s opinion, makes the patient 
unsuitable for study participation. 
 
15. Patients not available for follow-up assessments. 
 
16. Patients with known sensitivity to any of the products to be administered during dosing. 
 
 
5 STUDY ENTRY AND WITHDRAWAL: STUDY PROCEDURES 
5.1 Study Entry Procedures 
 
The study-specific assessments are detailed in this section and outlined in the study calendar. 
Screening assessments must be performed within 28 days prior to enrollment. Any results 
falling outside of the reference ranges may be repeated at the investigator’s discretion. Contact 
the medical monitor regarding screening/rescreening concerns. Treatment or visit delays for 
public holidays or weather conditions do not constitute a protocol violation but should be 
properly documented. 
 
A written, signed informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. A signed ICF copy will be given to the subject and a copy will be 
filed in the medical record. The original will be kept on file with the study records. 
 
All patients who are consented will be registered in OnCore®, the MCW Cancer Center 
Clinical Trial Management System. The system is password protected and meets HIPAA 
requirements. 
 
5.1.1 Registration Process 
 
Once a subject is identified by the investigator, the option of participation in the trial should 
be presented to the subject. Patients will be consented by either the treating oncologist or 
his/her authorized agent. Patients may enroll on trial without consenting for acquisition of de 
novo tissue or blood/serum samples. The only exception would be if there is no slides or 
blocks left from the primary diagnosis.  These subjects will need a new biopsy to prove 
disease. 
 
Registration of both aspects — study-directed treatment and blood/tissue donation 
for exploratory analyses — will be noted at registration. 
 
This is a planned multi-site trial.  Patients will be screened locally at the institution where they 
are being treated. Registration will be local. Each site will be assigned a site number, and 

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subjects will be numbered chronologically per the local site enrollment.  All screening data will 
be entered into OnCore and screening source documentation will be de-identified and uploaded 
in OnCore for verification by the parent site, Medical College of Wisconsin.  The PI will 
determine eligibility of subjects and will sign off on the subject enrollment form which should 
be uploaded into OnCore along with screening data for confirmation of eligibility by the 
sponsor-PI. A delegate will be assigned if the sponsor-PI is unavailable. 
 
5.1.2 Pretreatment Period 
The screening procedures and assessments must be completed within 28 days prior to treatment 
 
▪ Blood chemistry assessment, including: comprehensive metabolic panel, magnesium, 
phosphorus, non-fasting cholesterol, thyroid function tests (TSH, free T4, total T3) 
▪ Complete Blood Count (CBC) with differential. 
▪ Urine protein/creatine ratio 
▪ Complete medical history – Medical history will include all active conditions and any 
condition diagnosed within the prior 10 years that are considered to be clinically significant 
by the Investigator. 
▪ Concomitant medications 
▪ Evaluation of adverse events 
▪ Performance status (ECOG, KPS, etc.) 
▪ Physical examination 
▪ Prothrombin time (PT)/ international normalized ratio (INR), partial thromboplastin time 
(PTT) 
▪ Pregnancy test if subject has child bearing capacity (Urine or Serum hCG)  
▪ Radiographic tumor assessment (CT of Chest/Abdomen/Pelvis), or MRI of Abdomen/Pelvis 
with Chest imaging of physician choice. Chest may be omitted in subsequent imaging if not 
involved in recurrent disease.  CT is preferred imaging. 
▪ Vital signs 
▪ Urinalysis 
▪ Blood for correlative studies if consented (only once prior to treatment, either in screening 
or on Cycle 1, Day 1 pre-treatment) 
▪ Stool Sample (to be collected by patient within 7 days before Cycle 1, Day 1) 
▪ ECG 
▪ 2-D Echocardiography 
Assessment within four weeks prior to entry and every three months while on study, 
with one echo after completion of study-directed treatment: 
Conventional 2D Echocardiography 
 
All enrolled patients will undergo baseline standard 2D echocardiography (GE E9 and E95, 

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as well as Philips EPIQ) and Doppler assessment. Parasternal long and short axis, apical 4- 3- 
and 2 chamber and subcostal imaging will be performed. Doppler of mitral inflow and tissue 
Doppler imaging of the mitral annulus will also be assessed in order to perform a diastolic 
function assessment (Nagueh et al., 2016). The left ventricular ejection fraction will be 
estimated by Simpson’s biplane method, using the apical 4- and 2-chamber views. Left atrial 
volumes will be measured estimated, using the atrial-focused 4- and 2-chamber views. 
Parasternal long axis views will be employed to measure indexed LV mass using the ASE 
method (Lang et al., 2015). Pulmonary artery systolic pressure will be estimated using the 
tricuspid regurgitation velocity when the signal permits (Rudski et al., 2010). Thus, LV 
systolic and diastolic function, RV systolic function, atrial size, LV mass and pulmonary 
artery pressures will be reported for each patient. The presence of a pericardial effusion will 
also be reported. 
 
Global Longitudinal Strain Analysis 
Where available, GE software will be used to perform strain analysis (Thavendiranathan et al., 
2014). Endocardial borders at end systole and at end diastole will be traced within the apical 4- 
3- and 2-chamber views, using the aortic valve pulse wave doppler recording to guide timing of 
valve closure. Speckles will be tracked frame by frame throughout the cardiac cycle. The 
average strain per segment will be determined and reported on a polar map, using a 17-segment 
model. 
 
The global longitudinal strain (GLS) will be reported as the average strain of all 17 segments. 
A GLS of < -18% will be reported to be abnormal. 
 
Serial Echo Monitoring 
 
Patients will undergo surveillance echocardiography per protocol. After the initial full study, 
a limited study will be performed assessing left ventricular size and function, as well as right 
ventricular size and function. These parameters, in addition to the global longitudinal strain, 
will be reported during the serial echo monitoring period. 
 
5.1.3 Treatment Period 
 
During the treatment period, the following procedures will be performed. 
 
5.1.3.1 Cycles 1 and 2 Day 1 
▪ Assessment of AEs 
▪ Review of demographics and medical history – if any changes since screening 
▪ Review of concomitant medications 
▪ Physical Examination 
▪ Vital signs and weight 
▪ ECOG performance status 
▪ Complete Blood Count (CBC) with differential 

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▪ Blood Chemistry -Comprehensive Metabolic Panel (CMP); Magnesium, Phosphorous, 
nonfasting cholesterol, thyroid function tests (TSH, free T4, total T3) 
▪ Blood samples for correlative studies if consented (once prior to treatment on Cycle 1, Day 
1 and then again prior to treatment on Cycle 2, Day 1) 
▪ Urine protein via dipstick or urinalysis on Day 1 of every even cycle (i.e. cycles 2, 4, 6, 8 
and so on while subject is on study directed therapy) 
▪ Prothrombin time/PTT/INR (if method used to monitor subject’s anticoagulation therapy) 
▪ Pregnancy test if subject has child bearing capacity (Urine or Serum hCG)  
▪ Administration of study drug(s) 
 
5.1.3.2 Cycles 1 and 2 Days 8 and 15 
▪ Complete blood count with differentials 
▪ Comprehensive Metabolic Panel (CMP) 
▪ Vital signs 
▪ Assessment of AEs 
▪ Review of concomitant medications 
 
5.1.3.3 Cycles 3 and beyond Day 1 
▪ Assessment of AEs 
▪ Review of demographics and medical history if any changes from screening. 
▪ Review of concomitant medications 
▪ Physical Examination 
▪ Vital signs and weight 
▪ ECOG performance status 
▪ Complete Blood Count (CBC) with differential 
▪ Blood Chemistry- Comprehensive Metabolic Panel (CMP); Magnesium, Phosphorous, non-
fasting cholesterol 
▪ Blood samples for correlative studies if consented (prior to treatment on Day 1 of each cycle. 
The last pretreatment sample will be collected on Cycle 8, Day 1) 
▪ Stool sample for correlative studies if consented (to be collected by patient within 7 days 
before Cycle 4 Day 1) 
▪ Urine protein/Creatinine ratio on Day 1 of every other cycle (i.e. cycles 3, 5, 7, 9 and so on 
while subject is on study directed therapy) 
▪ Urine protein via dipstick or urinalysis on Day 1 of every even cycle (i.e. cycles 2, 4, 6, 8 
and so on while subject is on study directed therapy) 
▪ Prothrombin time/PTT/INR (if it is the method used to monitor subject‘s anticoagulation 
therapy) 

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▪ Pregnancy test if subject has child bearing capacity (Urine or Serum hCG) 
▪ Administration of study drug(s) 
▪ ECG to be collected every 3 months (i.e. 90 days) +/- 7 days while on study directed 
treatment 
▪ 2-D Echocardiography to be collected every 3 months (i.e. 90 days) +/- 7 days while on 
study directed treatment 
 
5.2 End of Treatment 
 
5.2.1 End-of-Treatment Procedures 
End of treatment visit should occur up to but no more than +7 days after last exposure to rucaparib or, 
if rucaparib is discontinued, no more than +21 days after last exposure to bevacizumab and/or 
atezolizumab. 
▪ Physical examination, vitals, medical history, ECOG performance status, medication review 
▪ Complete Blood Count (CBC) with differential, Comprehensive Metabolic Panel (CMP), 
Magnesium, Phosphorus, thyroid function tests (TSH, free T4, total T3)  
▪ Evaluation of adverse events 
▪ 2-D Echocardiography, ECG (to be collected within +/- 7 days of end of treatment visit) 
▪ Blood samples for correlative studies if consented (to be collected at end of treatment visit) 
▪ Stool sample for correlative studies if consented (to be collected by patient within 7 days 
before 30-Day Follow-Up visit) 
 
5.3 Post-treatment 
 
5.3.1 Follow-Up Visits 
There will be a 30-day and 90-day follow-up for safety assessment. The 30-day follow-up should occur 
30 days +/- 7 days after the end of treatment visit, and the 90-day follow-up should occur 90 days +/- 7 
days after the end of treatment visit. The 90-day follow up may be done via phone to assess Adverse 
Events.  Resolution or continuation of AE’s will be documented. 
▪ Assessment of AEs (AEs for 90-day follow-up collected by phone) 
▪ Review of demographics and medical history if any changes from screening. 
▪ Review of concomitant medications 
 
5.3.2 Survival Follow-up 
Survival Follow-up should occur every three months (i.e. 90 days) +/- 7 days via medical records or 
best efforts to contact the patient (e.g. phone or letter) until death or lost to follow up. 
5.3.2.1 Adverse Event Follow-up 
If a subject is taken off-study for adverse events, adverse events should be followed to 
resolution through best efforts to contact the patient. 

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5.4 Study Withdrawal Procedures 
 
5.4.1 Duration of Therapy 
 
Patients are allowed to withdraw at any time should they choose. In the absence of 
withdrawal, patient will continue on study-directed treatment continue for or until: 
 
▪ Disease progression 
▪ General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the investigator’s judgment. 
▪ Inter-current illness that prevents further treatment administration 
▪ Patient decides to withdraw from the study 
▪ Significant patient noncompliance with protocol 
▪ Unacceptable adverse event(s) 
 
Patients with progression who, in the opinion of the treating physician are receiving clinical 
benefit on study directed therapy, may stay on study directed therapy after consultation with 
the sponsor-investigator. 
 
Patients who withdraw from treatment due to progression or toxicity are asked to remain 
on study for follow up. 
 
5.4.2 Patient-Initiated Withdrawal 
 
A patient may decide to withdraw from the study at any time from either treatment, follow up, 
or both. Subject data will be used from the time of enrollment until death or they are lost to 
follow- up unless they withdraw from follow up. Patients who withdraw will not be replaced 
unless they have not received any study directed treatment. 
 
5.4.3 Investigator-Initiated Withdrawal 
 
The investigator will withdraw a patient whenever continued participation is no longer in the 
patient’s best interests. Reasons for withdrawing a patient include, but are not limited to, 
disease progression, the occurrence of an adverse event or a concurrent illness, a patient’s 
request to end participation, a patient’s noncompliance or simply significant uncertainty on 
the part of the investigator that continued participation is prudent. If a patient is benefiting 
clinically, she may continue on study-directed treatment after progression and after 
consultation with the sponsor-investigator.  There may also be administrative reasons to 
terminate participation. 
 
5.4.4 Sponsor-Initiated Withdrawal 
 
Sponsor’s decision to discontinue the study. 
 

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5.4.5 Withdrawal Documentation Procedure 
 
The reason for study withdrawal and the date the patient was removed from the study must 
be documented in the case report form. 
 
6 TREATMENT PLAN 
6.1 Investigational Agent Administration 
 
Cycle length = 21 days  
 
Atezolizumab 1,200mg IV on ay 1 Bevacizumab 15mg/kg IV on day 1 
Rucaparib 600mg orally twice daily by continuous dosing 
 
The atezolizumab infusion should be administered first, followed by the bevacizumab infusion 
in the following manner: 
 
• 
Atezolizumab 1,200 mg administered over 60 (± 15) minutes (for the first 
infusion, reducing to 30 [± 10] minutes for subsequent infusions if first infusion 
is tolerated. Followed by 
• 
Bevacizumab 15 mg/kg administered over 90 (± 15) minutes (for the first infusion, 
reducing to 60 [± 15] minutes and then 30 [± 10] minutes for subsequent infusions if 
prior infusion is tolerated) 
• 
Actual body weight from baseline will be used to calculate the bevacizumab dose. If 
the patient’s weight changes by +/- 10 % during the course of the study, the dose will 
be recalculated with the new weight, per institutional standards 
 
For the first atezolizumab infusion and all subsequent infusions, the patient’s vital signs (heart 
rate, respiratory rate, BP and temperature) should be determined the day of treatment prior to 
infusion. Vital signs will be recorded during and after the infusion only if clinically indicated 
or if the patient experienced an infusion-related reaction (IRR) during any previous infusions. 
Patients will be informed about the possibility of delayed post-infusion symptoms and 
instructed to contact their study physician if they develop such symptoms. 
 
6.2 Dose Escalation/De-escalation Schedule 
 
There is no planned dose escalation or de-escalation. Rucaparib may be dose reduced for 
toxicity as described in section 8.2.2. Bevacizumab or Atezolizumab may be halted for 
toxicity per sections 8.1.3 and 8.1.4. 
 
6.3 General Concomitant Medication and Supportive Care Guidelines 
 
6.3.1 Premedication 
 
No premedication will be allowed for the first dose of atezolizumab. Premedication with 
antihistamines may be administered for cycles ≥ 2 at the discretion of the treating physician if 

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the patient experienced IRRs during any previous infusions. 
 
6.3.2 Usage of Concurrent/Concomitant Medications 
 
All concomitant medication taken within 28 days prior to C1D1 and any taken during the 
study up to 30 days after the last dose of study treatment will be recorded in the source 
documents and CRF. This includes all prescription, over-the-counter (OTC) and herbal 
supplements. If changes occur during the trial period, documentation of drug dosage, 
frequency, route and date should also be included on the CRF. 
 
6.3.3 Dietary Restrictions 
 
Rucaparib may be taken with or without food. 
 
6.3.4 Prohibited Medications 
 
Subjects are prohibited from receiving the following therapies during the screening 
and treatment phase: 
 
Any concomitant therapy intended for the treatment of cancer that is not specified in this 
protocol, whether health authority approved or experimental, is prohibited. This includes but 
is not limited to the following: 
 
• Any hormonal therapy directed at the malignant tumor must be discontinued at least seven 
days prior to Cycle 1 Day 1 of treatment. 
• Any other prior therapy directed at the malignant tumor, including chemotherapy, 
biological therapy and immunologic agents must be discontinued at least 21 days prior to 
Cycle 1 Day 1 of treatment 
• Any prior radiation therapy must be completed at least 28 days prior to Cycle 1 Day 1 
of treatment 
 
The following medications are excluded while the patient is receiving study treatment: 
 
• Receptor activator of nuclear factor kappa-B ligand−inhibitor (denosumab). Patients who 
are receiving denosumab prior to study start date must be willing and eligible to receive a 
bisphosphonate instead while in the study. 
• Treatment with systemic immunostimulatory agents (including but not limited to, 
interferon- alpha or interleukin-2) within six weeks prior to Cycle 1 Day 1, during 
treatment and for 10 weeks post-treatment. 
• Treatment with systemic immunosuppressive medications (including but not limited to 
prednisone dose (or dose equivalent) >10 mg/day, cyclophosphamide, azathioprine, 
methotrexate and anti TNF agents) within two weeks prior to Cycle 1 Day 1 and during 
treatment. 
o Patients who have received acute, low-dose, systemic immunosuppressant 
medications may be allowed at prednisone dose (or dose equivalent) <=10 mg/day. 
o The use of inhaled corticosteroids and mineral corticoids (i.e., fludrocortisone) 

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for patients with orthostatic hypotension or adrenocortical insufficiency is 
allowed. 
• Administration of a live, attenuated vaccine within four weeks before cycle 1, day 1 or 
during the study. 
o Influenza vaccination should be given during influenza season, however, patients 
must agree not to receive live, attenuated influenza vaccine within 28 days prior to 
the start of treatment, during treatment or within five months of the last 
atezolizumab dose. 
 
Rucaparib, in vitro, was metabolized primarily by CYP2D6 and to a lesser extent by CYP1A2 
and CYP3A4. It is reported to be a minor substrate of CYP1A2, CYP2D6, CYP3A4 and P- 
glycoprotein/ABCB1. Concomitant treatment with proton pump inhibitors has no meaningful 
change in steady-state exposures of rucaparib. In vitro, rucaparib induced CYP1A2, and down-
regulated CYP2B6 and CYP3A4. Clinically, rucaparib is a moderate inhibitor of CYP1A2, and 
a weak inhibitor of CYP2C9, CYP2C19, and CYP3A4. Sensitive substrates of these enzymes 
may be used with caution. 
 
6.4  Monitoring Subject Compliance 
 
Pill counts will be taken for the compliance of rucaparib. These will be reported at each visit. 
Patients will be provided a pill diary and educated on the use prior to study directed treatment 
and then at each visit after while on study directed treatment. 
 
7 PHARMACEUTICAL INFORMATION 
7.1 Bevacizumab 
 
7.1.1 Product Description 
 
Classification:  "Monoclonal antibody" and "anti-angiogenesis" drug. 
 
Mechanism of Action: Bevacizumab is a recombinant humanized monoclonal antibody that 
blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A). VEGF-A 
is a chemical signal that stimulates angiogenesis in a variety of diseases, especially in cancer. 
 
Metabolism:  Bevacizumab is metabolized and eliminated via the reticuloendothelial system. 
 
Contraindications: Pregnancy (category C), lactation; nephrotic syndrome; active bleeding; 
surgery within 28 days; dental work within 20 days. 
 
Side Effects: (1%) Body as a Whole: Asthenia, pain, wound dehiscence. CNS: Syncope, 
headache, dizziness, confusion, abnormal gait. CV: DVT, hypertension, heart failure, intra- 
abdominal thrombosis, cerebrovascular events. GI: Abdominal pain, diarrhea, constipation, 
nausea, vomiting, anorexia, stomatitis, dyspepsia, weight loss, flatulence, dry mouth, colitis, 
gastrointestinal perforation. Hematologic: Leukopenia, neutropenia, thrombocytopenia, 

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thromboembolism. Metabolic: Hypokalemia, hyperbilirubinemia. Musculoskeletal: Myalgia. 
Respiratory: Upper respiratory infection, epistaxis, dyspnea, hemoptysis. Skin: Exfoliative 
dermatitis, alopecia. Special Senses: Taste disorder, increased tearing. Urogenital: Proteinuria, 
urinary frequency/urgency. 
 
7.1.2 Solution Preparation 
 
Infusion: Withdraw the desired dose of 15 mg/kg and dilute in 100 mL of NS injection per 
institution standards. 
 
7.1.3 Investigational Agent Administration 
 
IV Infusion: DO NOT administer IV push or bolus. Infuse first dose over 90 (± 15) minutes; if 
well tolerated, infuse second dose over 60 (± 15) minutes; if well tolerated, infuse all 
subsequent doses over 30 (± 10) minutes. 
 
7.1.4 Storage Requirements 
 
Store Bevacizumab 100mg or 400mg vials at 2°–8° C (36°–46° F) and protect from light. Do 
not freeze or shake. 
 
7.1.5 Stability 
 
Store diluted solution at 2°–8° C (36°–46° F) for up to eight hours. 
 
7.1.6 Route of Administration 
 
Intravenous. 
 
7.1.7 Nursing (RN) Implications 
 
Monitor for signs and symptoms of an infusion reaction (hypersensitivity); infusion should be 
interrupted in all patients with severe infusion reactions and appropriate therapy instituted. 
Monitor for dizziness, lightheadedness or loss of balance. Take appropriate safety measures. 
 
7.1.8 Handling 
 
Use institutional standards for appropriate handling and disposal. 
 
7.1.9 Availability 
 
Commercially available. 
 
7.1.10 Agent Ordering 
 
Pharmacies will obtain supplies from normal commercial supply chain or wholesaler. 

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7.1.11 Agent Accountability 
 
The investigational pharmacist will manage drug accountability records. Commercial supply 
bevacizumab will be accounted for per institutional standards 
 
7.1.12 Agent Destruction and Return 
 
Appropriate precautions for handling and disposal will be used per institutional standards. 
 
7.2 Rucaparib (Rubraca®) 
 
7.2.1 Product Description 
 
Rubraca is available as 200 mg, 250 mg and 300 mg tablets. 
 
Classification:  Rubraca is a poly (ADP-ribose) polymerase (PARP) inhibitor. 
 
Mechanism of Action: Rucaparib is an inhibitor of poly (ADP-ribose) polymerase 
(PARP) enzymes, including PARP-1, PARP-2, and PARP-3, which play a role in DNA 
repair. 
 
Metabolism: In vitro, rucaparib had a low metabolic turnover rate in human liver microsomes, 
and was metabolized primarily by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. 
Based on population pharmacokinetic analyses, steady-state concentrations following 
rucaparib 600 mg twice daily did not differ significantly across CYP2D6 or CYP1A2 genotype 
subgroups. 
 
Contraindications:  Pregnancy (category C), lactation. 
 
Side Effects: Most common adverse reactions (≥ 20%) were nausea, fatigue (including 
asthenia), vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased 
appetite, diarrhea, thrombocytopenia, and dyspnea. 
 
7.2.2 Solution Preparation 
 
Not applicable. 
 
7.2.3 Investigational Agent Administration 
 
This is an oral agent. 
 
7.2.4 Storage Requirements 
 
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) 
[see USP Controlled Room Temperature]. 
 

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7.2.5 Stability 
(This section is intentionally left empty) 
 
7.2.6 Route of Administration 
 
Oral. 
 
7.2.7 Nursing (RN) Implications 
 
Advise patient that the drug may cause photosensitivity. Precautions should be taken such as 
applying sunscreen (sun protection factor 50+) and /or covering exposed skin with clothing and 
wearing a hat and sunglasses. 
 
7.2.8 Handling 
 
Use institutional standards for appropriate handling and disposal. 
 
7.2.9 Availability 
Rucaparib was approved (accelerated) in December 2016 for the treatment of patients with 
deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who 
have been treated with two or more chemotherapies. 
Rucaparib is provided by Clovis Oncology. The agent is supplied as immediate release 200, 
250mg and 300 mg tablets. 
 
7.2.10 Agent Ordering 
 
To order drug, the Clinical Trial Material form must be completed and faxed to Clovis Oncology. 
 
7.2.11 Agent Accountability 
 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of receipt, dispensing, and final disposition of the investigational product. 
 
7.2.12 Agent Destruction and Return 
 
Investigational rucaparib patient returns should be documented and reconciled on site 
and destroyed on site according to the institution’s standard operating procedure. 
 
7.3 Atezolizumab 
 
7.3.1 Product Description 
 
Drug is available as 1,200 mg/20 mL (60 mg/mL) solution in a single-dose vial. 
 
Classification: A fully humanized, engineered monoclonal antibody of IgG1 isotype against 

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the protein programmed cell death-ligand 1. 
 
Mechanism of Action: Atezolizumab blocks the interaction of PD-L1 with programmed cell 
death protein 1 (PD-1) and CD80 receptors (B7-1Rs). PD-L1 can be highly expressed on certain 
tumors, which is thought to lead to reduced activation of immune cells (cytotoxic T-cells in 
particular) that might otherwise recognize and attack the cancer. Inhibition of PD-L1 by 
atezolizumab can remove this inhibitor effect and thereby engender an anti-tumor response. It 
is one of several ways to block inhibitory signals related to T-cell activation, a more general 
strategy known as "immune checkpoint inhibition.” 
 
Metabolism: Terminal half-life of atezolizumab is 27 days. Steady state is achieved after six to 
nine weeks of therapy (two to three cycles). 
 
Contraindications:  Pregnancy and lactation. 
 
Side Effects: >10% All grades unless otherwise stated Fatigue (52%), Decreased appetite 
(26%), Nausea (25%), Urinary tract infection (22%), Constipation (21%), Pyrexia (21%), 
Diarrhea (18%), Peripheral edema (18%), Abdominal pain (17%), Vomiting (17%), Dyspnea 
(16%), Back/neck pain (15%), Rash (15%), Arthralgia (14%), Pruritus (13%). 
 
7.3.2 Solution Preparation 
 
The dose should be diluted in 250ml 0.9% NaCl and infused through a 0.2 micron in-line filter. 
 
7.3.3 Investigational Agent Administration 
 
Administer the initial dose over a minimum of 60 (± 15) minutes. If no adverse infusion-related 
reactions occur, administer the second and all subsequent doses over a minimum of 30 (± 10) 
minutes. If infusion-related adverse reactions occur, all subsequent infusions should be 
administered over the shortest period that was well tolerated. 
 
7.3.4 Storage Requirements 
 
- Discard product if it contains particulate matter, is cloudy, or discolored. 
- Discard unused portion. Do not store for later use. 
- Do not freeze. 
- Protect from light. 
- Refrigerate (between 36 and 46° F). 
- Store in original container. 
 
7.3.5 Stability 
 
The prepared solution may be stored at 2-8°C or room temperature for up to 8 hours. 
 

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7.3.6 Route of Administration 
 
Intravenous. 
 
7.3.7 Nursing (RN) Implications 
 
Instruct patient that adverse events may occur and to report them. Assess baseline comfort 
and self-care strategies to maintain comfort and energy conservation. 
 
7.3.8 Agent Ordering 
 
To order drug, the Clinical Trial Material form must be completed and faxed to Genentech 
Oncology. 
 
7.3.9 Agent Accountability 
 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of receipt, dispensing, and final disposition of the investigational product. 
 
7.3.10 Agent Destruction and Return 
 
Used or unused atezolizumab vials requiring destruction should be documented and 
reconciled on site and destroyed on site according to the institution’s standard operating 
procedure. 
 
8 DOSING DELAYS/DOSE MODIFICATIONS 
8.1 Monitoring and Toxicity Management 
 
The severity of adverse events will be graded according to the NCI CTCAE v5.0 grading system. 
 
• Dose reduction of atezolizumab and bevacizumab is not permitted. 
• When several toxicities with different grades of severity occur at the same time, the dose 
modifications should be according to the highest grade observed. 
• If, in the opinion of the investigator, a toxicity is considered to be due solely to one 
component of the study treatment (i.e., rucaparib, atezolizumab or bevacizumab) and the 
dose of that component is delayed or modified in accordance with the guidelines below, the 
other component may be administered, if there is no contraindication. 
• When treatment is temporarily interrupted because of toxicity caused by rucaparib, 
atezolizumab and/or bevacizumab (if applicable), the treatment cycles will be restarted such 
that the atezolizumab and bevacizumab infusions remain synchronized (if applicable). 
• A subject that has one or two drugs stopped for toxicity may continue treatment on study 
with the remaining drug(s). 
 
8.2 Rucaparib 

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The starting dose of rucaparib is 600 mg ingested twice a day (BID). Patients may take rucaparib 
with or without food. Each dose should be taken with approximately 8 ounces (240 mL) of room 
temperature water. Tablets should be swallowed whole without crushing or chewing. 
 
Patients should take rucaparib doses as close as possible to 12 hours apart, preferably at the 
same times every day. If a patient misses a dose (i.e., does not take it within four hours of the 
scheduled time), the patient should skip the missed dose and resume taking rucaparib with the 
next scheduled dose. Missed or vomited doses should not be made up. 
 
Modification of rucaparib dose may be a necessary component of AE management, and study- 
specific protocol guidelines for dose modifications should be followed. 
 
8.2.1 Toxicity Management 
 
Toxicity 
Action 
Renal Impairment 
Creatinine Clearance < 
30a 
Hold. 
a Creatinine clearance should be calculated per 
institutional standard. 
 
8.2.2 Table 2. Dose Adjustments - Rucaparib 
 
Dose level Dose 
Starting 
dose 
600 mg twice daily (two 300 mg tablets or 3 200 
mg tablets) 
-1 
500 mg twice daily (two 250 mg tablets) 
-2 
400 mg twice daily (two 200 mg tablets) 
-3 
300 mg twice daily 
 
8.2.2.1 Rucaparib Dose Modification Criteria 
 
Treatment with rucaparib should be held if any of the following are observed and a dose 
reduction should be considered or implemented. 
• Grade 3 or 4 hematologic toxicity. Anemia should be managed as described below in 
section 8.2.2.2. 
 
• Grade 3 or 4 nonhematologic toxicity (except for alopecia, nausea, vomiting, or diarrhea 
adequately controlled with systemic antiemetic/antidiarrheal medication administered in 
standard doses according to the study center routines). Grade 3 or Grade 4 ALT/AST 
elevations should be managed as described below in section 8.2.2.3. 
 
• In addition, and at the discretion of the investigator, the dose of rucaparib may be held 
and/or reduced for Grade 2 toxicity not adequately controlled by concomitant 

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medications and/or supportive care. If rucaparib is held, it can be re-started when toxicity 
is controlled per the investigator discretion. 
For patients who meet treatment interruption guidelines above, treatment with rucaparib should 
be held until the toxicity improves to ≤ CTCAE Grade 2. Twice daily dosing may then be 
resumed at either the same dose or a lower dose, per investigator discretion. If treatment is 
resumed at the same dose and the patient experiences the same toxicity, treatment should be 
interrupted then resumed at a reduced dose following resolution of the event to ≤ CTCAE 
Grade 2. If the patient continues to experience toxicity, additional dose reduction steps are 
permitted;  
 
however, the investigator should consult with the sponsor’s medical monitor before reducing 
to 300 mg BID. If a patient continues to experience toxicity despite dose reduction steps to 300 
mg BID, or if dosing with rucaparib is interrupted for > 14 consecutive days due to toxicity, 
treatment should be discontinued, unless otherwise agreed and documented between the 
investigator and the sponsor. 
 
8.2.2.2 Management of Anemia including Evaluation for MDS/AML and Follow-up 
of Patients Who Discontinue Treatment with Ongoing Anemia: 
 
• If the patient develops anemia CTCAE Grade ≥ 3, rucaparib treatment should be held until 
the anemia improves to CTCAE Grade ≤ 2 whereupon daily dosing may then be resumed 
at either the same dose or a lower dose, per investigator discretion. 
• If the duration of dosing is interrupted for > 14 consecutive days due to anemia CTCAE 
Grade ≥ 3, treatment should be permanently discontinued, unless otherwise agreed and 
documented between the investigator and the sponsor or designee. 
• In addition, if anemia CTCAE Grade ≥ 3 persists for > 14 consecutive days, or a 
dependence upon blood transfusion occurs, then weekly complete blood counts should 
be performed until resolution of the event. 
• If, after 42 days of interruption of rucaparib, the anemia has not improved to CTCAE Grade 
≤ 1, then the patient should be referred to a hematologist and analysis of the bone marrow 
with cytogenetic studies is recommended according to standard hematologic practice. 
• The bone marrow analysis should include a bone marrow aspirate (for cellular 
morphology, cytogenetic analysis, and flow cytometry) and a core biopsy (for bone 
marrow cellularity). 
• Transfusion of PRC is acceptable as clinically indicated. 
 
8.2.2.3 Management of Rucaparib Treatment-Emergent ALT/AST Elevations: 
 
• Grade 4 ALT/AST elevations: hold rucaparib until values have improved to Grade 2 or 
less, then resume rucaparib with a dose reduction. Monitor liver function tests weekly for 
three weeks after rucaparib has been restarted. 
• Grade 3 ALT/AST elevations, in the absence of other signs of liver dysfunction, should 
be managed as follows: 
• Monitor liver function tests weekly until improvement to ≤ Grade 2. 

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• Continuation of rucaparib with elevation of ALT/AST up to Grade 3 is permitted 
provided bilirubin is < ULN and alkaline phosphatase is < 3 x ULN. 
• If patient has Grade 3 ALT/AST and continues on rucaparib, and levels do not decline 
within two weeks or they continue to rise, treatment interruption and resolution to ≤ Grade 
2 will be required before rucaparib can be resumed, either at the current dose or at a reduced 
dose. 
Drug-induced liver injury (DILI) is described in the US FDA Guidance for Industry, Drug- 
Induced Liver Injury: Premarketing Clinical Evaluation and should be referenced when 
managing treatment-emergent ALT/AST elevations. 
 
https://www.federalregister.gov/documents/2009/07/30/E9-18135/guidance-for-industry-
on- drug-induced-liver-injury-premarketing-clinical-evaluation-availability 
 
Rucaparib treatment must be interrupted if biochemical criteria for suspected DILI are 
met, according to presence of the following laboratory abnormalities: 
 
ALT or AST > 3 x ULN 
 
and 
 
Bilirubin > 2 x ULN 
 
While treatment is interrupted, the patient should be evaluated for the presence of confounding 
factors including malignant disease in the liver, co-administration of other suspect drugs, 
cholestasis, and viral or autoimmune hepatitis that could have caused the laboratory 
abnormalities. Other laboratory investigations of liver function such as international normalized 
ratio (INR) should be implemented as indicated. If no alternative cause is identified, rucaparib 
must be permanently discontinued. 
 
All cases of possible DILI should be followed until all abnormalities have returned to normal, 
returned to baseline levels, or an alternative cause is found to explain the combination of the 
increased transaminases and total bilirubin. 
 
8.2.2.4 Rucaparib Dose Reduction Steps 
 
Dose reduction steps are presented in Table 2 above. 
 
Dose reescalation upon improvement of toxicity to ≤ CTCAE Grade 1 is permitted at the 
discretion of the investigator. Dose modifications (interruption, reduction, and reescalation) 
must be recorded for each patient in the appropriate section of the eCRF. 
 

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Rucaparib Retreatment Criteria 
 
Treatment may resume if:  
 
• ANC ≥ 1.0 x 109/L 
• Platelet count ≥ 50.0 x 109/L 
• 
Hemoglobin ≥ 8.0 g/dL 
• Creatinine Clearance: ≥ 30 
• Nonhematologic toxicities have returned to baseline or ≤ CTCAE Grade 1 severity (or, at 
the investigator’s discretion, ≤ CTCAE Grade 2 severity if not considered a safety risk for 
the patient).  
• 
Grade 3 or Grade 4 ALT/AST elevations should be managed as described above in section 
8.2.2.3. 
 
8.3 Atezolizumab 
 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice. Additional tests, such as autoimmune serology or 
biopsies, should be used to evaluate for a possible immunogenic etiology. 
 
Although most immune-related adverse events observed with immunomodulatory agents have 
been mild and self-limiting, such events should be recognized early and treated promptly to 
avoid potential major complications. Discontinuation of atezolizumab may not have an 
immediate therapeutic effect, and in severe cases, immune-related toxicities may require acute 
management with topical corticosteroids, systemic corticosteroids or other immunosuppressive 
agents. 
 
The investigator should consider the benefit-risk balance a given subject may be experiencing 
prior to further administration of atezolizumab. In subjects who have met the criteria for 
permanent discontinuation, resumption of atezolizumab may be considered, if the subject is 
deriving benefit and has fully recovered from the immune-related event. Subjects can be 
rechallenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the medical monitor. 
 
8.3.1 Pulmonary Events 
 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab. Subjects will be assessed for pulmonary signs and 
symptoms throughout the study and will also have CT scans of the chest 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 3. 

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Table 3. Management Guidelines for Pulmonary Events, including Pneumonitis 
Pulmonary 
Events/Pneumonitis 
Severity 
Management 
Grade 1 
• Continue atezolizumab and monitor closely. 
• Re-evaluate on serial imaging. 
• Consider patient referral to pulmonary specialist. 
• For recurrent pneumonitis, treat as a Grade 3 or 4 event. 
Grade 2 
• Withhold atezolizumab. 
• Refer subject to pulmonary and infectious disease 
specialists and consider bronchoscopy or BAL. 
• Initiate treatment with 1–2 mg/kg/day oral prednisone or 
equivalent. 
• Resume atezolizumab if event resolves to Grade 1 or better within 
12 weeks.a, b 
• Permanently discontinue atezolizumab and contact medical 
monitor, if event does not resolve to Grade 1 or better within 12 
weeks.a, b, c 
• For recurrent events, treat as Grade 3 or 4 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 oral prednisone or 
equivalent. 
• If event does not improve after 48 hours of initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
BAL = bronchoscopic alveolar lavage; IVIG = intravenous immunoglobulin 
a If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced 
to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be 
agreed upon by the investigator and the medical monitor. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-related event. Patients can be rechallenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the medical monitor. 
 
8.3.2 Hepatic Events 
 
Immune-related hepatitis has been associated with the administration of rucaparib and 
atezolizumab. Eligible subjects 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 4. 
 
Subjects with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting 
should have LFTs performed immediately and reviewed before administration of the next dose 

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of study drug. 
 
For subjects with elevated LFTs, concurrent medications, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 
 
Table 4. Management Guidelines for Hepatic Events 
Hepatic Events 
Severity 
Management 
Grade 1 
• Continue atezolizumab. 
• Monitor LFTs until values resolve to within 
normal limits if levels were normal at baseline. 
If Grade 1 at baseline, may be monitored per study 
calendar. 
Grade 2 
All events: 
• Monitor LFTs weekly until return to baseline 
values. 
Events of > 5 days’ duration: 
• Withhold atezolizumab. 
• Initiate treatment with 1–2 mg/kg/day oral 
prednisone or equivalent. 
• Resume atezolizumab if event resolves to Grade 1 or 
better within 12 weeks.a,b 
• Permanently discontinue atezolizumab and contact 
medical monitor if event does not 
resolve to Grade 1 or better within 12 weeks.a,b,c 
Grade 3 or 4 
• Permanently discontinue and contact medical 
monitor.c 
• Consider subject referral to gastrointestinal 
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. 
LFT = liver function tests 
a If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced 
to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be agreed 
upon by the investigator and the medical monitor. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from 
the immune-related event. Patients can be rechallenged with atezolizumab only after approval has been documented 
by both the investigator (or an appropriate delegate) and the medical monitor. 
 

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8.3.3 Gastrointestinal Events 
 
Immune-related colitis has been associated with the administration of atezolizumab. 
Management guidelines for diarrhea or colitis are provided in Table 5. 
 
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 5. Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
Severity 
Management 
Grade 1 
Diarrhea or 
Colitis 
• Continue atezolizumab. 
• Initiate symptomatic treatment. 
• Endoscopy is recommended if symptoms persist for >7 days. 
• Monitor closely. 
• Withhold atezolizumab. 
• Initiate symptomatic treatment. 
GI Events 
(Diarrhea/Colitis) 
Grade 2 
Diarrhea or 
Colitis 
• Subject 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. 
• Resume atezolizumab if event resolves to Grade 1 or better within 
12 weeks.a, b 
• Permanently discontinue atezolizumab and contact medical 
monitor, if event does not resolve to Grade 1 or better within 
12 weeks. a, b, c 
Grade 3 
Diarrhea or 
Colitis 
• Withhold atezolizumab. 
• Refer subject to gastrointestinal specialist for evaluation and 
confirmatory biopsy. 
• Initiate treatment with 1−2 mg/kg/day intravenous 
methylprednisolone or equivalent and convert to 1–2 mg/kg/day 
oral prednisone or equivalent upon improvement. 
• Resume atezolizumab, if event resolves to Grade 1 or better within 
12 weeks.a, b 
• Permanently discontinue atezolizumab and contact medical 
monitor if event does not resolve to Grade 1 or better within 
12 weeks.a, b, c 

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Grade 4 
Diarrhea or 
Colitis 
• Permanently discontinue atezolizumab and contact medical 
monitor.c 
• Refer subject to gastrointestinal specialist for evaluation and 
confirmation biopsy. 
• Initiate treatment with 1−2 mg/kg/day intravenous 
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, taper corticosteroids over 
≥ 1 month. 
a If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to 
≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be agreed 
upon by the investigator and the medical monitor. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from
the immune-related event. Patients can be rechallenged with atezolizumab only after approval has been documented
by both the investigator (or an appropriate delegate) and the medical monitor. 
 
8.3.4 Endocrine Events 
 
Thyroid disorders or adrenal insufficiency has been associated with the administration of 
atezolizumab. Management guidelines for endocrine events are provided in table 6 below. 
Subjects with unexplained symptoms, such as fatigue, myalgias, impotence, mental status 
changes or constipation should be investigated for the presence of thyroid, pituitary or adrenal 
endocrinopathies. The subject should be referred to an endocrinologist, if an endocrinopathy is 
suspected. Thyroid-stimulating hormone (TSH) and free T3 and T4 levels should be measured 
to determine whether thyroid abnormalities are present. TSH, prolactin, and a morning cortisol 
level will help to differentiate primary adrenal insufficiency from primary pituitary 
insufficiency. 
 
Table 6.   Management Guidelines for Endocrine Events 
Severity 
Management 
Asymptomatic 
Hypothyroidism 
• Continue atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH weekly. 
Symptomatic 
Hypothyroidism 
• Withhold atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH weekly. 
• Consider subject referral to an endocrinologist. 
• Resume atezolizumab when symptoms are controlled and thyroid 
function is improving. 

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Endocrine 
Events 
Asymptomatic 
Hyperthyroidism 
TSH ≥0.1 mU/L and < 0.5 mU/L: 
• Continue atezolizumab. 
• Monitor TSH every 4 weeks. 
TSH < 0.1 mU/L: 
Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic 
Hyperthyroidism 
• Withhold atezolizumab. 
• Initiate treatment with antithyroid drug such as methimazole or 
carbimazole as needed. 
• Consider subject referral to endocrinologist. 
• Resume atezolizumab when symptoms are controlled and thyroid 
function is improving. 
• Permanently discontinue atezolizumab and contact medical monitor 
for life-threatening immune-related 
hyperthyroidism. c 
Symptomatic 
adrenal 
insufficiency, 
Grade 2 – 4 
• Withhold atezolizumab. a 
• Refer subject to endocrinologist. 
• Perform appropriate imaging. 
• Initiate treatment with 1–2 mg/kg per day intravenous 
methylprednisolone or equivalent and convert to 1–2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• Resume atezolizumab, if event resolves to Grade 1 or better and subject is 
stable on replacement therapy (if required) within 12 weeks.a, b 
• Permanently discontinue atezolizumab and contact medical monitor, if 
event does not resolve to Grade 1 or better or subject is not stable on 
replacement therapy 
within 12 weeks.a, b, c 
Hyperglycemia, 
Grade 1 or 2 
• Continue atezolizumab. 
• Initiate treatment with insulin, if needed. 
• Monitor for glucose control. 
Hyperglycemia, 
Grade 3 or 4 
• Withhold atezolizumab. 
• Initiate treatment with insulin. 
• Monitor for glucose control. 
• Resume atezolizumab when symptoms resolve and glucose levels are stable. 
TSH = thyroid-stimulating hormone 
a If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to 
≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be agreed 
upon by the investigator and the medical monitor. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be rechallenged with atezolizumab only after approval has been documented by both
the investigator (or an appropriate delegate) and the medical monitor. 
 

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Table 6.1   Management Guidelines for Endocrine Events - Hypophysitis 
Event 
Management 
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3  
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• Initiate hormone replacement if clinically indicated. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact Medical 
Monitor. c 
• For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 4  
• Permanently discontinue atezolizumab and contact Medical Monitor. c 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• Initiate hormone replacement if clinically indicated. 
IV = intravenous; MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be agreed upon by the investigator and the Medical 
Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of  10 
mg/day oral prednisone before atezolizumab can be resumed. 
c 
Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical Monitor. 
  
 
8.3.5 Ocular Events 
 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events). 
Management guidelines for ocular events are provided in Table 7. 
 
Table 7. Management Guidelines for Ocular Events 
Severity 
Management 
Grade 1 
• Continue atezolizumab. 
• Subject 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. 

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Ocular Events 
Grade 2 
• Withhold atezolizumab. 
• Subject referral to ophthalmologist is strongly 
recommended. 
• Initiate treatment with topical corticosteroid eye drops and 
topical immunosuppressive therapy. 
• Resume atezolizumab if event resolves to Grade 1 or better 
within 12 weeks. a, b 
• Permanently discontinue atezolizumab and contact 
medical monitor, if event does not resolve to Grade 1 
or better within 12 weeks.a, b, c 
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 If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to
≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be agreed 
upon by the investigator and the medical monitor. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-related event. Patients can be rechallenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the medical monitor. 
 
8.3.6 Infusion-Related Reactions 
 
No premedication is indicated for administration of cycle 1 of atezolizumab. However, 
subjects who experience an infusion-related reaction with cycle 1 of atezolizumab may receive 
premedication with antihistamines or antipyretics/analgesics (e.g., acetaminophen) for 
subsequent infusions. 
Guidelines for medical management of infusion-related reactions during Cycle 1 are provided 
in Table 8. For subsequent cycles, infusion-related reactions should be managed according to 
institutional guidelines. 
 
Table 8. Management Guidelines for Infusion-Related Reactions 
Infusion-Related 
Reactions 
Severity 
Management 
Grade 1 
• Reduce infusion rate to half the rate being given at the 
time of event onset. 
• After the event has resolved, the investigator should wait 
for 30 minutes while delivering the infusion at the reduced 
rate. 
• If the infusion is tolerated at the reduced rate for 30 
minutes after symptoms have resolved, the infusion 
rate may be increased to the original rate. 

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Grade 2 
• Interrupt atezolizumab infusion. 
• Administer aggressive symptomatic treatment (e.g., oral 
or 
IV 
antihistamine, 
antipyretic, glucocorticoids, 
epinephrine, bronchodilators, oxygen). 
• After symptoms have resolved to baseline, resume 
infusion at half the rate being given at the time of event 
onset. 
• For subsequent infusions, administer oral premedication 
with antihistamine and antipyretic and 
monitor closely for IRRs. 
Grade 3 or 4 
• Stop infusion. 
• Administer aggressive symptomatic treatment (e.g., oral 
or 
IV 
antihistamine, 
antipyretic, glucocorticoids, 
epinephrine, bronchodilators, oxygen). 
• Permanently discontinue atezolizumab and contact 
medical monitor.a 
IRR = infusion-related reactions; IV = intravenous. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-related event. Patients can be rechallenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the medical monitor. 
 
8.3.7 Pancreatic Events 
 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab. The differential 
diagnosis of acute abdominal pain should include pancreatitis. Appropriate workup should 
include an evaluation for ductal obstruction, as well as serum amylase and lipase tests. 
Management guidelines for pancreatic events, including pancreatitis, are provided in Table 9. 
 
Table 9.   Management Guidelines for Pancreatic Events, Including Pancreatitis 
Severity 
Management 
Amylase and/or Lipase 
Elevation, Grade 1 
• Continue atezolizumab. 
• Monitor amylase and lipase prior to dosing. 
Amylase and/or Lipase 
Elevation, Grade 2 
Amylase and/or lipase > 1.5-2.0 x ULN: 
• 
Continue atezolizumab. 
• 
Monitor amylase and lipase weekly. 
• 
For prolonged elevation (e.g., > 3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase > 2.0-5.0 x ULN: 
• Treat as a Grade 3 event. 

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Pancreatic Events 
Amylase and/or Lipase 
Elevation, Grade 3 or 4 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Monitor amylase and lipase every other day. 
• If no improvement, consider treatment with corticosteroids 
equivalent to 1-2 mg/kg/day oral prednisone. 
• 
If event resolves to Grade 1 or better, resume 
• 
atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
• 
For recurrent events, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
Immune-related 
Pancreatitis, Grade 2 or 
3 
• Withhold atezolizumab. 
• Refer subject to gastrointestinal specialist. 
• Initiate treatment with 1–2 mg/kg/day intravenous 
methylprednisolone or equivalent and convert to 1–2 mg/kg/day 
oral prednisone or equivalent upon improvement. 
• Resume atezolizumab, if event resolves to Grade 1 or better 
within 12 weeks.a, b 
• Permanently discontinue atezolizumab and contact medical 
monitor, if event does not resolve to Grade 1 or better within 12 
weeks.a, b, c 
• For recurrent events, permanently discontinue atezolizumab and 
contact medical monitor. c 
Immune-related 
Pancreatitis, Grade 4 
• Permanently discontinue atezolizumab and contact medical 
monitor. c 
• Refer subject to gastrointestinal specialist. 
• Initiate treatment with 1−2 mg/kg/day intravenous 
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 If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to ≤ 10 
mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be agreed upon by the 
investigator and the medical monitor. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune- 
related event. Patients can be rechallenged with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the medical monitor. 
 
8.3.8 Dermatologic Events 
Treatment-emergent rash has been associated with atezolizumab. The majority of cases of rash 
were mild in severity and self-limited, with or without pruritus. A dermatologist should 
evaluate persistent and/or severe rash or pruritus. A biopsy should be considered unless 

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contraindicated. Management guidelines for dermatologic events are provided in Table 10. 
 
Table 10. Management Guidelines for Dermatologic Events 
Dermatologic 
Events 
Severity 
Management 
Grade 1 
• Continue atezolizumab. 
• Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Grade 2 
• Continue atezolizumab. 
• Consider subject referral to dermatologist. 
• Initiate treatment with topical corticosteroids. 
• Consider treatment with higher-potency topical corticosteroids if 
event does not improve. 
Grade 3 
• Withhold atezolizumab. 
• Refer subject to dermatologist. 
• 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. 
• Resume atezolizumab, if event resolves to Grade 1 or better within 
12 weeks.a, b 
• Permanently discontinue atezolizumab and contact medical 
monitor, if event does not resolve to Grade 1 or better within 12 
weeks.a, b, c 
Grade 4 
• Permanently discontinue atezolizumab and contact medical 
monitor.c 
a If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to ≤ 10 
mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be agreed upon by the 
investigator and the medical monitor. 
c 
Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be rechallenged with atezolizumab only after approval has been documented by both the
investigator (or an appropriate delegate) and the medical monitor. 
 
8.3.9 Neurologic Disorders 
 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab. Subjects may present with signs and symptoms of sensory and/or motor 
neuropathy. Diagnostic workup is essential for an accurate characterization to differentiate 
between alternative etiologies. Management guidelines for neurologic disorders are provided 
in Table 11. 
 
Table 11.   Management Guidelines for Neurologic Disorders 
Severity 
Management 
Grade 1 
• Continue atezolizumab. 
• Investigate etiology. 

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Immune-related 
Neuropathy 
Grade 2 
• Withhold atezolizumab. 
• Investigate etiology. 
• Initiate treatment as per institutional guidelines. 
• Resume atezolizumab if event resolves to Grade 1 or better within 
12 weeks. a, b 
• Permanently discontinue atezolizumab and contact medical 
monitor, if event does not resolve to Grade 1 or better within 12 
weeks. a, b, c 
Grade 3 or 4 
• Permanently discontinue atezolizumab and contact medical 
monitor.c 
• Initiate treatment, as per institutional guidelines. 
Myasthenia 
Gravis and 
Guillain-Barre 
Syndrome 
All Grades 
• Permanently discontinue atezolizumab and contact medical 
monitor.c 
• Refer subject to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of 1–2 mg/kg/day oral or intravenous 
prednisone or equivalent. 
a If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to ≤ 10 
mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be agreed upon by the 
investigator and the medical monitor. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-
related event. Patients can be rechallenged with atezolizumab only after approval has been documented by both the investigator
(or an appropriate delegate) and the medical monitor. 
 
8.3.10 Immune-Related Events: Immune-Related Meningoencephalitis 
 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab. Immune-related meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction and altered or 
depressed level of consciousness. Encephalopathy from metabolic or electrolyte imbalances 
needs to be distinguished from 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 12. 
 
Table 12. Management Guidelines for Immune-Related Meningoencephalitis 
Event 
Management 

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Immune-related 
meningoencephalitis, all 
grades 
• 
Permanently discontinue atezolizumab and contact medical monitor. a 
• 
Refer patient to neurologist. 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone 
or equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 
month. 
IV = intravenous. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-related event. Patients can be rechallenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the medical monitor. 
 
8.3.11 Immune-Related Events: Renal Events and Immune-Related Nephritis 
 
Immune-related nephritis has been associated with the administration of atezolizumab. 
Eligible patients must have adequate renal function, and renal function, including serum 
creatinine, should be monitored throughout study treatment. Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as nonsteroidal 
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. If no alternative cause of acute kidney injury is identified, patients 
with signs and symptoms of acute kidney injury, in the absence of an identified alternate 
etiology, should be treated according to the management guidelines for immune-related 
renal events in the table below. 
 
Table 12.1. Management Guidelines for Renal Events 
Event 
Management 
Renal event, 
Grade 1 
• Continue atezolizumab. 
• Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values. 
Renal event, 
Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to renal specialist. 
• Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 

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Renal event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab and contact Medical 
Monitor. 
• Refer patient to renal specialist and consider renal biopsy. 
• Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day oral prednisone. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. 
The acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 
mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be re-challenged with atezolizumab only after 
approval has been documented by both n appropriate delegate) and the Medical Monitor. 
 
8.3.12 Immune-Related Events: Immune-Mediated Myositis 
Immune-mediated myositis has been associated with the administration of atezolizumab.  Myositis or 
inflammatory myopathies are a group of disorders sharing the common feature of inflammatory 
muscle injury; dermatomyositis and polymyositis are among the most common disorders.  Initial 
diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in dermatomyositis), 
biochemical (serum creatine kinase increase), and imaging (electromyography/MRI) features, and is 
confirmed with a muscle biopsy. 
Patients with signs and symptoms of myositis, in the absence of an identified alternate etiology, should 
be treated according to the guidelines in Table 12.2. 
Table 12.2   Management Guidelines for Immune-Mediated Myositis 
Severity 
Management 
Immune-
mediated 
myositis, 
Grade 1 
• Continue atezolizumab. 
• Refer patient to rheumatologist or neurologist.  
• Initiate treatment as per institutional guidelines. 

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

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8.3.13 Immune-related Events: Immune-mediated Myelitis 
 
• Patients should be monitored for clinical signs and symptoms that are suggestive of 
myelitis. Diagnostic workup is essential for an accurate characterization to differentiate 
between alternative etiologies. 
• Refer patient to neurologist. 
• For Grade 1 myelitis, continue immunotherapy unless symptoms worsen or do not 
improve. 
• Initiate treatment as per institutional guidelines. 
• Atezolizumab should be permanently withdrawn for ≥Grade 2 immune-mediated 
myelitis. 
 
8.3.14 Immune-related Events: Immune-mediated Facial Paresis 
• Patients may present with signs and symptoms of sensory and/or motor neuropathy. 
Diagnostic workup is essential for an accurate characterization to differentiate between 
alternative etiologies. 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Atezolizumab should be withheld for patients with Grade 1 or 2 immune-mediated facial 
paresis and permanently withdrawn for ≥ Grade 3 immune-mediated facial paresis 
8.4 Bevacizumab 
 
Temporary suspension of bevacizumab must occur if a patient experiences a serious adverse 
event or a Grade 3 or 4 nonserious adverse event assessed by the investigator as related to 
bevacizumab. If the event resolves to Grade ≤ 1, bevacizumab may be restarted at the same dose. 
If bevacizumab is delayed due to toxicity for > 42 days beyond when the next dose should have 
been given, the patient must be permanently discontinued from bevacizumab. 
 
The appropriate interval between the last dose of bevacizumab and major surgery is unknown. 
Because bevacizumab has a half-life of approximately 21 days respectively, elective surgery 
should be delayed whenever possible, but if necessary, bevacizumab should be withheld for a 
minimum of 28 days prior to the procedure. Reinitiation of bevacizumab following surgery 
should not occur for at least 28 days and until wounds have fully healed. Reinitiation of 
bevacizumab after surgery requires documented approval from the medical monitor. 
 
Infusion of bevacizumab should be interrupted in patients who develop dyspnea or clinically 
significant hypotension. Patients who experience an NCI CTCAE Grade 3 or 4 allergic 
reaction/hypersensitivity, adult respiratory distress syndrome or bronchospasm (regardless of 
grade) will be discontinued from bevacizumab treatment. 
 
Guidelines for management of specific adverse events are outlined in Table 13. 
 
Table 13. Guidelines for Management of Bevacizumab-Specific Adverse Events 
Event 
CTCAE.v5.0 
Grade 
Action to Be Taken 

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Allergic reactions 
or 
Acute infusional reactions/ 
cytokine release syndrome 
Grade 1–3 
• If infusion-related or allergic reactions occur, 
premedications should be given with the next dose 
and infusion time may not be reduced for the 
subsequent infusion. Follow the guidelines in the 
package insert for bevacizumab administration. 
 
• For patients with Grade 3 reactions, 
bevacizumab infusion should be stopped and not 
restarted on the same day. At the physicians’ 
discretion, bevacizumab may be permanently 
discontinued or reinstituted with premedications 
and at a rate of 90 +15 min. If bevacizumab is 
reinstituted, the patient should be closely 
monitored during and following the 
administration of bevacizumab. 
Grade 4 
• Discontinue bevacizumab. 
Arterial Thrombosis 
- Cardiac ischemia/ 
infraction 
- CNS ischemia (TIA, 
CVA) 
- any peripheral or 
visceral arterial 
ischemia/thrombosis 
Grade 2 (if new 
or worsened 
since 
bevacizumab 
therapy) 
• Discontinue bevacizumab. 
Grade 3–4 
• Discontinue bevacizumab. 

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Venous Thrombosis 
Grade 3 
• Hold bevacizumab treatment. If the planned 
duration of full-dose anticoagulation is < 2 weeks, 
bevacizumab should be held until the full-dose 
anticoagulation period is over. 
• If the planned duration of full-dose anticoagulation is 
>2 weeks, bevacizumab may be resumed during the 
period of full-dose anticoagulation IF all of the criteria 
below are met: 
• The subject must have an in-range INR (usually 2–3) on 
a stable dose of warfarin or be on a stable dose of 
heparin prior to restarting bevacizumab. 
• The subject must not have pathological conditions that 
carry high risk of bleeding (e.g., tumor involving major 
vessels or other conditions). 
• The subject must not have had hemorrhagic events 
while on study. 
• If thromboemboli worsen/recur upon resumption of 
study therapy, discontinue bevacizumab. 
Grade 4 
• Discontinue bevacizumab. 
Hypertension* 
[Treat with antihypertensive medication as needed. The goal of BP control should 
be consistent with general medical practice.] 
Grade 1 
• Consider increased BP monitoring. 
Grade 2 asymptomatic 
and 
diastolic BP < 100 
mmHg 
• Begin antihypertensive therapy and continue 
bevacizumab. 
Grade 2-3 
Symptomatic OR 
Diastolic BP > 100 
mmHg 
• Hold bevacizumab until symptoms resolve AND 
BP < 160/90mmHg. 
Grade 4 
• Discontinue bevacizumab. 
Congestive Heart 
Failure 
Grade 3 
• Discontinue bevacizumab. 
Grade 4 
• Discontinue bevacizumab. 
Proteinuria 
Proteinuria should be monitored by urine dipstick or urine protein creatinine 
(UPC) ratio, if dipstick is > 2 plus then a UPC ratio should be performed. 
UPC ratio < 3.5 
(<Grade 3) 
• Continue bevacizumab. 
UPC ratio 3.5 and up 
(>=Grade 3) 
• Hold bevacizumab until UPC recovers to < 3.5. 
Nephrotic syndrome 
• Discontinue bevacizumab. 
Hemorrhage (CNS or 
pulmonary) 
Grade 2–4 
• Discontinue bevacizumab. 

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Hemorrhage (non- 
CNS; non- 
pulmonary) 
Grade 3 
• Patients receiving full-dose anticoagulation should 
discontinue bevacizumab 
• For patients not on full-dose anticoagulation, hold 
bevacizumab until ALL of the following criteria are 
met: 
• the bleeding has resolved and Hb is stable. 
• there is no bleeding diathesis that would increase the 
risk of therapy. 
• there is no anatomic or pathologic condition that could 
increase the risk of hemorrhage recurrence. 
• Patients who experience recurrence of Grade 3 
hemorrhage should discontinue study therapy. 
Grade 4 
• Discontinue bevacizumab. 
RPLS (reversible posterior 
leukoencephalopathy syndrome or PRES (posterior 
reversible encephalopathy syndrome) 
• Hold bevacizumab in patients with symptoms 
/ signs suggestive of RPLS; 
• subsequent management should include MRI 
• scans and control of HTN. 
• Discontinue bevacizumab upon diagnosis of 
RPLS. 
Wound dehiscence requiring medical or surgical 
intervention 
• Discontinue bevacizumab. 
GI perforation, GI leak or fistula 
• Discontinue bevacizumab. 
Bowel obstruction 
Grade 2 
requiring 
medical 
intervention 
• Hold bevacizumab until complete resolution, with a 
minimum of four weeks after surgery. 
Grade 3-4 
• Hold bevacizumab until complete resolution. 
If surgery is required, patient may restart bevacizumab 
after full recovery from surgery, and at investigator’s 
discretion. 
Other unspecified 
bevacizumab-related AEs 
(except controlled 
nausea/vomiting). 
Grade 3 
• Hold bevacizumab  until  symptoms  resolve   to 
< grade 1. 
Grade 4 
• Discontinue bevacizumab. 
• Upon consultation with the study chair, resumption 
of bevacizumab may be considered, if a patient is 
benefiting from therapy and the Grade 4 toxicity is 
transient, has recovered to < Grade 1 and unlikely to 
recur with retreatment. 
 
9 ADVERSE EVENTS: DEFINITIONS AND 
REPORTING REQUIREMENTS 
9.1 Definitions of Adverse Events 
 
An AE is defined as any untoward medical occurrence in a patient administered a medicinal 
product that does not necessarily have a causal relationship with this treatment. An AE can, 
therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, whether or 

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not related to the investigational medicinal product or other protocol-imposed intervention, 
regardless of attribution. This includes the following: 
 
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with {insert condition being 
studied} that were not present prior to the AE reporting period. 
• 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations) 
• 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
• 
An exacerbation of preexisting conditions or events, intercurrent illnesses, drug 
interaction, or the significant worsening of the indication under investigation that is not 
recorded elsewhere on the eCRF under specific efficacy assessments. Anticipated 
fluctuations of preexisting conditions, including the disease under study, that do not 
represent a clinically significant exacerbation or worsening, are not considered AEs. 
 
It is the responsibility of the investigator to document all AEs that occur during the study. AEs 
should be elicited by asking the patient a nonleading question (e.g., “Have you experienced any 
new or changed symptoms since we last asked/since your last visit?”). The existence of an AE 
may be concluded from a spontaneous report of the patient; from the physical examination; or 
from special tests such as the ECG, laboratory assessments, or other study-specified procedure 
(source of AE). Symptoms reported spontaneously by the patient during the physical 
examination would also qualify as an AE (and hence documented on the AE eCRF, not on the 
physical examination eCRF, which is reserved for physical signs or findings). 
 
Expected adverse events are those adverse events that are listed or characterized in the Package 
Insert (P.I) or current Investigator Brochure (I.B). 
 
Unexpected adverse events are those not listed in the P.I or current I.B or not identified. This 
includes adverse events for which the specificity or severity is not consistent with the description 
in the P.I. or I.B. For example, under this definition, hepatic necrosis would be unexpected if 
the 
P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
 
9.1.1 Definition of a Serious Adverse Event 
 
An SAE is any untoward medical occurrence that occurs at any dose (or, occurs after informed 
consent is given and prior to dosing if the SAE is related to a study procedure) that: 
• Results in death. Any event resulting in death during the reporting period (from date of 
first dose of study drugs through 30 days after last dose) must be treated as an SAE and 
reported as such. An event related to a study procedure that occurs after informed 
consent, but prior to dosing, that results in death must also be reported as an SAE. 
• Is life-threatening (patient is at immediate risk of death from the event as it occurred) 
• Requires in-patient hospitalization (formal admission to a hospital for medical reasons) 
or prolongation of existing hospitalization 
• Results in persistent or significant disability/ incapacity 

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• 
Results in a congenital anomaly or birth defect in a neonate/infant born to a mother 
exposed to the IMP  
 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home or the development of drug 
dependency or drug abuse. 
 
9.1.1.1 Events or Outcomes Not Qualifying as Serious Adverse Events 
 
The following are not considered SAEs and therefore do not need to be reported as such: 
• 
Preplanned or elective hospitalization including social and/ or convenience situations 
(e.g., respite care) 
• 
Hospital visits of less than 24 hours duration (e.g., patient presents to the emergency 
room, but is not admitted to a ward) 
• 
Overdose of either study drugs or concomitant medication unless the event meets SAE 
criteria (e.g., hospitalization). However, the event should still be captured as a 
nonserious AE on the appropriate eCRF page. 
• 
Events of progression of the patient’s underlying cancer as well as events clearly related 
to progression of the patient’s cancer (signs and symptoms of progression) should not 
be reported as an AE/SAE unless the outcome is fatal within the safety reporting period. 
If the event has a fatal outcome within the safety reporting period, then the event of 
progression of disease must be recorded as an AE and as an SAE with CTCAE Grade 
5 (fatal outcome) indicated. 
• 
Events that meet the SAE criteria and occur after informed consent, but before the first 
dose of study directed treatment, which are considered unrelated to screening 
procedures. 
 
9.1.2 Clinical Laboratory Assessments as Adverse Events and Serious Adverse Events 
 
It is the responsibility of the investigator to assess the clinical significance of all abnormal 
values as defined by the list of reference ranges from the local laboratory. In some cases, 
significant changes in lab values within the normal range will require similar judgment. An 
abnormal laboratory value that is not already associated with an AE is to be recorded as an AE 
only if any one of the following criteria is met: 
• an action on rucaparib, atezolizumab, or bevacizumab treatment is made as a 
result of the abnormality 
• intervention for management of the abnormality is required 
• at the discretion of the investigator should the abnormality be deemed 
clinically significant. 
9.1.3 Definition of an Adverse Event of Special Interest 
 
AESIs (serious or nonserious) are defined as AEs of scientific and medical concern specific to 
the sponsor’s product or program, for which ongoing monitoring and rapid communication by 

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the investigator to the sponsor can be appropriate. Such an event might warrant further 
investigation in order to characterize and understand it. Depending on the nature of the event, 
rapid communication by the trial sponsor to other parties (e.g., regulators) might also be 
warranted. 
 
Details on the sponsor’s currently agreed list of AESIs for study drugs can be found in the 
current study drug IBs. These AESIs are to be reported to the sponsor expeditiously (see below). 
 
The Atezolizumab Events of Special Interest are: 
Non-Drug Specific AESIs: 
Adverse events of special interest for this study include the following: 
• 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: 
o Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
o Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
• Suspected transmission of an infectious agent by Atezolizumab and/or Bevacizumab, as 
defined below: 
o Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in 
a patient exposed to a medicinal product. This term applies only when a 
contamination of the study drug is suspected 
 
Atezolizumab AESIs 
 
• Pneumonitis 
• Colitis 
• Endocrinopathies: 
diabetes 
mellitus, 
pancreatitis, 
adrenal 
insufficiency, 
hyperthyroidism, and hypophysitis 
• Hepatitis, including AST or ALT > 10 × ULN 
• Systemic lupus erythematosus 
• Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
• Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, influenza-like illness, systemic inflammatory response syndrome, and 
systemic immune activation 
• Nephritis 
• Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
• Myositis 

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• 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) 
 
Bevacizumab AESIs: 
 
• Hypertension ≥ Grade 3 
 
• Proteinuria ≥ Grade 3 
 
• GI perforation, abscesses and fistulae (any Grade) 
 
• Wound healing complications ≥ Grade 3 
 
• Hemorrhage ≥ Grade 3 (any grade CNS bleeding; > Grade 2 hemoptysis) 
 
• Arterial thromboembolic events (any Grade) 
 
• Venous thromboembolic events ≥ Grade 3 
 
• Posterior reversible encephalopathy syndrome (PRES - any grade) 
 
• CHF ≥ Grade 3 
 
• Non-GI fistula or abscess ≥ Grade 2 
 
Rucaparib AESIs: 
Myelodysplastic Syndrome and Acute Myeloid Leukemia 
 
A review of all reports of MDS and AML that have occurred in the entire clinical 
development program up to 10 April 2017 revealed a total of 10 reports in patients exposed 
to rucaparib in Studies CO-338-010, CO-338-017, and CO-338-014. Reports in each study 
are as follows: 
 
Rucaparib 
• CO-338-010 (2 MDS), 
• CO-338-017 (2 MDS, 1 AML), 
• CO-338-014 (2 MDS, 2 AML, 1 MDS evolving to AML). 
 
Placebo 
• CO-338-014 (1 AML). 
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up, and 0.9% for all patients including during the long-term safety follow-up (rate is calculated 
based on overall safety population of 1077 patients exposed to at least one dose of oral 
rucaparib in all clinical studies). 
 
There was one case of AML in 189 patients exposed to placebo in Study CO-338-014. 
 
All of the patients diagnosed with MDS or AML had received multiple cycles and regimens of 
prior chemotherapy, including platinum- and/or taxane-containing regimens. One patient had 
also received prior treatment with an alkylating agent (cyclophosphamide) and 2 patients had 
received radiation for breast cancer (1 patient received rucaparib and 1 received placebo). One 
patient was discontinued from rucaparib 14 months prior to MDS diagnosis and was treated 
with olaparib for 13 months between rucaparib discontinuation and MDS diagnosis. One 
patient discontinued rucaparib 9 months prior to MDS diagnosis and was treated with cisplatin 
and trabectedin for an unspecified time between rucaparib discontinuation and MDS diagnosis. 
Exposure to DNA-damaging therapies for ovarian and breast cancer present an increased risk 
of developing MDS or AML. 
 
In patients diagnosed with MDS, duration from start of primary disease treatment to diagnosis 
was between approximately 1 and 23 months (i.e., 35 days to approximately 693 days). In 
patients diagnosed with AML, duration from start of primary disease treatment to AML 
diagnosis was between approximately 3.5 and 28.5 months (i.e., 106 to 868 days). In the patient 
with MDS that evolved into AML, the duration of time from starting treatment with rucaparib 
to diagnosis of MDS was approximately 12.5 months (i.e., 380 days) and from start of rucaparib 
to diagnosis of AML was approximately 18 months (i.e., 541 days). 
 
Nearly 
every 
patient 
who 
developed 
MDS/AML 
reported 
having 
experienced 
multiple/persistent cytopenias prior to the diagnosis of MDS/AML. The cytogenetic 
abnormalities currently available in 3 of the 4 patients diagnosed with AML were consistent 
with aberrations (primarily abnormalities in chromosome 5) typically observed in patients with 
secondary MDS/AML due to prior chemotherapy. One patient who developed both MDS and 
AML had chromosomal abnormality in chromosome 7. The patients who have developed MDS 
and AML have significant confounding risk factors, including prior cytotoxic chemotherapy, 
as well as a deleterious BRCA mutation presenting a higher risk of developing one or more 
malignancy(ies). 
 
Based upon the above confounding factors, there is insufficient scientific evidence to 
conclude that MDS and AML are causally related to rucaparib. 
 
Events of MDS and AML have also been reported with other PARP inhibitors. While the 
etiology of these events is confounded by prior treatments and the relationship to rucaparib is 
not clear, Clovis has added these potential risks to all Informed Consent Forms (ICFs) / Patient 
Information Sheets (PISs). AESI’s (both serious and non-serious) will be reported to Clovis 
within 24 hours of awareness and will continue to be reported to Clovis under SAE reporting 
requirements. 
 

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9.1.4 Pregnancy or Drug Exposure during Pregnancy 
 
If a patient becomes pregnant during the course of the study, study drug dosing should be 
held immediately. 
 
Pregnancy is not considered to be an AE or SAE; however, all pregnancies occurring during 
study participation or within six months of last dose of study drug, must be reported 
expeditiously to the sponsor using the Clinical Pregnancy Report Form within the same 
timelines as for an SAE. 
 
All pregnancies should be followed through to outcome whenever possible. Once the outcome 
of a pregnancy is known, the Clinical Pregnancy Outcome Report Form should be completed 
and submitted to the sponsor. Abortion, whether accidental, therapeutic, or spontaneous, should 
always be classified as serious, and expeditiously reported as an SAE. Similarly, any congenital 
anomaly/birth defect in a child born to a female subject exposed to the study drug should be 
reported as an SAE. 
 
AEs, SAEs, or AESIs that occur during pregnancy will be assessed and processed according 
to the AE or SAE/ AESI processes using the appropriate AE or SAE/ AESI forms. 
 
9.2 Recording of Events 
 
Events that occur after signing of informed consent, but prior to initiation of rucaparib, 
atezolizumab, or bevacizumab, unless serious and due to a protocol-mandated procedure, 
should be recorded on the Medical History eCRF. Any serious event related to a protocol-
mandated procedure should be reported as an SAE during the screening period. Any AE that 
occurs after first dose of rucaparib, atezolizumab, or bevacizumab through 30 days after 
receiving the last dose of rucaparib atezolizumab, or bevacizumab will be recorded on the AE 
eCRF. 
 
In order to avoid vague, ambiguous, or colloquial expressions, the AE should be recorded in 
standard medical terminology rather than the patient’s own words. Whenever possible, the 
investigator should combine signs and symptoms that constitute a single disease entity or 
syndrome into a final diagnosis, if appropriate. For example, fever, cough, and shortness of 
breath may be reported as pneumonia, if that is a reasonable diagnosis. 
 
Each AE is to be evaluated for duration, severity, seriousness, and causal relationship to 
the investigational drug. The action taken and the outcome must also be recorded. 
 
SAEs and AESIs that occur during the study or within 30 days after receiving the last dose of 
rucaparib, atezolizumab, or bevacizumab, whether or not related to rucaparib, atezolizumab, 
or bevacizumab, must be reported immediately (i.e., within 24 hours of knowledge of the 
event) to the sponsor. The contact information for reporting of SAEs/AESIs can be found on 
the SAE/AESI Reporting Form. After the 30-day reporting window after discontinuation of 
rucaparib, atezolizumab, or bevacizumab treatment, only SAEs assessed as related to 
rucaparib, atezolizumab, or bevacizumab,  and all AESIs, irrespective of causality, need to be 

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reported. 
Information on the follow-up of AEs, SAEs, and AESIs is provided below. 
 
9.2.1 Intensity of Adverse Events 
 
The severity of each AE will be graded using the NCI CTCAE, Version 5.0 or later grading 
scale: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quic
k_R eference_8.5x11.pdf. 
 
Severity is not the same as serious. 
 
For AEs not covered by NCI CTCAE, the severity will be characterized as mild, moderate, 
severe, life-threatening, or fatal according to the following definitions: 
• 
Mild events are usually transient and do not interfere with the patient’s daily activities 
• 
Moderate events introduce a low level of inconvenience or concern to the patient 
and may interfere with daily activities 
• 
Severe events interrupt the patient’s usual daily activities and hospitalization 
(or prolongation of hospitalization) may be required 
• 
Life-threatening events require urgent intervention to prevent death 
• 
Fatal events are those events that led to the patient’s death 
9.2.2 Causal Relationship of Adverse Events to Rucaparib, Atezolizumab, or Bevacizumab 
 
Medical judgment should be used to determine the cause of the AE considering all relevant 
factors such as, but not limited to, the underlying study indication, coexisting disease, 
concomitant medication, relevant history, pattern of the AE, temporal relationship to the 
study medication, and de-challenge or re-challenge with rucaparib, atezolizumab, or 
bevacizumab. 
 
Table 14. Causal Relationship of Adverse Events to Rucaparib, 
Atezolizumab, or Bevacizumab 
Causality 
Description 
Not Related 
to rucaparib, 
atezolizumab, 
or 
bevacizumab 
• 
An AE that is clearly due to extraneous causes (e.g., concurrent 
disease, concomitant medications, disease under study, etc.) 
• 
It does not follow a reasonable temporal sequence from administration of 
rucaparib, atezolizumab, or bevacizumab 
• 
It does not follow a known pattern of response to rucaparib, 
atezolizumab, or bevacizumab, 
• 
It does not reappear or worsen when rucaparib, atezolizumab, or 
bevacizumab is restarted 
• 
An alternative explanation is likely, but not clearly identifiable 

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Related to 
rucaparib, 
atezolizumab, 
or 
bevacizumab 
• 
An AE that is difficult to assign to alternative causes 
• 
It follows a strong or reasonable temporal sequence from 
administration of rucaparib, atezolizumab, or bevacizumab 
• 
It could not be reasonably explained by the patient’s clinical state, 
concurrent disease, or other concomitant therapy administered to the patient 
• 
It follows a known response pattern to rucaparib, atezolizumab, or 
bevacizumab 
• 
It is confirmed with a positive re-challenge or supporting laboratory data 
 
Outcome and Action Taken 
 
The investigator will record the action taken and outcome for each AE according to 
the following criteria: 
 
Action Taken with Study Drug (note all that apply) 
• 
None 
• 
Dose reduced/delayed 
• 
Study drug temporarily interrupted 
• 
Study drug permanently discontinued 
• 
Other (specify) 
Outcome 
• 
Recovered 
• 
Recovered with sequelae 
• 
Recovering/ Resolving/ Improving 
• 
Ongoing 
• 
Death 
• 
Lost to follow-up 
9.2.3 Follow-up of Adverse Events, Serious Adverse Events 
 
All AEs (including SAEs and AESIs) occurring during the study are to be followed up in 
accordance with good medical practice until resolved; judged no longer clinically significant; 
or, if a chronic condition, until fully characterized through 30 days after the last dose of 
rucaparib, atezolizumab, or bevacizumab for statistical considerations. Any SAEs, AESIs, and 
treatment-related Grade 3/4 AEs must be followed until resolution or stabilization, death, or 
until lost to follow-up. After the 30-day window, treatment-related SAEs and all AESIs, 
irrespective of causality, need to be reported. 
 
9.2.4 Regulatory Aspects of Serious Adverse Event and Adverse Events of Special 
Interest Reporting 
 
All SAEs and AESIs, regardless of relationship to rucaparib, atezolizumab, or bevacizumab, 
must be reported to the sponsor/SAE designee within 24 hours of knowledge of the event, 
during the 

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 study through 30 days after receiving the last dose of study treatment, according to the 
procedures below. After the 30-day specified window, only SAEs considered to be treatment- 
related and all AESIs, regardless of treatment relationship, should be reported. It is important 
that the investigator provide an assessment of relationship of the SAE or AESI to study 
treatment at the time of the initial report. The Serious Adverse Event (SAE)/Adverse Events 
of Special Interest (AESI) Report Form must be used for reporting SAEs and AESIs. The 
contact information for reporting of SAEs and AESIs can be found on the SAE/AESI Report 
Form and Pregnancy Report Form. 
The sponsor or its designee is responsible for submitting reports of AEs associated with the use 
of the drug that are both serious and unexpected to the US FDA, according to 21 Code of Federal 
Regulations (CFR) 312.32; to the European regulatory authorities according to the European 
Commission Clinical Trials Directive (2001/20/EC); and to other applicable regulatory 
authorities, according to national law and/or local regulations. All investigators participating in 
ongoing clinical studies with the study medication will receive copies of these reports for 
prompt submission to their IRB or IEC. In accordance with the European Commission Clinical 
Trials Directive (2001/20/EC), the sponsor or its designee will notify the relevant ethics 
committees in concerned member states of applicable suspected unexpected serious adverse 
reactions (SUSARs) as individual notifications or through periodic line listings. 
 
The sponsor or its designee will submit all safety updates and periodic reports to the 
regulatory authorities as required by applicable regulatory requirements. 
 
9.2.5 Specific Instructions for Recording Adverse Events 
 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 
 
a. Diagnosis vs. Signs and Symptoms 
 
If known at the time of reporting, a diagnosis should be reported 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, it is 
acceptable to report the information that is currently available. If a diagnosis is subsequently 
established, it should be reported as follow-up information. 
 
b. Deaths 
 
All deaths that occur during the protocol-specified AE reporting period, regardless of 
attribution, will be reported to the appropriate parties. When recording a death, the event or 
condition that caused or contributed to the fatal outcome should be reported as the single 
medical concept. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, report “Unexplained Death”. 
 

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c. Preexisting Medical Conditions 
 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be 
re- assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, 
or character of the condition worsens during the study. When reporting such events, it is 
important to convey the concept that the preexisting condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 
 
 
Adverse Event Reporting 
The Medical College of Wisconsin will track all protocol-defined AE and pregnancy 
reports originating from the Study for the Product. 
 
Each participating site will be responsible for adverse event assessment and reporting to the 
respective site IRBs per institutional guidelines. Each serious unexpected event must be 
reported to the Sponsor-Investigator within 24 hours as specified in the protocol. The Sponsor- 
Investigator will further evaluate the event and report to regulatory agencies. 
 
A member of the study staff from each site should complete the SAE eCRF within 24 hours 
of learning of the event and fax (414-805-6622) the completed form signed by the site 
investigator to the Medical College of Wisconsin. 
Investigators must report all Adverse events (AEs), Serious Adverse events (SAEs), AEs of 
Special Interest (AESIs), pregnancy reports and special situation reports (if applicable) 
adequately to the sponsor within the stated timelines. The completed MedWatch/case report 
should be faxed immediately upon completion to IIT EndoBARR at: 
Fax: +1-414-805-6622 
Email: BradleyIITEndoBARR@mcw.edu 
Relevant follow-up information should be submitted to the sponsor as soon as it becomes 
available and/or upon request. 
 
10 REPORTING AND DOCUMENTING RESULTS (MEASUREMENT OF 
EFFECT) 
10.1 Evaluation of Efficacy (or Activity) 
 
10.2 Antitumor Effect – Solid Tumors 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version1.1). Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria 
 

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10.2.1 Definitions 
 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their 
first treatment on study. 
 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease reevaluated 
will be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non- 
target disease. The response assessment is based on the presence, absence, or unequivocal 
progression of the lesions. 
 
10.2.2 Disease Parameters 
 
Measurable disease: Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 
mm with CT scan, or >10 mm with calipers by clinical exam. All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area will not be considered 
measurable unless progression is documented or a biopsy is obtained to confirm persistence at 
least 90 days following completion of radiation therapy. 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 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. 

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Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that 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 which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow- 
up. 
 
10.2.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using annotation on the 
source image (CT or MRI). All baseline evaluations should be performed as closely as possible 
to the beginning of treatment 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 follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g. for body scans), but NOT 
lung. 
 

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Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of 
MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of 
the scanning sequences used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up should be the same as was 
used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is 
beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should 
be used and the image acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements. PET-CT 
scans are not always done with oral and IV contrast. In addition, the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed. 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation 
is not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
 
Cytology, Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
 
10.2.4 Response Criteria 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 

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taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is 
the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new 
lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of Best Overall Response: 
The best overall response is the best response recorded from the start of the treatment until  
 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that progressive disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements. 
 
Progression-Free Survival: 
 
Progression-Free Survival (PFS) is defined as the duration of time from date of study entry 
to time of progression or death, whichever occurs first. 
 
Survival: 
 
Survival is defined as the duration of time from date of study entry to time of death or the date 
of last contact. 
 
11 CORRELATIVE STUDIES/SPECIAL STUDIES 
Correlative studies are planned using the primary tumor specimens and subject blood and serum 
if consent is provided. Associations between markers identified and between the markers (e.g. 
MSI, HRD mutations, Immuno-environment) and histological subtypes (e.g., endometrioid, 
clear cell, serous, carcinosarcoma) and disease status at entry will be evaluated. Additionally, 
the association between each marker and clinical endpoints will be assessed for each agent. 

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The aim is to prioritize likely candidates for prediction of outcome worthy of future 
confirmatory study. 
 
Tissue samples will be batch shipped to Foundation Medicine for FoundationOneCDX testing 
as well as PD-L1IHC, utilizing Ventana SP142 stain slides. Plasma and stool samples will be 
batch shipped to the Medical College of Wisconsin, PI office via FedEx (label will be 
provided). 
 
Kits with specimen containers and instructions for stool collection will be 
provided.  
 
Planned correlatives include: 
1. Measurement of tumor Microsatellite Instability (MSI) via IHC. This will be done at the 
local sites from the primary tumor as standard of care.  
 
2. Evaluation of genes leading to homologous recombination deficiency including but not 
limited to: 
 
a. ATM 
 
b. AATRX 
 
c. BARD1 
 
d. BLM 
 
e. BRCA1 
 
f. BRCA2 
 
g. NBN 
 
h. PALB2 
 
i. PTEN 
 
j. WRN 
 
k. FANCA 
 
l. FANCC 
 
m. FANCD2 
 
n. FANC3 
 

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o. FANCF 
 
p. FANCG 
 
q. FANCL 
 
r. MRE11A 
 
s. RAD50 
 
t. RAD51 
 
u. PMS2 
 
v. MLH1 
 
w. MSH2 
 
x. MSH6 
 
y. POLE 
z. P53 
 
These will be read out from Foundation Medicine. 
 
3. Measure of PD-1/PD-L1 in the tumor and immune environment. This will be read out from 
Foundation Medicine. 
 
4. Tumor mutational burden by number of mutations per megabase to be divided into low (≤5), 
intermediate (6-19), and high (≥20). This will be run at Foundation Medicine. 
 
5. Measurement of circulating tumor/cell free DNA both before and during treatment. This will 
be measured at Medical College of Wisconsin. 
 
Table 15. Lab protocol 
Time of Samples 
Blood collection 
before study 
directed therapy 
Blood collection 
pre-dose of study 
directed therapy 
Cycles 1 through 8. 
Blood collection at 
the time of 
Radiographic 
progression or End 
of treatment visit 
Cohort: 
10 ml peripheral 
blood into an EDTA 
tube (purple top) and 
Streck Cell-Free 
DNA BCT 
10 ml peripheral 
blood into an EDTA 
tube (purple top) and 
Streck Cell-Free 
DNA BCT 
10 ml peripheral blood 
into an EDTA tube 
(purple top) and 
Streck Cell-Free DNA 
BCT 

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In this study, it is requested that blood sample (before initiation of study directed therapy, three 
months after initiation of study directed therapy, and at the time of progression, 10 ml each 
time point) be submitted for translational research. 
 
Blood specimens will be prepared in the lab by a qualified technician. 
 
• Specimens are collected in purple-top tube (10 mL tube). 
• The tubes may be kept refrigerated (4-8° C) until processing (tubes may be on ice up to 
two hours.). Whole blood specimens will be centrifuged at approximately 2500 RPM in a 
standard clinical centrifuge for 10 minutes. 
• Using sterile techniques to avoid contamination, aliquot 0.5-1 mL plasma into cryovials and 
Freeze at -80° C. Care will be taken to collect only plasma and avoid collecting any white 
blood cell (white layer) before transferring plasma into the cryovials. 
• Each aliquot will be labelled with study protocol, study-specific case numbers, the data 
collection time point (i.e. A, B, C, or D), and specimen type (i.e., plasma). 
• One cryovial of white blood cells (white layer) is also aliquoted and stored at -80°C. The 
remaining portion will be thrown away. 
• The specimen can be transported frozen by MCW study staff. A specimen tracking log will 
provide documentation and accountability for specimen processing and transport to MCW. 
To better preserve the biospecimens, we will guarantee the following in sample transport: 
• sample identification and traceability, handling and transport conditions required for 
the blood and plasma, and proper training for the personnel handling and preparing the 
samples. Placement of this cooler in the transport vehicle will be in accordance with 
IATA rules to ensure both sample and occupant safety. 
• Immediately after arrival at Dr. Wang’s laboratory, these biospecimen will be put in -
80°C  for 
longer storage. Sample transportation will comply with applicable IRB protocol, 
including appropriate training for all study staff involved in specimen transport. 
• Blood samples will be processed by MCW staff via standard DNA analysis pipeline. 
Once 
this test is completed, the leftover plasma will be destroyed with bleach (1:10). 
 
6. Microbiome of the stool 
 
Shipping Instructions for Microbiome 
 
1. Provide patient with stool collection kit several days prior to the treatment visit. Note: 
Label the SAMPLE and OUTER stool collection containers with the patient name, date 
of birth, and date and time of sample collection (as specified in the stool collection kit 
instructions) prior to providing the kit to the patient. The SAMPLE and OUTER stool 
collection containers must be relabeled as described below before sending to the MCW. 
2. Review the EasySampler stool collection instructions (provided with the stool 
collection kit) with patient and instruct the patient to collect the sample within 24 hours 
of the treatment visit, as close to the visit as possible. Note: The patient must refrigerate 
the stool sample within one hour of collection (as specified in the patient collection 

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instructions) and keep the sample refrigerated until it is returned to the clinic. The 
patient should note the collection time and the time the sample was refrigerated (as 
specified in the patient collection instructions). 
3. Upon receipt in the clinic, record the collection date on the label provided and adhere 
it to the sealing bag. 
4. Place the frozen stool in a -70oC to -80oC freezer until ready to batch ship. If a -70oC 
to -80oC freezer is not available for storage, store and ship on dry ice within 24 hours 
of collection. 
5. When completing Form TR, the collection time noted by the patient should be 
recorded as “Collection Time.” The “Estimated Processing Time” should be recorded 
as the amount of time elapsed between sample collection and sample freeze (as noted 
by the patient). 
 
Labeling Stool Biospecimens 
 
A waterproof permanent marker or printed label should be used to label each translational 
science biospecimen with: 
 
Biospecimen code (# #) 
 
Collection date (mm/dd/yyyy)* 
 
*Collection date should be recorded on the label provided and adhered to the sealing bag 
after the patient returns the sample at the treatment visit. 
 
12 STATISTICAL CONSIDERATIONS 
12.1 Study Endpoints 
 
Primary Efficacy Variables 
 
The primary efficacy variables are the overall response rate (ORR) of patients with persistent 
or recurrent endometrial cancer when treated with the combination of rucaparib, bevacizumab 
and atezolizumab. 
 
ORR will be measured beginning on the date of initiation of study-directed therapy to the 
date of the first clinical, biochemical or radiological evidence of response, progression or 
death due to any cause or to date of last assessment. Response will be measured by RECIST 
1.1.  ORR will be censored at the last assessment of disease progression for patients who 
have not progressed or died. 
 
Secondary Efficacy Variables 
Progression free survival (PFS) of patients with persistent or recurrent endometrial cancer, 
when treated with the combination of rucaparib, bevacizumab and atezolizumab. 
Overall survival (OS) of patients with persistent or recurrent endometrial cancer, when treated 

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with the combination of rucaparib, bevacizumab and atezolizumab. 
 
Biomarker Variables 
 
The relationship of ORR, PFS, and OS to 
• 
Microsatellite instability — both genetic and epigenetic 
• 
Homologous recombination deficiency 
• 
PD-L1 expression in the tumor 
• 
Tumor mutational burden 
• 
Loss of heterozygosity 
• 
Circulating tumor DNA 
• 
Stool microbiome 
 
12.2 Study Design 
 
This is an open-label, non-blinded, phase II protocol with safety lead-in, anticipated to accrue for two 
years. Subjects will be followed until progression, death, or until withdrawal of consent. 
 
Safety population 
 
The safety population will consist of all patients who have received at least one dose of 
study medication, whether withdrawn prematurely or not. 
 
Analysis Population 
The observed cases (OC) 
 
This will include all patients who have undergone tumor assessment at baseline, received at least 
the first cycle of the combination of rucaparib-, bevacizumab- and atezolizumab-based 
chemotherapy, and have had at least one post-dose tumor assessment. 
 
The OC will be used to describe the population from which the sample is taken. 
 
This will be the primary population for all analyses of primary and secondary efficacy variables 
of the observed cases (i.e., the actual assessments at each visit). All other populations will be 
exploratory 
 
The modified observed cases (OC) 
 
The modified OC cases will be the OC for which there is at least one post enrollment evaluable 
assessment. 
 
The per-protocol population will be defined as the subset of the OC who completed all 
treatments and who did not have any major protocol violations (such as lack of compliance to 
the study medication schedule). The definitions of these protocol violations will be finalized 

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before the database closure and will be documented in the analysis plan. The analysis of this 
group will be exploratory. 
 
12.3 Randomization 
 
There is no randomization. For documentation purposes in OnCore, date of randomization is 
considered to be the same as date of verification of enrollment when signed by sponsor- 
investigator at MCW. 
 
12.4 Exploratory Analysis 
 
ORR will be summarized by 
• 
Microsatellite instability — both genetic and epigenetic 
• 
Homologous recombination deficiency 
• 
PD-L1 expression in the tumor 
• 
Tumor mutational burden 
• 
Loss of heterozygosity 
• 
Stool microbiome 
 
12.5 Determination of Sample Size and Accrual Rate 
The sample size will be 30 with accrual up to the end of the two-year period. Patients will 
be followed until progression, death, or until withdrawal of consent. 
 
 
12.6 Sample Size Justification and Futility Analysis 
 
The primary outcome is ORR. If the ORR is 27% (Castonguay) the one sided lower 95% 
CI bound is 14%. If the ORR is 23% the one sided lower 95% CI bound is 11%. 
 
Futility analysis 
 
Our plan is to stop if, in the first 12 subjects, at most 1 has a response to be considered in the 
ORR. Suppose we want a lower bound of 15% for a CI; then for 27 we would have a 94% CI 
and for 23 we would have an 84% CI. A Simon 2 stage approach at an alpha of 0.05 with 80% 
power requires more than 30 patients. The null hypothesis is 15% and the alternative is 30% 
with 30 patients. We will stop if there is 1 or less patients in 12 but continue if there are 2 or 
more. If we have 7 or 8 patients with ORR, the probability of an early stop is 44%. If we see 9 
patients with ORR, the probability of an early stop is 9%. If the true ORR is 30%, the probability 
of seeing 23% or better is 84% and of seeing 8/30 is 72%. 
 
12.7 Replacement Policy 
 
Subjects who are removed from study prior to receiving therapy will be replaced. 

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12.8 Accrual Estimates 
 
We expect to accrue one to two patients each month. 
 
12.9 Interim Analyses and Stopping Rules 
 
12.9.1 Toxicity/Futility Monitoring 
 
Because this is a first-time trial combining these three agents, a safety lead in will be 
undertaken. The first six patients will be assessed for DLTs after completing one cycle of 
therapy.  If there are zero to one DLTs related to study treatment, the cohort will be expanded 
to the planned 30. If two of the first six patients suffers a DLT thought to be associated with 
treatment, the safety cohort will be expanded to nine.  If three subjects experience a DLT in the 
first cycle (either in the cohort of six or nine), the trial will be halted and assessed by the DSMC, 
PI, and sponsors. 
 
12.9.2 Definition of a Dose-Limiting Toxicity (DLT) – Must be related to study 
directed therapy 
 
For the safety lead-in of this study a DLT is defined as: 
• Any Grade 4 immune related adverse event 
• Any ≥ grade 3 colitis 
• Any Grade 3 or 4 noninfectious pneumonitis (irrespective of duration) 
• Any Grade 2 noninfectious pneumonitis that does not resolve to ≤ grade 1 within 7 days 
of the initiation of maximal supportive care 
• Liver transaminase elevation > 8 x ULN or total bilirubin > 5 x ULN 
• Any grade 4 non immune related adverse event except for the exclusion list below 
• Delay of initiation of cycle 2 of greater than 3 weeks due to failure to recover AE/failure 
to meet protocol directed treatment parameters for restart after management of AE 
• Any treatment related death 
 
A DLT does not include: 
• Grade 3 fatigue, anorexia or constipation lasting less than one week 
• Grade 3 endocrine disorders (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replace therapy 
and the subject is asymptomatic 
• Grade 3 infusion related reaction 
• Grade 3 or 4 neutropenia (that is not associated with fever or infection) lasting ≤7 days 
• Grade 3 or 4 lymphopenia 
• Grade 3 thrombocytopenia that is not associated with clinically significant bleeding 
• Isolated grade 3 electrolyte abnormalities that are not associated with clinical signs 
or symptoms and are reversed with appropriate maximal medical intervention 
• Grade 3 hypertension 
 

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12.9.3 Anticipated 
toxicities 
from 
therapy 
include: Bevacizumab 
• Febrile Grade 4 neutropenia and/or Grade 4 thrombocytopenia, regardless of the relationship 
to treatment 
• Grade ≥ 2 fistula 
• GI perforation 
• Major surgery or wound healing complications 
• Medically significant hypertension not controlled with antihypertensive therapy, 
hypertensive crisis or hypertensive encephalopathy  
• Grade ≥ 3 left ventricular dysfunction (CHF)  
• Nephrotic syndrome  
• Arterial thrombosis/embolism (any grade)  
• Grade ≥ 3 venous thrombosis/embolism  
• CNS bleeding (any Grade) or ≥ Grade 3 bleeding of any kind  
• Grade ≥ 2 hemoptysis  
• Hypersensitivity/allergic reactions related to bevacizumab  
• PRES (or RPLS)  
 
Atezolizumab 
• Grade 4 pneumonitis 
• AST or ALT > 5×ULN or total bilirubin >3×ULN 
• Grade 4 diarrhea or colitis 
• Grade 4 hypophysitis 
• Any grade myasthenic syndrome/myasthenia gravis, Guillain-Barré or 
meningoencephalitis 
• Grade 4 ocular inflammatory toxicity 
• Grade 4 pancreatitis or any grade of recurrent pancreatitis 
• Grade 4 rash 
• Any grade myocarditis 
• Grade 3 pneumonitis 
• Grade 3 Ocular inflammatory toxicity 
• Grade 3 infusion related reactions 
 
Rucaparib 
 
• Grade 4 ALT/AST elevations 
 
12.10 Analyses Plans 
 
All efficacy data will be analyzed. For all efficacy variables, the baseline value will be defined 
as the last value taken prior to the start of the first study medication. 
 
12.10.1 Primary Analysis (or Analysis of Primary Endpoints) 
 
ORR will be summarized with a one sided lower 95% CI. 
 

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Best objective response (percentage of tumor reduction per RECIST 1.1): The percentage will 
be summarized as mean and 95% confidence interval (CI) or median and 95% CI (using a 
bootstrap method). The proportion receiving at least 20% reduction of target lesions will be 
obtained. The proportion will be compared between the stratification groups using a Fisher 
exact test. 
 
12.10.2 Secondary Analysis (or Analysis of Secondary Endpoints) 
 
PFS and OS: PFS, and OS will be summarized using Kaplan Meier curves. As an explorative 
analysis, strata such as 1) Microsatellite instability — both genetic and epigenetic, (2) 
homologous recombination deficiency, (3) PD-L1 expression in the tumor (4) Loss of 
heterozygosity and (5) tumor mutational burden will be shown and compared using a Wilcoxon 
rank sum test. A Cox proportional hazards model will be also fitted using at most 6 variables as 
covariates (due to sample size). 
 
The percentage reduction will be compared using a general or generalized linear model 
with stratification groups and demographic and clinical variables. The number of 
covariates considered will be limited due to sample size. 
 
Percent Survival at Six Months: This will be reported with 95% exact confidence 
intervals (CI). Survival at six months between groups will be compared using a Fisher’s 
exact test. 
 
12.10.3 Other Analyses/Assessments 
 
Patient Demographics and Characteristics Data: To evaluate generalizability of results, 
patient characteristics at baseline, demographic and disease characteristics will be summarized, 
using descriptive statistics. In addition, previous and concomitant diseases and medications 
will be summarized. Further results will be presented stratified by groups defined by (1) 
Microsatellite instability — both genetic and epigenetic, (2) homologous recombination 
deficiency, (3) PD-L1 expression in the tumor and (4) tumor mutational burden. All 
information will be listed by group and by patient and will be summarized. Frequencies will be 
presented for the categorical variables (e.g. race) and descriptive statistics will be presented for 
continuous variables (e.g. weight, age). 
 
Missing Data Handling: The dropout pattern will be plotted and summarized. To assess effects 
of dropouts, the dropout cohort analysis will be performed by summarizing the change of 
primary and secondary efficacy variables by using different dropout cohorts. Dropout cohorts 
will be formed by patients that had their last primary efficacy measurement in the same 
assessment interval. Patients who drop out or are removed from the study due to an adverse 
symptom profile will be reported as a safety outcome. In particular, the OC and the modified 
OC cohorts will be compared to check if the modified OC group appears biased. 
 
To allow for bias due to varying assessment times, symptomatic/non-radiologic events and 
missing data due to lack of follow-up, sensitivity analyses, as per Bhattacharya (Bhattacharya 
et al., 2009) will be performed. Briefly, simulation studies with varying hypothetical ORR 

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and/or progression times simulated by a uniform distribution within the assessment times will 
be used and times backdated to the last progression-free assessment. In another analysis, we 
will restrict the definition of the lack of PFS to only include those who have radiologic 
evidence. Finally, we will make conservative assumptions for the treatment arm and not for 
the historical controls in a comparison. 
12.11 Evaluation of Safety 
 
All information on AEs and SAEs will be listed by patient and will be summarized. The SAE 
report will include event term(s), serious criteria, and the sponsor-investigator’s or sub- 
investigator’s determination of both the intensity of the event(s) and the relationship of the 
event(s) to study drug administration. Intensity for each SAE, including any lab 
abnormalities, will be determined by using the NCI CTCAE as a guideline whenever 
possible. 
Frequencies will be presented for the categorical variables (e.g., race) and descriptive 
statistics will be presented for continuous variables (e.g., weight, age). 
 
Adverse Events of Special Interest (Immediately Reportable to the Sponsor) 
 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see Section 
5.4.2 for reporting instructions). Adverse events of special interest for this study are as 
follows: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law 
and based on the following observations: 
o Treatment-emergent ALT or AST > 3 ×  ULN (or > 3 ×  baseline value in disease 
states where LFTs may be elevated at baseline) in combination with total bilirubin 
> 2 ×  ULN (of which ≥ 35% is direct bilirubin) 
o Treatment-emergent ALT or AST > 3 ×  ULN (or >3 ×  baseline value in disease 
states where LFTs may be elevated at baseline) in combination with clinical 
jaundice 
• 
Suspected transmission of an infectious agent by the study treatment, as defined below: 
o 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 

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• 
Hepatitis, including AST or ALT >10 × ULN 
• 
Systemic lupus erythematosus 
• 
Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or myasthenia 
gravis, and meningoencephalitis 
• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, influenza-like illness, systemic inflammatory response syndrome, and 
systemic immune activation 
• 
Nephritis 
• 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
• 
Myositis 
• 
Myopathies, including rhabdomyolysis 
• 
Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
• 
Vasculitis 
• 
Autoimmune hemolytic anemia 
• 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis) 
13 DATA AND SAFETY MONITORING PLAN (DSMP) 
Please refer to the MCWCC DSMC Charter. 
 
Data and Safety Management Overview 
 
The Medical College of Wisconsin (MCW) Data Safety Monitoring Committee (DSMC) and 
the MCW Institutional Review Board (IRB) will approve protocol-specific DSM plans. A 
local, investigator-initiated trial will be required to be continuously monitored by the principal 
investigator of the study with biannual safety and progress reports submitted to the DSMC. 
 
13.1 Study Team 
 
The study team minimally consists of the principal investigator, the clinical research 
coordinator, regulatory specialist and the study biostatistician. While subjects are on treatment, 
the principal investigator will meet regularly with the research coordinator and the study 
biostatistician to review study status. This review will include but not be limited to reportable 
SAEs and UPIRSOs and an update of the ongoing study summary that describes study progress 
in terms of the study schema. The appropriateness of further subject enrollment and the specific 
intervention for a next subject enrollment is addressed. All meetings including attendance are 
documented. 
 
13.2 Quality Assurance 
 
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responsible for ongoing oversight, monitoring, source documentation confirmation, protocol 
compliance, adverse events, etc. 
• The study will be reviewed annually by MCW. 
• 10% of subject files will be selected randomly for review (max 10 subjects at each 
monitoring timepoint). 
• Consent/eligibility and objective based data will be reviewed for those files selected 
• 1 file will be selected randomly for a comprehensive review at each monitoring time point. 
After each QA review, a letter/report will be provided to the study staff and the DSMC. 
Necessary corrective action or training will be provided to the staff as needed throughout and 
following each QA review. Directed audits may be requested at any time by the CCCTO QA 
Staff, DSMC, Research Manager, study staff member, or administrative staff. 
 
The MCW Principal Investigator will have access to the study data for all of the patients entered 
onto this study. Data storage is carried out according to MCW Institutional Policy. 
 
13.3 Clinical Trials Office 
The MCWCC Clinical Trials Office [CTO] provides administrative assistance and support to 
the DSMC. 
 
13.4 DSMC 
 
The Medical College of Wisconsin Cancer Center places the highest priority on ensuring the 
safety of patients participating in clinical trials. Every cancer interventional trial conducted at 
MCW includes a plan for safety and data monitoring. 
 
More information can be found related to the MCWCC Data and Safety Monitoring Plan at the 
MCWCC website. 
 
This study will be reviewed by the Medical College of Wisconsin Cancer Center Data and Safety 
Monitoring Committee (MCWCC DSMC). A summary of the MCWCC DSMC activities are as 
follows: 
 
▪ 
Review the clinical trial for data integrity and safety 
 
▪ 
Review all unexpected Grade 3, and all Grade 4, and 5 adverse events, as well as any 
others requiring expedited reporting as defined in this protocol. (Grades 4 and 5 events 
must be reported to the DSMC within five calendar days of study staff’s knowledge.) 
 
▪ 
Review all DSM reports 
 
▪ 
Submit a summary of any recommendations related to study conduct 
 
▪ 
Terminate the study if deemed unsafe for patients 

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A copy of the MCWCC Data and Safety Monitoring Plan and membership roster will be 
maintained in the study research file and updated as membership changes. The committee will 
review reports from the study PI twice annually (or more frequently if needed) and provide 
recommendations on trial continuation, suspension or termination as necessary. 
 
Any available DSMC letters will be submitted to the IRB of record as required. 
 
14 REGULATORY COMPLIANCE, ETHICS AND STUDY 
MANAGEMENT 
14.1 Ethical Standard 
 
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
 
14.2 Regulatory Compliance 
 
This study will be conducted in compliance with: 
 
▪ 
The protocol 
▪ 
Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards) and §312 
(Investigational New Drug Application; and 45 CFR 46 Subparts A (Common Rule), B 
(Pregnant Women, Human Fetuses and Neonates), C (Prisoners), and D (Children), 
GCP/ICH guidelines, and all applicable regulatory requirements. The IRB must comply 
with the regulations in 21 CFR §56 and applicable regulatory requirements. 
 
14.3 Prestudy Documentation 
 
Prior to implementing this protocol at MCWCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the MCW 
IRB. 
 
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 
 
14.4 Institutional Review Board 
 
The protocol, the proposed informed consent form and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the MCW Institutional Review Board. Prior to obtaining MCW approval, the 

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protocol must be approved by the Medical College of Wisconsin Cancer Center Scientific 
Review Committee. The initial protocol and all protocol amendments must be approved by the 
IRB prior to implementation. 
 
Informed Consent Process 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and their families. 
Consent forms describing in detail the study interventions/products, study procedures and risks 
are given to the subject and written documentation of informed consent is required prior to 
starting intervention/administering study product. 
 
Consent forms will be IRB-approved and the subject (and Legally Authorized Representative, if 
necessary) will be asked to read and review the document. Upon reviewing the document, the 
investigator will explain the research study to the subject and answer any questions that may 
arise. In accordance with 46 CR 46.111, the subject will sign and date the informed consent 
document prior to any procedures being done specifically for the study. 
 
A witness should only sign when required, per FH/MCW IRB policy. If a witness signs the 
document when not required, the study staff should document in the legal medical record (or note 
to file) the relationship to the patient and why a witness signed. (i.e., “Although not required, the 
subject’s spouse was present during the consenting process and signed as the witness.” Or 
“Although not required, hospital staff was present for consenting process and signed as a 
witness.”) 
 
The subjects will have the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. The subjects may withdraw consent at any time throughout the 
course of the trial. 
A copy of the informed consent document will be given to the subjects for their records. The 
rights and welfare of the subjects will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this study. If 
there are changes to the consent form, all revisions will be reviewed with study subject at the 
next appropriate opportunity. Patients that require reconsenting will be defined in the IRB 
approved amendment submission. The process for obtaining informed consent will again be 
performed. Study subjects will not be reconsented for continuing reviews. The MCWCC CTO 
will follow the MCW/FH IRB’s policy for subjects who demonstrate limited English proficiency 
or limited literacy. 
 
After the subject’s visit in which the consent is signed, it is documented in the clinic chart that 
the consent has been signed and that all questions have been answered to the subject’s satisfaction 
after adequate time for review of the consent. It is also documented that a copy of the consent is 
given to the subject. The original consent is kept with the subject’s study file, and a copy of the 
consent is sent to the OCRICC office, which will then submit to HIM a copy of the signed consent 
to be scanned into EPIC, the legal medical record. 
 

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14.5 Subject Confidentiality and Access to Source Documents/Data 
 
Subject confidentiality is strictly held in trust by the sponsor-investigator, participating 
investigators, and any staff, [and the sponsor(s) and their agents]. This confidentiality includes 
the clinical information relating to participating subjects, as well as any genetic or biological 
testing. 
 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor-investigator. 
 
The conditions for maintaining confidentiality of the subjects’ records are required for the life of 
the data. These rules apply equally to any and all MCWCC projects. 
 
One risk of taking part in a research study is that more people will handle the personal health 
information collected for this study. The study team will make every effort to protect the 
information and keep it confidential, but it is possible that an unauthorized person might see it. 
Depending on the kind of information being collected, it might be used in a way that could 
embarrass the subject or affect his/her ability to get insurance. 
 
While data are being collected and after all data have been collected but are still in the process 
of being analyzed, the subject’s data/PHI are stored in the locked Clinical Research office in the 
Clinical Trials Office. Databases in which the study subject information is stored and accessed 
are  
 
password protected, allowing for limited access by authorized personnel only. Data/PHI kept in 
the Case Report Forms contain the study identifiers, subject initials, date of birth and date of 
service. 
 
The sponsor-investigator will allow access to all source data and documents for the purposes of 
monitoring, audits, IRB review, and regulatory inspections. 
 
The study monitor or other authorized representatives of the sponsor-investigator may inspect all 
documents and records required to be maintained by the investigator, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the subjects in this study. 
The clinical study site will permit access to such records. 
 
14.6 Protection of Human Subjects 
 
14.6.1 Protection from Unnecessary Harm 
 
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the IRB mechanism and the informed consent process. The IRB 
reviews all proposed studies involving human experimentation and ensures that the subject’s 
rights and welfare are protected and that the potential benefits and/or the importance of the 
knowledge to be gained outweigh the risks to the individual. The IRB also reviews the informed 

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consent document associated with each study in order to ensure that the consent document 
accurately and clearly communicates the nature of the research to be done and its associated 
risks and benefits. 
 
14.6.2 Protection of Privacy 
 
As noted, patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this discussion, they 
will be asked to sign informed consent documents. The original signed document will become 
part of the patient’s medical records, and each patient will receive a copy of the signed 
document. 
 
14.7 Changes in the Protocol 
 
Once the protocol has been approved by the MCW IRB, any changes to the protocol must be 
documented in the form of an amendment. The amendment must be signed by the investigator 
and approved by IRB prior to implementation. 
 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval. In this circumstance, however, the 
Investigator must then notify the IRB in writing within five working days after implementation. 
 
The IRB may provide, if applicable regulatory authority(ies) permit, expedited review and 
approval/favorable opinion for minor change(s) in ongoing studies that have the approval 
/favorable opinion of the IRB. The investigator will submit all protocol modifications to the 
sponsor and the regulatory authority(ies) in accordance with the governing regulations. 
 
Changes to the protocol may require approval from the sponsor. 
 
Any departures from the protocol must be fully documented in the source documents. 
 
14.8 Investigator Compliance 
 
The investigator will conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB and the appropriate regulatory authority(ies). 
 
Onsite Audits 
 
Auditing is essential to ensure that research conducted at the Medical College of Wisconsin 
(MCW) Cancer Center is of the highest quality and meets MCW and regulatory agency 
standards. 
Regulatory authorities, the IRB and/or sponsor may request access to all source documents, data 
capture records and other study documentation for on-site audit or inspection. Direct access to 
these documents must be guaranteed by the investigator, who must provide support at all times 
for these activities. 

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14.9 Product Complaints 
 
What is a product complaint? 
 
A product complaint is any written or oral information received from a complainant that alleges 
deficiencies related to identity, quality, safety, strength, purity, reliability, durability, 
effectiveness or performance of a product after it has been released and distributed to the 
commercial market or clinical trial.  
 
How do I file a product complaint? 
 
For all Investigator Initiated Studies (interventional and non-interventional):  
• Product Complaints with an AE (adverse event) should be reported via email/fax to: 
usds_aereporting-d@gene.com OR 650-238-6067  
• Product Complaints without an AE (adverse event) should be reported via email to: 
kaiseraugst.global_impcomplaint_management@roche.com  
 
All complaints must be filed within 1 business day for pre-approved products and 15 calendar 
days for approved products. Complaints can be reported using a Medwatch, CIOMS or any 
Genentech-approved reporting form (same as SAEs, AESI etc.). 
 
15 DATA HANDLING AND RECORD KEEPING 
15.1 Overview 
 
Every effort is made to uphold the integrity of the project, the research, the institution, and the 
researchers involved. Data collection guidelines and methodologies are carefully developed 
before the research begins. Investigators focus on the following to ensure data integrity: well- 
trained data collectors/recorders to ensure consistency and quality, well-designed data 
collection protocols and ongoing monitoring. In this way, study rigor and validity are 
maintained. Data is protected from physical damage as well as from tampering, loss or theft. 
This project’s data management is a multidisciplinary activity that includes investigators, 
research coordinators and nurses, data mangers, support personnel, biostatisticians and 
database programmers. Quality control will be applied to each stage of data handling to ensure 
that all data are reliable and have been processed correctly. 
 
15.2 Data Management Responsibilities 
 
15.2.1 Principal Investigator 
 
The principal investigator oversees the management of patient records/case report forms and 
ensures that a) complete and accurate data will be obtained and provided to the sponsor; b) 
patient records are maintained to include history, prescribed medication and investigational 
product(s), measurements,  
 

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exams, evaluations and adverse events; c) corrections are applied to clinical research data 
according to principles of good research practice (i.e., single-line delete, date and initial). He 
or she will ensure that there is correlation between the case report forms and the source 
documents. 
 
15.2.2 Research Coordinator 
 
A research coordinator creates, collects and organizes clinical trial documentation. He or she 
ensures that source documentation and data abstraction and entry are being done at protocol 
specified time points. 
 
15.2.3 Research Nurse/Medical Staff 
 
The research nurse and medical staff documents protocol-required care or assessment of the 
subject’s outcomes, adverse events and compliance to study procedures. 
15.2.4 Biostatistician 
 
The biostatistician may assist in CRF development (content and design), dataset specifications 
(annotation of CRFs and record layout) and validation. 
 
15.3 Handling and Documentation of Clinical Supplies 
 
The MCWCC Principal Investigator will maintain complete records showing the receipt, 
dispensation, return, or other disposition of all investigational drugs. The date, quantity and 
batch or code number of the drug, and the identification of patients to whom study drug has 
been dispensed by patient number and initials will be included. The sponsor-investigator 
will maintain written records of any disposition of the study drug. 
 
The principal investigator shall not make the investigational drug available to any 
individuals other than to qualified study patients. Furthermore, the principal investigator will 
not allow the investigational drug to be used in any manner other than that specified in this 
protocol. 
 
15.4 Source Documents 
 
Source documents for clinical information (patient history, diagnosis, clinical and diagnostic 
test reports, etc.) are maintained in the patient’s clinical file. Source documents for the 
correlative studies are maintained in the laboratory conducting the study. 
 
The source documents for this protocol are as follows: 
 
Original documents, data and records (e.g., hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate copies, microfiches, photographic negatives, microfilm or 
magnetic media, X- rays, subject files and records kept at the pharmacy, at the laboratories and 

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at medico-technical departments involved in the clinical trial). 
 
Table 16. All source documents will be written following ALCOA standards: 
ALCOA Attribute 
Definition 
Attributable 
Clear who has documented the data. 
Legible 
Readable and signatures identifiable. 
Contemporaneous 
Documented in the correct time frame along with the flow of 
events. If a clinical observation cannot be entered when made, 
chronology should be recorded. Acceptable amount of delay 
should be defined and justified. 
Original 
Original, if not original should be exact copy; the first record 
made by the appropriate person. The investigator should have 
the original source document. 
Accurate 
Accurate, consistent and real representation of facts. 
Enduring 
Long-lasting and durable. 
Available and 
accessible 
Easily available for review by treating physicians and 
during audits/inspections. The documents should be 
retrievable in 
reasonable time. 
Complete 
Complete until that point in time. 
Consistent 
Demonstrate the required attributes consistently. 
Credible 
Based on real and reliable facts. 
Corroborated 
Data should be backed up by evidence. 
 
 
15.5 Case Report Forms 
 
The principal investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study- 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis. All study data will be entered into OnCore® via standardized 
CRFs, in accordance with the study calendar, using single data entry with a secure access 
account. The Clinical Research Coordinator will complete the CRFs as soon as possible upon 
completion of the study visit; the investigator will review and approve the completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the patient’s medical records maintained by 
MCWCC personnel. All source documentation should be kept in separate research folders for 
each patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The principal investigator will 
approve all completed CRFs to attest that the information contained on the CRFs is true and 
accurate. 
All source documentation and data will be available for review/monitoring by the MCWCC 

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DSMC and regulatory agencies. 
15.6 Study Record Retention 
 
The principal investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity and use by subjects, as well as written records of the disposition of the  
drug when the study ends. 
 
The principal investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study. 
 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
sponsor-investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 
In accordance with FDA regulations, the investigator shall retain records for a period of two 
years following the date a marketing application is approved for the drug for the indication for 
which it is being investigated; or, if no application is to be filed or if the application is not 
approved for such indication, until two years after the investigation is discontinued and FDA is 
notified. 

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REFERENCES 
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Arielle Lutterman Heeke, T.B., Filipa Lynce, Michael J. Pishvaian, Claudine Isaacs (2017). 
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Coleman, R.L., Sill, M.W., Lankes, H.A., Fader, A.N., Finkler, N.J., Hoffman, J.S., Rose, P.G., 
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reduced recurrence-free survival. Gynecologic oncology 146, 588-595. 
 
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with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic 
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Gabrilovich, D.I., Chen, H.L., Girgis, K.R., Cunningham, H.T., Meny, G.M., Nadaf, S., 
Kavanaugh, D., and Carbone, D.P. (1996). Production of vascular endothelial growth factor by 
human tumors inhibits the functional maturation of dendritic cells. Nature medicine 2, 1096- 
1103. 
 
Goldberg, S.B., Narayan, A., Kole, A.J., Decker, R.H., Teysir, J., Carriero, N.J., Lee, A., 
Nemati, R., Nath, S.K., Mane, S.M., et al. (2018). Early Assessment of Lung Cancer 
Immunotherapy Response via Circulating Tumor DNA. Clinical cancer research : an official 
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Goodfellow, P.J., Billingsley, C.C., Lankes, H.A., Ali, S., Cohn, D.E., Broaddus, R.J., Ramirez, 
N., Pritchard, C.C., Hampel, H., Chassen, A.S., et al. (2015). Combined Microsatellite 
Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome 
Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic 
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of Clinical Oncology 33, 4301-4308. 
 
Gopalakrishnan, V., Spencer, C.N., Nezi, L., Reuben, A., Andrews, M.C., Karpinets, T.V., 
Prieto, P.A., Vicente, D., Hoffman, K., Wei, S.C., et al. (2018). Gut microbiome modulates 
response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97-103. 
 
Heinzerling, L., Ott, P.A., Hodi, F.S., Husain, A.N., Tajmir-Riahi, A., Tawbi, H., Pauschinger, 

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M., Gajewski, T.F., Lipson, E.J., and Luke, J.J. (2016). Cardiotoxicity associated with CTLA4 
and PD1 blocking immunotherapy. Journal for immunotherapy of cancer 4, 50. 
 
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Evaluation and management of patients with heart disease and cancer: cardio-oncology. Mayo 
Clinic proceedings 89, 1287-1306. 
 
Higuchi, T., Flies, D.B., Marjon, N.A., Mantia-Smaldone, G., Ronner, L., Gimotty, P.A., and 
Adams, S.F. (2015). CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in 
BRCA1-Deficient Ovarian Cancer. Cancer immunology research 3, 1257-1268. 
 
Jiao, S., Xia, W., Yamaguchi, H., Wei, Y., Chen, M.K., Hsu, J.M., Hsu, J.L., Yu, W.H., Du, Y., 
Lee, H.H., et al. (2017). PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer- 
Associated Immunosuppression. Clinical cancer research : an official journal of the American 
Association for Cancer Research 23, 3711-3720. 
 
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F.A., Foster, E., Goldstein, S.A., Kuznetsova, T., et al. (2015). Recommendations for cardiac 
chamber quantification by echocardiography in adults: an update from the American Society of 
Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc 
Echocardiogr 28, 1-39 e14. 
 
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Luber, B.S., Azad, N.S., Laheru, D., et al. (2015). PD-1 Blockade in Tumors with Mismatch-
Repair Deficiency. The New England journal of medicine 372, 2509-2520. 
 
Lee, J.M., Cimino-Mathews, A., Peer, C.J., Zimmer, A., Lipkowitz, S., Annunziata, C.M., Cao, 
L., Harrell, M.I., Swisher, E.M., Houston, N., et al. (2017). Safety and Clinical Activity of the 
Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) 
Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor 
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: official journal of the American Society of Clinical Oncology 35, 2193-2202. 
 
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The Lancet Oncology 15, 1207-1214. 

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Makker, V., Green, A.K., Wenham, R.M., Mutch, D., Davidson, B., and Miller, D.S. (2017). 
New therapies for advanced, recurrent, and metastatic endometrial cancers. Gynecol Oncol Res 
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Gajewski, T.F. (2018). The commensal microbiome is associated with anti-PD-1 efficacy in 
metastatic melanoma patients. Science 359, 104-108. 
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M.A., Backes, F.J., Landrum, L.M., Zaino, R., et al. (2016). Clinicopathologic Significance of 
Mismatch Repair Defects in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology 
Group Study. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 34, 3062-3068. 
 
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Flachskampf, F.A., Gillebert, T.C., Klein, A.L., Lancellotti, P., et al. (2016). Recommendations 
for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from 
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Imaging. J Am Soc Echocardiogr 29, 277-314. 
 
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Mehnert, J.M., Aung, K.L., Lopez, J., et al. (2017). Safety and Antitumor Activity of 
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Vascular Endothelial Growth Factor as Combination Therapy for Metastatic Melanoma: An 
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recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group 
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(2017). Immune Checkpoint Inhibitors and Cardiac Toxicity: An Emerging Issue. Current 
medicinal chemistry. 
 
 

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APPENDIX 1. PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity 
Fully active, able to carry on all 
pre-disease performance without 
restriction 
100 
Normal, no complaints, no evidence 
of disease 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease 
1 
Symptoms, but ambulatory 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry out 
work of a light or sedentary 
nature (e.g., light housework, 
office work) 
80 
Normal activity with effort; some 
signs or symptoms of disease 
70 
Cares for self, unable to carry on 
normal activity or to do active work 
2 
In bed < 50% of the time 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities 
Up and about more than 50% of 
waking hours 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs 
50 
Requires considerable assistance 
and frequent medical care 
3 
In bed > 50% of the time 
Capable of only limited self- 
care, confined to bed or chair 
more than 50% of waking hours 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization 
indicated 
Death not imminent 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
20 
Very sick, hospitalization indicated 
Death not imminent 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 
 
 
 

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APPENDIX 2. PREGNANCY FORM 
Pregnancy occurring in participant in a Clinical Trial of Investigational Medicinal Product, while 
not considered an adverse event or serious adverse event, requires monitoring and follow up. 
 
The investigator must collect pregnancy information for female trial subjects or female partners 
of male trial subjects. This includes subjects who become pregnant while participating in a 
clinical trial or during a stage where the fetus could have been exposed to the investigational 
medicinal product (e.g., if the active substance or one of its metabolites has a long half-life). 
 
Any pregnancy should be reported by the PI to the sponsor using either a study specific or generic 
pregnancy reporting form (see below). 
 
The pregnancy should be followed up by the investigator until delivery. It may be necessary to 
monitor the development of the newborn for an appropriate period post delivery. Any 
occurrences that result in a Serious Adverse Event should be reported as per the SAE reporting 
procedure. 
 
The below form will be used. 

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Study Drug: 
Study/Protocol No: 
Investigator’s name: 
PATIENT ID 
Patient’s Initials  
1. 
2. fam. 
If applicable 
Centre No. Patient No 
REPORT TYPE 
Initial 
Follow-Up 
STUDY PREGNANCY FORM 
Page 1 of 
1. Country: 
2. LOCAL CASE ID: 
I. 
MATERNAL INFORMATION 
3.    DATE OF BIRTH 
4.    AGE 
5. RACE 
6. HEIGHT 
7. WEIGHT 
day 
month 
year 
yrs./mo. 
Caucasian 
Oriental 
Black 
Other 
cm 
kg 
8. 
Date of Last Menstrual Period 
day 
month 
year 
9. 
Expected Date of Delivery 
day 
month 
year 
10. 
Method of Contraception 
11.   Contraception used as instructed 
yes 
no 
uncertain 
II. 
HISTORY 
12. PATIENT’S PAST MEDICAL HISTORY (include information on familial disorders, known risk factors or 
conditions that may affect the outcome of the pregnancy e.g. alcohol, smoking, other substance consumption, 
hypertension, eclampsia, diabetes including gestational, infections during pregnancy, environmental or occupationa
exposure that may pose a risk factor). 
13. 
PREVIOUS OBSTETRIC HISTORY – provide details on all previous pregnancies below, including abortion or stillbirth (use page 3 if needed) 
Gestation week 
Outcome including any abnormalities 
1 
2 
3 
4 
5 
14. 
DRUG INFORMATION – please list the Novartis drug(s) first and all other therapies taken prior to or during pregnancy 
Drug Names 
Daily Dose 
Route 
Treatment Dates 
Indication 
(specify week of pregnancy) 
Start 
Stop 
Start 
Stop 
 

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STUDY PREGNANCY FORM 
Page 2 of 3 
2. LOCAL CASE ID: 
III. 
PREGNANCY INFORMATION 
15. 
Date of Pregnancy Confirmation:  
/ 
/ 
 
16. 
Method of Pregnancy Confirmation (Serum, Urine, Ultrasound, etc): 
17. 
PRENATAL 
Have any specific tests, e.g. amniocentesis, ultrasound, maternal serum AFP, been performed during the pregnancy so far? 
No 
Yes 
Not known 
If yes, please specify test date and results: 
18. 
PREGNANCY OUTCOME 
Delivery 
Normal 
Forceps/Ventouse 
Caesarean section 
Maternal complications or problems related to birth:  
_  
 
Abortion 
Therapeutic 
Planned 
Spontaneous 
Please, specify reason and any abnormalities (if known) 
 
Unspecified 
Date of abortion/delivery 
day 
month 
year 
at week   
 
19. 
MATERNAL PREGNANCY ASSOCIATED EVENTS: 
If the mother experiences a serious adverse drug reaction (ADR) during a pregnancy, please complete a SAE form and submit as requested. 
IV. 
CHILD INFORMATION 
20. 
Neonate 
Normal 
Abnormal 
Stillbirth 
please specify any abnormalities:    
 
Sex 
Height 
Weight 
Apgar Scores 
Head circumference 
Male 
Female 
i nches 
pounds 
1 min. 
5 mins. 
10 mins. 
inches 
For additional information, please use page 3 (please provide copies of relevant documentation) 
V. 
ASSESSMENT OF PREGNANCY OUTCOME 
24. 
SERIOUSNESS CRITERIA 
Non Serious 
day 
month  year 
day 
month  year 
Mother died 
Stillbirth / Neonate Died 
Involved or prolonged inpatient hospitalization 
Life-threatening 
Results in persistent or significant disability/incapacity 
Other Seriousness Criteria: 
Congenital anomaly/birth defect 
Other significant medical events 
25. 
ASSESSMENT OF CAUSALITY 
Please indicate the relationship between pregnancy outcome and Novartis study drug 
Not suspected 
Suspected 
INFORMATION SOURCE 
 

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26. NAME, ADDRESS AND TELEPHONE NUMBER OF INVESTIGATOR 
27. REPORTING DATE BY INVESTIGATOR/PERSON REPORTING 
EVENT 
day 
month 
year 
 

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STUDY PREGNANCY FORM 
Page 3 of 3 
2. LOCAL CASE ID: 
FOR ADDITIONAL INFORMATION: 
INFORMATION SOURCE 
29. NAME, ADDRESS AND TELEPHONE NUMBER OF INVESTIGATOR 
Signature: 
30. REPORTING DATE BY INVESTIGATOR/PERSON REPORTING 
day 
month 
year 
PLEASE SEND FORM TO: iitendobarr@mcw.edu or fax to +1.414.805.6622 

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Site No: 
APPENDIX 3. ENROLLMENT WORKSHEET 
 
 
 
 
The EndoBARR Trial (Endometrial Bevacizumab, Atezolizumab, 
Rucaparib): An Open Label, Non-Randomized Multisite Phase II 
Trial Combining Bevacizumab, Atezolizumab and Rucaparib for 
the Treatment of Previously Treated Recurrent and Progressive 
Endometrial Carcinoma. 
Enrollment Worksheet 
 
Subject Initials:           / 
 
 / 
 Subject D.O.B:           /  
/ 
 Subject ID#:  
 
  
  
Rucaparib 600mg BID + Bevacizumab 15mg/kg and Atezolizumab 1,200mg 
every 21days. Expected start date: 
Did the patient meet all inclusion criteria and none of the exclusion criteria? ☐ Yes ☐ No 
If No, Which inclusion criteria are not met and/or exclusion criteria are met? 
 
 
 
(Please attach a copy of the signed Informed consent, Inclusion/exclusion and all relevant 
screening source documents to this enrollment form for sponsor approval.) 
 
 
 
 
Name of Principal Investigator or Authorized Representative (Please Print) 
 
 
Signature of Principal Investigator or Authorized Representative. 
Date. 
 
 
 
*For Sponsor Use only 
Is subject approved to go on study? 
□ Yes 
☐NO 
Medical Monitor (or designee) Name: 
Signature: 
Date: 
PI Name: 

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APPENDIX 4. SAE REPORTING 
 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY 
VARIABLES 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, are collected and reported to the Sponsor-Investigator, 
appropriate IRB(s), Clovis Oncology, and Genentech, Inc. in accordance with CFR 
312.32 (Safety Reports). MCW (PI as sponsor) will obtain reporting on AEs and SAEs 
from co-investigatory sites and report as required. MCW as lead site will report to FDA 
as indicated. OnCore is used by all sites to collect data and events. MedWatch 3500 
will be used for all SAEs and reported to sponsor within 24 hours of becoming aware. 
Sponsor will report AE/SAEs and SAEs of special interest to Genentech and Clovis 
Oncology as described below. 
 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by 
its duration (i.e., start and end dates), regulatory seriousness criteria if applicable, 
suspected relationship to the Atezolizumab and/or Bevacizumab and/or Rucaparib (see 
following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should 
apply the following general guideline: 
 
Yes 
There is a plausible temporal relationship between the onset of the AE and 
administration of Atezolizumab and/or Bevacizumab and/or Rucaparib, and the AE 
cannot be readily explained by the subject’s clinical state, intercurrent illness, or 
concomitant therapies; and/or the AE follows a known pattern of response to 
Atezolizumab and/or Bevacizumab and/or Rucaparib; and/or the AE abates or resolves 
upon discontinuation of Atezolizumab and/or Bevacizumab and/or Rucaparib or dose 
reduction and, if applicable, reappears upon re- challenge. 
 
No 
Evidence exists that the AE has an etiology other than the Atezolizumab and/or 
Bevacizumab and/or Rucaparib (e.g., preexisting medical condition, underlying 
disease, intercurrent illness, or concomitant medication); and/or the AE has no 
plausible temporal relationship to Atezolizumab and/or Bevacizumab and/or 
Rucaparib administration (e.g., cancer diagnosed 2 days after first dose of 
Atezolizumab and/or Bevacizumab and/or Rucaparib). 
 

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PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE 
EVENTS 
 
Eliciting Adverse Events 
 
A consistent methodology for eliciting AEs at all subject evaluation time points should 
be adopted. Examples of non-directive questions include: 
• “How have you felt since your last clinical visit?” 
• “Have you had any new or changed health problems since you were last here?” 
 
Hospitalizations for Medical or Surgical Procedures 
 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE. If a subject is hospitalized to undergo a medical or 
surgical procedure as a result of an AE, the event responsible for the procedure, not the 
procedure itself, should be reported as the SAE. For example, if a subject is hospitalized 
to undergo coronary bypass surgery, record the heart condition that necessitated the 
bypass as the SAE. 
• 
Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for preexisting conditions 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of 
the study 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity. The below table should be used for assessing severity 
for adverse events that are not specifically listed in the NCI CTCAE. 
 
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 

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NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: Based on the most recent version of NCI CTCAE (v5.0), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b. 
Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using the toilet, 
and taking medications, as performed by patients who are not bedridden. 
c. 
If an event is assessed as a "significant medical event," it must be reported as a serious adverse event 
d. 
Grade 4 and 5 events must be reported as serious adverse events 
 
Post-Study Adverse Events 
The investigator after the end of the adverse event reporting period (defined as 30 days 
after the last dose of study drugs) should report all deaths, (regardless of cause), and any 
serious adverse event including development of cancer or a congenital anomaly in a 
subsequently conceived offspring of a female subject or pregnancy occurring in the partner 
of a male study subject who participated in the study that is believed to be related to prior 
exposure to study drugs. 
 
Case Transmission Verification will be performed by both parties during this period to 
ensure successful transmission of Single case reports 

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Case Transmission Verification of Single Case Reports 
 
The Sponsor agrees to conduct the Case Transmission verification to ensure that all single 
case reports have been adequately received by Genentech via the Medical College of 
Wisconsin emailing Genentech a Quarterly line-listing documenting single case reports 
sent by the Medical College of Wisconsin to Genentech in the preceding time period. The 
periodic line-listing will be exchanged within seven (7) calendar days of the end of the 
agreed time period. Confirmation of receipt should be received within the time period 
mutually agreed upon. 
 
If discrepancies are identified, the sponsor and investigator will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a case-
by-case basis until satisfactory resolution. The investigator and sponsor shall receive 
reconciliation guidance documents within the ‘Activation Package’. 
 
Following Case Transmission Verification, single case reports which have not been 
received by Genentech/Roche as well as Clovis shall be forwarded by The Medical College 
of Wisconsin to Genentech/Roche and/or Clovis within five (5) calendar days from request 
by Genentech/Roche or Clovis Oncology. 
 
At the end of the study, a final cumulative Case Transmission Verification report will be 
sent to Genentech/Roche and Clovis Oncology. 
AEs of Special Interest (AESIs) 
AEs of Special Interest are defined as a potential safety problem, identified as a result of 
safety monitoring of the product. 
 
SADRs (Drug-related SAEs) 
Serious AE reports that are related to the Product shall be transmitted to Genentech/ Roche 
and/or Clovis Oncology within one (1) calendar days of the awareness date. 
Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech / 
Roche and/or Clovis Oncology within one (1) calendar days of the awareness date. 
AESIs 
AESIs shall be forwarded to Genentech/ Roche and/or Clovis Oncology within one (1) 
calendar days of the awareness date. 
Pregnancy reports 
 
While such reports are not serious AEs or ADRs per se, as defined herein, any reports of 
pregnancy (including pregnancy occurring in the partner of a male study subject), where 
the fetus may have been exposed to the Product, shall be transmitted to Genentech/Roche 
and/or Clovis Oncology within two (2) calendar days of the awareness date. Pregnancies 
will be followed up until the outcome of the pregnancy is known, whenever possible, based 

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upon due diligence taken to obtain the follow-up information 
 
Special situation reports 
 
In addition to all AEs, pregnancy reports and AESIs, the following Special Situations 
Reports should be collected even in the absence of an Adverse Event and transmitted to 
Genentech/Roche and/or Clovis Oncology within thirty (30) calendar days: 
• Data related to the Product usage during pregnancy or breastfeeding 
• Data related to overdose, abuse, off-label use, misuse, inadvertent/erroneous 
administration, medication error (including potentially exposed in case of medication 
errors or intercepted medication errors) or occupational exposure, with or without 
association with an AE/SAE unless otherwise specified in the protocol 
• Lack of therapeutic efficacy 
• Drug Interaction: No specific interactions are suspected. 
• Use of a Medicinal Product in a Pediatric and Elderly population (in addition, 
reasonable attempts should be made to obtain and submit the age or age group of the 
patient, in order to be able to identify potential safety signals specific to a particular 
population) 
 
Occasionally Genentech and/or Clovis Oncology may contact the reporter for additional 
information, clarification, or current status of the patient for whom an adverse event was 
reported. 
 
MEDWATCH 3500A REPORTING GUIDELINES 
 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (section 5) of the MedWatch 3500A form: 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the adverse event to 
each investigational product and suspect medication 
 
Follow-Up Information 
 
Additional information may be added to a previously submitted report by any of the 
following methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form 
• summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B. initial, patient number), protocol description and number, if 
assigned, brief adverse event description, and notation that additional or follow-up 
information is being submitted (The patient identifiers are important so that the 

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new information is added to the correct initial report) 
 
 
MedWatch 
3500A 
(Mandatory 
Reporting) 
form 
is 
available 
at 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsFo 
rms/Forms/UCM048334.pdf 
 
Reporting to the Data and Safety Monitoring Committee 
The investigator will use email to report SAEs to the DSMC. The SAE report must include 
event term(s), serious criteria, and the sponsor-investigator’s or sub-investigator’s 
determination of both the intensity of the event(s) and the relationship of the event(s) to 
study drug administration. Intensity for each SAE, including any lab abnormalities, will be 
determined by using the NCI CTCAE as a guideline whenever possible. 
 
Reporting to MCW Committee Institutional Review Board 
The principal investigator must report events to the MCW IRB within five business days 
of his/her awareness of the event. 
[Guidance on Adverse Event Reporting to the IRB is available online at MCW IRB 
Policies and Procedures.] 
The Medical College of Wisconsin, as the Sponsor of the Study, will be responsible for the 
expedited reporting of safety reports originating from the Study to the Regulatory 
Authorities (FDA) where it has filed  a clinical trial approval, in compliance with local 
regulations 
Genentech and/or Clovis Oncology will be responsible for the expedited reporting of safety 
reports originating from the Study to the EMA through Eudravigilance Clinical Trial 
Module (EVCTM). 
 
The Medical College of Wisconsin will be responsible for the distribution of safety 
information to its own investigators, where relevant. 
 
Additional Reporting Requirements for Holders (if applicable): For Investigator-Initiated 
Studies, some additional reporting requirements for the FDA apply in accordance with the 
guidance set forth in 21 CFR 
§600.80. 
Events meeting the following criteria need to be submitted to the Food and Drug 
Administration (FDA) as expedited Safety Reports according to the following guidance 
and timelines: 
 
Seven Calendar Day Telephone or Fax Report: 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event 
that is unexpected and assessed by the Investigator to be possibly related to the use of 
Atezolizumab, rucaparib, and bevacizumab. An unexpected adverse event is one that is not 

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already described in the Atezolizumab and/or Bevacizumab and/or Rucaparib Investigator 
Brochure. Such reports are to be telephoned or faxed to the FDA and Genentech/Roche 
and/or Clovis Oncology within seven calendar days of first learning of the event. 
 
Fifteen Calendar Day Written Report 
The investigator is also required to notify the FDA and all participating investigators, in a 
written Safety Report, of any serious, unexpected AE that is considered reasonably or 
possibly related to the use of Atezolizumab, rucaparib, or bevacizumab. An unexpected 
adverse event is one that is not already described in the Atezolizumab, rucaparib, or 
bevacizumab Investigator Brochure. 
Written Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR 
§ 312.32. All safety reports previously filed by the investigator with the concerning similar 
events should be analyzed and the significance of the new report in light of the previous, 
similar reports commented on. 
Written safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech/Roche and/or Clovis Oncology, in addition to all participating investigators 
within 15 calendar days of first learning of the event. The FDA prefers these reports on a 
MedWatch 3500 form, but alternative formats are acceptable (e.g., summary letter). 
 
 
FDA fax number for Safety Reports: 
Fax: 1 (800) FDA 0178 
 
All written Safety Reports submitted to the FDA by the Investigator must 
also be faxed to Genentech/Roche Drug Safety: 
Fax: (650) 225-4682 or (650) 225-4630 
 
Clovis Drug Safety: 
Fax: +1.303.261.8319 
Email: DrugSafety@clovisoncology.com 
 
And to the Site IRB: 
The Medical College of Wisconsin Human Research 
Protection Program 8701 Watertown Plank Rd 
Milwaukee, WI 53226 
 
For questions related to safety reporting, please contact Genentech/Roche Drug 
Safety: 
 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
 

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Clovis Drug Safety: 
Email: DrugSafety@clovisoncology.com 
 
ANNUAL REPORTS 
Copies to Genentech/Roche: 
All annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech/Roche and Clovis Oncology. Copies of such reports should be faxed to 
Genentech/Roche Drug Safety: 
Fax: (650) 225-4682 or (650) 225-4630 
 
Clovis Drug Safety: 
Fax: +1.303.261.8319 
Email: DrugSafety@clovisoncology.com 
 
AGGREGATE REPORTS; Either Annual Report or DSUR 
ANNUAL REPORTS 
All annual reports submitted to the FDA by the Sponsor-Investigator 
should be copied to Genentech/Roche and Clovis Oncology. 
Copies of such reports should be emailed to Genentech 
Drug Safety at: Genentech Drug Safety CTV mail 
box:ctvist_drugsafety@gene.com 
And 
Clovis Drug Safety: 
Fax: +1.303.261.8319 
Email: DrugSafety@clovisoncology.com 
Note: Investigators should also report events to their IRB as required 
 
STUDY CLOSE-OUT 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech/Roche and Clovis Oncology. This includes all annual reports and the Clinical 
Study Report (final study report). 
Additionally, any literature articles that are a result of the study should be sent to 
Genentech/Roche and Clovis Oncology. Copies of such reports should be mailed to the 
assigned Clinical Operations contact for the study: 
Atezolizumab IIS Clinical Operations 
Email: anti-pdl-1-mpd3280a-gsur@gene.com 
And to Genentech Drug Safety CTV oversight mailbox at: ctvist_drugsafety@gene.com 
 
Clovis Drug Safety: 
Email: DrugSafety@clovisoncology.com 
 

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QUERIES 
Queries related to the Study will be answered by MCW. However, responses to all safety 
queries from regulatory authorities or for publications will be discussed and coordinated 
between the Parties. The Parties agree that Genentech/Roche and Clovis Oncology shall 
have the final say and control over safety queries relating to the Product. MCW agrees that 
it shall not answer such queries from regulatory authorities and other sources relating to 
the Product independently but shall redirect such queries to Genentech/Roche and Clovis 
Oncology. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent 
requests for information or review of data are met. The Parties will clearly indicate on the 
request the reason for urgency and the date by which a response is required. 
 
SAFETY CRISIS MANAGEMENT 
In case of a safety crisis, e.g., where safety issues have a potential impact on the 
indication(s), on the conduct of the Study, may lead to labeling changes or regulatory 
actions that limit or restrict the way in which the Product is used, or where there is media 
involvement, the Party where the crisis originates will contact the other Party as soon as 
possible. 
The Parties agree that Genentech/Roche and Clovis Oncology shall have the final say 
and control over safety crisis management issues relating to the Product. Medical College 
of Wisconsin agrees that it shall not answer such queries from media and other sources 
relating to the Product but shall redirect such queries to Genentech/Roche and Clovis 
Oncology. 
US Department of Health and Human Services, Food and Drug Administration, CDER, 
CBER. Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation 
2009 
[Available 
from: 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf.] 
National Cancer Institute. Common Terminology Criteria for Adverse Events, Version 
5.0[Available 
from: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_
Quick_Reference_8.5x 11.pdf