Clinical trial NCT02724878
Conditions: Advanced Non-Clear Cell Kidney Cancer
Keywords: Kidney Cancer
Sponsor: Dana-Farber Cancer Institute
Start date: 2016-07-15; Completion date: 2024-12-31
Enrollment: 65 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is studying the combination of Atezolizumab and Bevacizumab as a possible treatment for Advanced Non-Clear Cell Kidney Cancer.

Detailed description:
This research study is a Phase II clinical trial. In this research the investigators are studying the combination of Atezolizumab with Bevacizumab. Participants will receive both vascular endothelial targeted therapy and immunotherapy.

The FDA (the U.S. Food and Drug Administration) has not approved Atezolizumab for Advanced Non-Clear Cell Kidney Cancer, but it has been approved for other uses.

The FDA has approved Bevacizumab with Interferon (IFNα) as a treatment option for Advanced Kidney Cancer.

Arms: arm 1: 1200 mg of Atezolizumab intravenously x 3 weeks

15 mg/kg of Bevacizumab intravenously x 3 weeks.

One cycle will be 3 weeks in duration.
Interventions: intervention 1: Bevacizumab intervention 2: Atezolizumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Title: Phase II Study of Atezolizumab + Bevacizumab in Patients with Advanced Non-Clear 
Cell Renal Cell Carcinoma 
 
NCT Number: NCT02724878 
 
Protocol Version Date: 11/04/2019 


NCI Protocol #: N/A 
DF/HCC Protocol #: 15-592 
Protocol Version Date: November 4, 2019
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DF/HCC Protocol #: 15-592 
 
 
TITLE: Phase II Study of Atezolizumab + Bevacizumab in Patients with Advanced Non-Clear 
Cell Renal Cell Carcinoma 
 
 
Coordinating Center: 
Dana-Farber Cancer Institute 
 
 
Principal Investigator: 
 
 
 
 
 
Other Investigators: 
 
 
 
 
 
 
 
 
 
 
 
 
Statistician: 
 
 
 
 
 
Responsible Research Nurse: 
 
 
 
 
 
 
Study Drugs: 
Bevacizumab (Avastin®), Supplied by Genentech, Inc. 
Atezolizumab (MPDL3280A), Supplied by Genentech, Inc. 
 
 
IND #: 
129117 
IND Sponsor: 
 
Dana Farber
IRB NUMBER: 15-592
IRB APPROVAL DATE: 04/17/2020


NCI Protocol #: N/A 
DF/HCC Protocol #: 15-592 
Protocol Version Date: November 4, 2019
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SCHEMA 
 
 
 
 
 
After progression/treatment discontinuation, participation will be followed for survival and 
receipt of next line therapies every 6 months until death or 2 years after treatment 
discontinuation. 
 
*Post-Treatment Tumor Biopsy is only required for a subset of patients who have a tumor 
response and subsequently progress. 
Metastatic 
RCC 
-Non-Clear 
Cell 
-Any Line 
of Therapy 
Pre-Treatment 
Tumor Biopsy 
(Mandatory) 
Atezolizumab 
+ 
Bevacizumab 
Radiographic 
Progression 
Post- 
Treatment 
Tumor 
Biopsy* 
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NCI Protocol #: N/A 
DF/HCC Protocol #: 15-592 
Protocol Version Date: November 4, 2019
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TABLE OF CONTENTS 
 
1. 
OBJECTIVES ......................................................................................................................... 5 
1.1 
Study Design ............................................................................................................................... 5 
1.2 
Primary Objectives ...................................................................................................................... 5 
1.3 
Secondary Objectives .................................................................................................................. 5 
1.4 
Exploratory Objectives ................................................................................................................ 6 
2. 
BACKGROUND .................................................................................................................... 7 
2.1 
Renal Cell Carcinoma .................................................................................................................. 7 
2.2 
Bevacizumab ............................................................................................................................... 7 
2.3 
Atezolizumab (MPDL3280A) ................................................................................................... 13 
2.4 
Rationale .................................................................................................................................... 15 
2.5 
Correlative Studies Background ................................................................................................ 18 
3. 
PARTICIPANT SELECTION .............................................................................................. 20 
3.1 
Eligibility Criteria ...................................................................................................................... 20 
3.2 
Exclusion Criteria ...................................................................................................................... 21 
3.3 
Inclusion of Women and Minorities .......................................................................................... 23 
4. 
REGISTRATION PROCEDURES ...................................................................................... 24 
4.1 
General Guidelines for Dana-Farber/Harvard Cancer Center (DF/HCC) and Dana- 
Farber/Partners Cancer Care (DF/PCC) Institutions .............................................................................. 24 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions ..................................................... 24 
4.3 
General Guidelines for Other Investigative Sites ...................................................................... 25 
4.4 
Registration Process for Other Investigative Sites .................................................................... 25 
5. 
TREATMENT PLAN ........................................................................................................... 25 
5.1 
Treatment Regimen ................................................................................................................... 25 
5.2 
Pre-Treatment Criteria ............................................................................................................... 26 
5.3 
Atezolizumab ............................................................................................................................. 27 
5.4 
Bevacizumab ............................................................................................................................. 28 
5.5 
General Concomitant Medication and Supportive Care Guidelines .......................................... 29 
5.6 
Criteria for Taking a Participant off Protocol Therapy .............................................................. 31 
5.7 
Duration of Follow Up .............................................................................................................. 32 
5.8 
Criteria for Taking a Participant off Study ................................................................................ 32 
5.9 
Replacement .............................................................................................................................. 33 
5.10 
Study and Site Discontinuation ................................................................................................. 33 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ................................................................... 34 
6.1 
Atezolizumab Dose Modifications ............................................................................................ 34 
6.2 
Bevacizumab Dose Modifications ............................................................................................. 42 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................... 48 
7.1 
Adverse Events .......................................................................................................................... 48 
7.2 
Serious Adverse Event ............................................................................................................... 48 
7.3 
Methods and Timing for Assessing and Recording Safety Variables........................................ 49 
7.4 
Procedures for Eliciting, Recording, and Reporting Adverse Events ........................................ 49 
7.5 
Expedited Adverse Event Reporting ......................................................................................... 55 
7.6 
Expedited Reporting to the FDA ............................................................................................... 56 
7.7 
Expedited Reporting to Hospital Risk Management ................................................................. 56 
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DF/HCC Protocol #: 15-592 
Protocol Version Date: November 4, 2019
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7.8 
Routine Adverse Event Reporting ............................................................................................. 56 
8. 
PHARMACEUTICAL INFORMATION ............................................................................. 57 
8.1 
Atezolizumab ............................................................................................................................. 57 
8.2 
Bevacizumab ............................................................................................................................. 58 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................... 60 
9.1 
Blood Studies ............................................................................................................................. 60 
9.2 
Tissue Studies ............................................................................................................................ 60 
9.3 
Radiology Imaging Studies........................................................................................................ 61 
10. 
STUDY CALENDAR ...................................................................................................... 62 
11. 
MEASUREMENT OF EFFECT ....................................................................................... 64 
11.1 
Antitumor Effect – Solid Tumors .............................................................................................. 64 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS .......................................... 72 
12.1 
Data Reporting ........................................................................................................................... 72 
12.2 
Data Safety Monitoring ............................................................................................................. 72 
12.3 
Multicenter Guidelines .............................................................................................................. 72 
13. 
STATISTICAL CONSIDERATIONS .............................................................................. 73 
13.1 
Study Design/Endpoints ............................................................................................................ 73 
13.2 
Sample Size, Accrual Rate and Study Duration ........................................................................ 74 
13.3 
Definition of Study Population /Stratification Factors .............................................................. 75 
13.4 
Analysis of Demographics/Baseline Characteristics ................................................................. 75 
13.5 
Efficacy Analysis ....................................................................................................................... 75 
13.6 
Exploratory/Correlative Analysis .............................................................................................. 77 
13.7 
Safety Monitoring ...................................................................................................................... 78 
14. 
ETHICAL CONSIDERATIONS ...................................................................................... 80 
14.1 
Compliance with Laws and Regulations ................................................................................... 80 
14.2 
Informed Consent ...................................................................................................................... 80 
14.3 
Institutional Review Board or Ethics Committee Approval ...................................................... 80 
14.4 
Confidentiality ........................................................................................................................... 80 
14.5 
Study Medical Monitoring Requirements ................................................................................. 81 
14.6 
Study Medication Accountability .............................................................................................. 81 
14.7 
Data Collection .......................................................................................................................... 81 
14.8 
Retention of Records ................................................................................................................. 82 
15. 
PUBLICATION PLAN .................................................................................................... 83 
16. 
REFERENCES ................................................................................................................. 84 
17. 
APPENDIX A: PERFORMANCE STATUS CRITERIA ................................................ 86 
18. 
APPENDIX B: REQUIRED FORMS FOR REGISTRATION ....................................... 87 
19. 
APPENDIX C: MULTICENTER MONTIORING PLAN............................................... 88 
20. 
APPENDIX D: FKSI-19 ................................................................................................. 102 
21. 
APPENDIX E: BRIEF FATIGUE INVENTORY ......................................................... 104 
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1. OBJECTIVES 
 
1.1 Study Design 
This is an open, single-arm, phase II multi-center study designed to investigate the efficacy and 
safety of bevacizumab and atezolizumab in patients with advanced non-clear cell renal cell 
carcinoma (nccRCC). Eligible patients will be enrolled and will be treated with bevacizumab 15 
mg/kg intravenously (IV) every 3 weeks and atezolizumab 1200 mg IV every 3 weeks. Patients 
will be required to undergo a mandatory baseline fresh tumor biopsy if deemed medically 
feasible and safe. Patients will remain on therapy until radiographic progression, unacceptable 
adverse events, or other reason. Each cycle will be 3 weeks in duration. Patients who experience 
relapse after an initial response will be required to undergo a fresh tumor biopsy if medically 
safe. Patients will be evaluated clinically every 3 weeks and will undergo disease assessments 
with imaging every 6 weeks. Expected enrollment is 60 patients with an accrual rate of 3 patients 
per month. 
 
 
1.2 Primary Objectives 
 
To assess the overall response rate (ORR) by Response Evaluation Criteria In Solid Tumors 
(RECIST) version 1.1 in patients with advanced nccRCC treated with bevacizumab and 
atezolizumab. 
 
1.3 Secondary Objectives 
• To assess duration of ORR in patients with advanced nccRCC treated with 
bevacizumab and atezolizumab 
• To estimate the ORR according to histology subtypes 
• To assess the safety in patients with advanced nccRCC treated with bevacizumab and 
atezolizumab. 
• To assess the immune-related ORR in patients with advanced nccRCC treated with 
bevacizumab and atezolizumab by immune-related response criteria (irRC). 
• To assess progression-free survival (PFS) in patients with advanced nccRCC treated 
with bevacizumab and atezolizumab. 
• To assess overall survival (OS) in patients with advanced nccRCC treated with 
bevacizumab and atezolizumab. 
• To summarize ORR, PFS, and OS in patients with advanced nccRCC treated with 
bevacizumab and atezolizumab according to subgroups: 
o International mRCC Database Consortium (IMDC) risk groups. 
o Untreated versus previously treated patients. 
o According to histologic subtype (papillary vs. other nccRCC subtypes; 
sarcomatoid components present vs. absent) 
• To evaluate the effect of therapy on quality of life as assessed by the Functional 
Assessment of Cancer Therapy-Kidney Symptom Index (FKSI)-19 and the Brief 
Fatigue Inventory (BFI) 
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1.4 Exploratory Objectives 
• To assess the immunomodulatory properties of atezolizumab in combination with 
bevacizumab via assessment of archival and/or fresh tumor tissue and blood and 
correlate with ORR, PFS, and OS 
• To evaluate the relationship between programmed death-ligand 1 (PD-L1) tumor 
expression (and other prognostic and predictive tissue biomarkers) and efficacy 
outcomes (ORR, PFS, OS) 
• To evaluate the relationship between PD-L1 status in archival tissue and in fresh tumor 
specimens 
• To evaluate mechanisms of acquired resistance to atezolizumab in combination with 
bevacizumab in fresh tumor specimens obtained at time of radiographic progression 
• To assess molecular mechanisms of resistance to treatment via cfDNA assessment and to 
correlate cfDNA molecular profile with metastasis biopsy molecular profile. 
• Assess mechanisms of response and resistance to treatment via single cell molecular 
assessment (exome, genome, and transcriptome assessment) 
• Correlate single cell molecular profile with metastasis biopsy molecular profile 
 
 
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2. BACKGROUND 
 
2.1 Renal Cell Carcinoma 
RCC is the most common cancer of the kidney (>85%) and represents a heterogeneous disease 
divided generally into two major groups: clear-cell RCC (ccRCC), which comprises 
approximately 80% of renal epithelial tumors, and nccRCC, which encompasses the remaining 
percentage of tumors. Non-clear cell RCC includes different histologic and genetic subtypes to 
include: papillary, chromophobe, collecting duct, unclassified, translocation, and medullary 
carcinoma. Papillary and chromophobe histologies account for 80% of all nccRCC. 
 
Although many advances have been made in the treatment of metastatic RCC, the majority of 
studies to date have been limited to patients with a component of clear-cell disease. Three 
randomized clinical trials included patients with nccRCC. The Global ARCC trial phase III trial 
randomized 626 patients with previously untreated poor-risk metastatic RCC, including 73 
patients with nccRCC, to receive temsirolimus versus interferon-α (IFNα) or the combination. 
Post hoc subgroup analysis of this study suggested that mTOR inhibition could be a valid option 
in nccRCC (PFS 7.0 versus 1.8 months, hazard ratio (HR) 0.38, 95% confidence interval (CI) 
0.29-0.85; PS 11.6 versus 4.3 months, HR 0.49, 95% CI 0.29-0.85).1  RECORD-3, a phase II 
study evaluating sequential therapy with sunitinib followed by everolimus or vice versa included 
66 patients with nccRCC. Furthermore, the INTORSECT trial evaluating temsirolimus versus 
soarfenib included 90 patients with nccRCC. In a single arm phase II study, sunitinib was 
examined as a treatment for patients with non-clear cell histology.2 The ORR was 5% and the 
median PFS was 2.7 months. 
 
Though the general approach to treatment of nccRCC mirrors that of ccRCC, studies have 
indicated that the standard treatments for patients with clear cell histology are not as effective in 
patients with non-ccRCC.3 A recently published study investigated the nccRCC population in the 
IMDC. This large report assessed the first-, second, and third-line PFS in nccRCC in comparison 
with ccRCC and revealed a dismal prognosis in this population with an OS of 12.8 months 
compared to 22.8 months. 
 
Due to the poor prognosis of these heterogeneous populations, there is an urgent need for better 
treatment paradigms to improve outcomes for these patients. 
 
2.2 Bevacizumab 
 
2.2.1 Clinical Activity in RCC 
Bevacizumab is a monoclonal antibody that binds circulating (vascular endothelial growth 
factor) VEGF and prevents its interaction with the VEGF receptor. Bevacizumab has been 
studied in a multitude of Phase I, II, and III clinical trials in more than 22,000 patients and in 
multiple tumor types. Approximately 1,720, 000 patients have been exposed to bevacizumab as a 
marketed product or in clinical trials. Please refer to the bevacizumab Investigator Brochure for 
descriptions of all completed Phase I, II, and III trials reported to date. 
 
For patients with metastatic clear cell RCC, two phase III trials have demonstrated improved 
PFS with bevacizumab plus IFNα compared with IFNα alone. In the AVOREN trial, 649 
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previously untreated patients were randomly assigned to IFNα (9 million units three times per 
week for one year) plus either bevacizumab (10 mg/kg IV every two weeks) or placebo4-6. 
Bevacizumab (or placebo) was continued until there was evidence of progressive disease. IFNα 
plus bevacizumab resulted in the following compared with IFNα plus placebo: 1) an increase in 
PFS (median 10.2 versus 5.5 months HR 0.63, 95% confidence interval (CI) 0.45-0.72), 2) a 
significantly higher ORR (31 versus 13%), and 3) a trend toward improved OS (median survival 
23.3 versus 21.3 months, HR 0.86, 95% CI 0.72-1.04). Approximately 60% of patients received 
second-line therapy, potentially obscuring a survival difference between the two treatment arms. 
There were more common serious adverse events (SAEs) in patients treatment with bevacizumab 
(29 versus 16%). Grade 3 or 4 adverse events that were more common in patients treated with 
bevacizumab included thromboembolic events (3 versus 1%) and gastrointestinal (GI) 
perforation (1 versus 0%). 
 
In the Cancer and Leukemia Group B (CALBG) 90206 trial, 732 previously untreated patients 
with metastatic RCC were randomly assigned to IFNα plus bevacizumab (10 mg/kg IV every 2 
weeks) or IFNα plus placebo on schedules similar to that used in the AVOREN trial.7 Treatment 
with bevacizumab plus IFNα resulted in: 1) an improvement in PFS (median 8.5 versus 5.2 
months; HR 0.71, 0.61-0.83) and a significant improvement in the ORR (25.5 versus 13.1%). 
There was a trend toward improved OS favoring the use of combination therapy (median 18.3 
versus 17.4 months, HR 0.86, p = 0.07).8 However, this analysis was complicated by the fact that 
more than one-half of patients on both arms received second-line therapy, including VEGF- 
targeted therapy in 46% of those originally treated with IFNα alone. 
 
There is data to support the use of bevacizumab in patients with metastatic nccRCC. A phase II 
study evaluated the efficacy of bevacizumab (15 mg/kg IV every 3 weeks) alone in patient with 
advanced papillary RCC.9 Five patients were accrued to the study before the protocol was closed 
due to slow accrual. Three patients had undergone a prior nephrectomy, one patient underwent 
resection of a liver metastasis, and one patient had received prior temsirolimus. The PFS for 
these patients was 25, 15, 11, 10 and 6 months. 
 
These results supported the Food and Drug Administration (FDA) approval of bevacizumab with 
IFNα in metastatic RCC in July 2009. 
 
2.2.2 Safety Profile 
Hypertension: An increased incidence of hypertension (all grades) of up to 42.1% has been 
observed in patients treated with bevacizumab compared to up to 14% in the comparator arm. In 
clinical trials across all indications the overall incidence of National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 3 and 4 hypertension in patients 
receiving bevacizumab ranged from 0.4% to 17.9%. Grade 4 hypertension (hypertensive crisis) 
occurred in up to 1.0% of bevacizumab-treated patients, compared to up to 0.2% of patients 
treated with the same chemotherapy alone. Very rare cases of hypertensive encephalopathy have 
been reported, some of which were fatal. The risk of bevacizumab-associated hypertension did 
not correlate with the patients’ baseline characteristics, underlying disease or concomitant 
therapy. Analyses of the clinical safety data suggest that the occurrence of hypertension with 
bevacizumab therapy is likely to be dose-dependent. 
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Proteinuria: In clinical trials, proteinuria has been reported within the range of 0.7% to 38% of 
patients receiving bevacizumab. Proteinuria ranged in severity from clinically asymptomatic, 
transient, trace proteinuria to nephrotic syndrome. Grade 3 proteinuria was reported in up to 
8.1% of treated patients. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of 
treated patients. The proteinuria seen in bevacizumab clinical trials was not associated with renal 
impairment and rarely required permanent discontinuation of bevacizumab therapy. 
Analyses of the clinical safety data suggest that the occurrence of proteinuria with bevacizumab 
therapy is likely to be dose-dependent. Patients with a history of hypertension may be at 
increased risk for the development of proteinuria when treated with bevacizumab. There is 
evidence suggesting that Grade 1 proteinuria may be related to bevacizumab dose. 
 
Venous thromboembolism (VTE, including deep venous thrombosis, pulmonary embolism, 
and thrombophlebitis): Patients may be at risk of developing VTEs, including pulmonary 
embolism under bevacizumab treatment. In clinical trials across all indications the overall 
incidence of VTE events was 2.8%-17.3% in the bevacizumab-containing arms compared with 
3.2%-15.6% in the chemotherapy control arms. Grade 3-5 VTEs have been reported in up to 
7.8% of patients treated with chemotherapy plus bevacizumab compared with up to 4.9% in 
patients with chemotherapy alone. Patients who have experienced a VTE may be at higher risk 
for a recurrence if they receive bevacizumab in combination with chemotherapy versus 
chemotherapy alone. 
 
From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study 
GOG-0240), grade 3-5 VTEs have been reported in up to 10.6% of patients treated with 
chemotherapy and bevacizumab compared with up to 5.4% in patients with chemotherapy alone. 
In clinical trial BO21990, Grade 3-5 VTEs were observed in 7.6% of patients with newly 
diagnosed glioblastoma treated with bevacizumab in combination with chemotherapy and 
radiotherapy, compared to 8.0 % of patients treated with chemotherapy and radiotherapy alone. 
 
Arterial Thromboembolism (ATE): An increased incidence of ATE events was observed in 
patients treated with bevacizumab across indications including cerebrovascular accidents, 
myocardial infarction, transient ischemic attacks, and other ATEs. In clinical trials, the overall 
incidence ranged up to 5.9% in the bevacizumab- containing arms compared up to 1.7% in the 
chemotherapy control arms. Fatal outcome was reported in 0.8% of patients receiving 
bevacizumab in combination with chemotherapy compared to 0.5% of patients receiving 
chemotherapy alone. Cerebrovascular accidents (including transient ischemic attacks) were 
reported in up to 2.3% of bevacizumab treated patients versus 0.5% of patients in the control 
group. Myocardial infarction was reported in 1.4% of bevacizumab treated versus 0.7% of 
patients in the observed control group. 
 
In one clinical trial, AVF2192g, patients with metastatic colorectal cancer who were not 
candidates for treatment with irinotecan were included. In this trial ATEs were observed in 11% 
(11/100) of bevacizumab patients compared to 5.8% (6/104) in the chemotherapy control group. 
In an uncontrolled clinical trial, AVF3708g, in patients with relapsed glioblastoma, ATEs were 
observed in 6.3% (5/79) of patients who received bevacizumab in combination with irinotecan 
compared to 4.8% (4/84) of patients who received bevacizumab alone. 
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Patients receiving bevacizumab plus chemotherapy with a history of ATE, diabetes or age 
greater than 65 years have an increased risk of developing ATEs during bevacizumab therapy. 
Aspirin is a standard therapy for primary and secondary prophylaxis of ATEs in patients at high 
risk of such events, and the use of aspirin ≤ 325 mg daily was allowed in the five randomized 
studies discussed above. Use of aspirin was assessed routinely as a baseline or concomitant 
medication in these trials, though safety analyses specifically regarding aspirin use were not 
preplanned. Due to the relatively small numbers of aspirin users and ATEs, retrospective 
analyses of the ability of aspirin to affect the risk of such events were inconclusive. However, 
similarly retrospective analyses suggested that the use of up to 325 mg of aspirin daily does not 
increase the risk of grade 1-2 or grade 3-4 bleeding events. 
 
Gastrointestinal perforation: Bevacizumab has been associated with serious cases of GI 
perforation. GI perforations have been reported in clinical trials with an incidence of <1% in 
patients with metastatic breast cancer or non-squamous NSCLC, up to 2% in metastatic RCC, 
newly diagnosed glioblastoma, or in patients with ovarian cancer receiving front-line treatment, 
and up to 2.7% (including GI fistula and abscess) in patients with metastatic colorectal cancer. 
Cases of GI perforations have also been observed in patients with relapsed glioblastoma. Fatal 
outcome was reported in approximately a third of serious cases of GI perforations, which 
represents between 0.2-1.0% of all bevacizumab treated patients. 
 
In bevacizumab clinical trials, GI fistulae (all grade) have been reported with an incidence of up 
to 2% in patients with metastatic colorectal cancer and ovarian cancer, but were also reported 
less commonly in patients with other types of cancer. From a clinical trial in patients with 
persistent, recurrent, or metastatic cervical cancer (study GOG-0240), GI perforations, including 
GI fistulae and abscess (all grade) were reported in 10.1% of bevacizumab treated patients, all of 
whom had a history of prior pelvic radiation. Fatal outcome was reported in 0.9% of 
bevacizumab -treated patients. Most patients reported as having GI perforations in this study (15 
out of 22) had GI-vaginal fistulae. The presentation of these events varied in type and severity, 
ranging from free air seen on the plain abdominal X-ray, which resolved without treatment, to 
intestinal perforation with abdominal abscess and fatal outcome. In some cases underlying intra- 
abdominal inflammation was present, either from gastric ulcer disease, tumor necrosis, 
diverticulitis or chemotherapy-associated colitis. A causal association of intra-abdominal 
inflammatory process and GI perforation to bevacizumab has not been established. Patients may 
be at increased risk for the development of GI perforation and gallbladder perforation when 
treated with bevacizumab. 
 
Fistula: Bevacizumab use has been associated with serious cases of fistulae including events 
resulting in death. From a clinical trial in patients with persistent, recurrent, or metastatic 
cervical cancer (study GOG-0240), 4.1% of bevacizumab-treated patients and 2.3% of control 
patients were reported to have had vaginal, vesical or female genital tract fistulae (all grade), 
some of which were GI vaginal fistulae. The overall rate of GI-vaginal fistulae (all grade), 
combining both those reported as GI perforations and those reported as fistulae and abscess (as 
stated above) was 8.2% in bevacizumab-treated patients and 0.9% in control patients. 
Uncommon (≥0.1% to <1%) reports of other types of fistulae that involve areas of the body other 
than the GI tract (e.g., bronchopleural, urogenital, biliary fistulae) were observed across various 
indications.  Fistulae have also been reported in post-marketing experience. Events were reported 
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at various time points during treatment ranging from one week to greater than 1 year from 
initiation of bevacizumab, with most events occurring within the first 6 months of therapy. 
 
Wound healing complications: Bevacizumab may adversely affect the wound healing process. 
Serious wound healing complications with a fatal outcome have been reported. Necrotizing 
fasciitis including fatal cases, has rarely been reported in patients treated with bevacizumab; 
usually secondary to wound healing complications, GI perforation or fistula formation. 
 
As bevacizumab may adversely impact wound healing, patients who had major surgery within 
the last 28 days prior to starting bevacizumab treatment were excluded from participation in 
Phase III trials. Across metastatic colorectal cancer clinical trials there was no increased risk of 
post-operative bleeding or wound healing complications observed in patients who underwent 
major surgery between 28-60 days prior to starting bevacizumab therapy. An increased incidence 
of post-operative bleeding or wound healing complications occurring within 60 days of major 
surgery was observed if the patient was being treated with bevacizumab at the time of surgery. 
The incidence varied between 10% (4/40) and 20% (3/15). 
 
In locally recurrent and metastatic breast and ovarian cancer trials, Grade 3-5 wound healing 
complications were observed in up to 1.1% of patients receiving bevacizumab compared with up 
to 0.9 % of patients in the control arms. In the study of patients with relapsed glioblastoma 
(study AVF3708g), the incidence of post-operative wound healing complications (craniotomy 
site wound dehiscence and cerebrospinal fluid leak) was 3.6% in patients treated with single- 
agent bevacizumab and 1.3% in patients treated with bevacizumab plus irinotecan. In patients 
with newly diagnosed glioblastoma (study BO21990) the incidence of Grade 3-5 post-operative 
wound healing complications (including complications following craniotomy) was 3.3% when 
treated with bevacizumab in combination with chemotherapy and radiotherapy, compared with 
1.6 % when treated with chemotherapy and radiotherapy alone. 
 
Hemorrhage: In clinical trials across all indications the overall incidence of NCI-CTC Grade 3- 
5 bleeding events ranged from 0.4% to 6.9% in bevacizumab-treated patients, compared to 0 to 
4.5% of patients in the chemotherapy control group. The hemorrhagic events that have been 
observed in bevacizumab clinical studies were predominantly tumor- associated hemorrhage (see 
below) and minor mucocutaneous hemorrhage (e.g. epistaxis). 
 
Tumor-Associated Hemorrhage: Major or massive pulmonary hemorrhage or hemoptysis has 
been observed primarily in patients with NSCLC. Possible risk factors include squamous cell 
histology, treatment with anti-rheumatic/anti-inflammatory drugs, treatment with anticoagulants, 
prior radiotherapy, bevacizumab therapy, previous medical history of atherosclerosis, central 
tumor location and cavitation of tumors prior to or during therapy. The only variables that 
showed statistically significant correlations with bleeding were bevacizumab therapy and 
squamous cell histology. Patients with NSCLC of known squamous cell histology or mixed cell 
type with predominant squamous cell histology were excluded from subsequent studies, while 
patients with unknown tumor histology were included. 
 
In patients with NSCLC excluding predominant squamous histology, all Grade events were seen 
with a frequency of up to 9% when treated with bevacizumab plus chemotherapy compared with 
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5% in the patients treated with chemotherapy alone. Grade 3-5 events have been observed in up 
to 2.3% of patients treated with bevacizumab plus chemotherapy as compared with <1% with 
chemotherapy alone. Major or massive pulmonary hemorrhage/hemoptysis can occur suddenly 
and up to two thirds of the serious pulmonary hemorrhages resulted in a fatal outcome. 
 
Mucocutaneus Hemorrage: Across all bevacizumab clinical trials, mucocutaneous hemorrhage 
has been seen in 50% of patients treated with bevacizumab. These were most commonly NCI- 
CTC Grade 1 epistaxis that lasted less than 5 minutes, resolved without medical intervention and 
did not require any changes in bevacizumab treatment regimen. Clinical safety data suggest that 
the incidence of minor mucocutaneous hemorrhage (e.g. epistaxis) may be dose-dependent. 
There have also been less common events of minor mucocutaneous hemorrhage in other 
locations, such as gingival bleeding and vaginal bleeding. 
 
Posterior Reversible Encephalopathy Syndrome (PRES): PRES is a rare neurologic disorder 
that can present with the following signs and symptoms (among others): seizures, headache, 
altered mental status, visual disturbance, or cortical blindness, with or without associated 
hypertension. Brain imaging is mandatory to confirm the diagnosis of PRES. Two confirmed 
cases (0.8%) of PRES have been reported in one clinical study. Symptoms usually resolve or 
improve within days, although some patients have experienced neurologic sequelae. 
 
Congestive heart failure (CHF): In clinical trials, CHF was observed in all cancer indications 
studied to date, but predominantly in patients with metastatic breast cancer. In five Phase III 
studies (AVF2119g, E2100, BO17708, AVF3694g and AVF3693g) in patients with metastatic 
breast cancer, Grade ≥ 3 CHF was reported in up to 3.5% of patients treated with bevacizumab in 
combination with chemotherapy compared with up to 0.9% in the control arms. For patients in 
study AVF3694g who received anthracyclines concomitantly with bevacizumab, the incidences 
of Grade ≥ 3 CHF for the respective bevacizumab and control arms were similar to those in the 
other studies in metastatic breast cancer: 2.9% in the anthracycline + bevacizumab arm and 0% 
in the anthracycline + placebo arm. In addition, in study AVF3694g the incidence of any grade 
CHF was similar between the anthracycline + bevacizumab (6.2%) and the anthracycline + 
placebo arms (6.0%). Most patients who developed CHF during metastatic breast cancer trials 
showed improved symptoms and/or left ventricular function following appropriate medical 
therapy. 
 
In most clinical trials of bevacizumab, patients with pre-existing CHF of New York Heart 
Association (NYHA) II – IV were excluded, therefore, no information is available on the risk of 
CHF in this population. Prior anthracyclines exposure and/or prior radiotherapy to the chest wall 
may be possible risk factors for the development of CHF. 
 
An increased incidence of CHF has been observed in a clinical trial of patients with diffuse large 
B-cell lymphoma (BO20603) when receiving bevacizumab with a cumulative doxorubicin dose 
greater than 300 mg/m2. This phase III clinical trial compared 
rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) plus bevacizumab to 
R-CHOP without bevacizumab. While the incidence of CHF in both arms was above that 
previously observed for doxorubicin therapy the rate was higher in the R-CHOP plus 
bevacizumab arm. 
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Events consistent with CHF were reported in clinical trials. The findings ranged from 
asymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiring 
treatment or hospitalization. 
 
Ovarian Failure/Fertility: The incidence of new cases of ovarian failure, defined as 
amenorrhoea lasting 3 or more months, follicle stimulating hormone (FSH) level ≥ 30mIU/ml 
and a negative serum β-HCG pregnancy test, has been evaluated. New cases of ovarian failure 
were reported more frequently in patients receiving bevacizumab. After discontinuation of 
bevacizumab treatment, ovarian function recovered in the majority of women. Long term effects 
of treatment with bevacizumab on fertility are unknown. 
 
Neutropenia: Increased rates of severe neutropenia, febrile neutropenia, or infection with severe 
neutropenia (including some fatalities) have been observed in patients treated with some 
myelotoxic chemotherapy regimens plus bevacizumab in comparison to chemotherapy alone. 
 
Hypersensitivity reactions, infusion reactions: Patients may be at risk of developing infusion/ 
hypersensitivity reactions. In some clinical trials anaphylactic and anaphylactoid-type reactions 
were reported more frequently in patients receiving bevacizumab in combination with 
chemotherapies than with chemotherapy alone. The incidence of these reactions in some clinical 
trials of bevacizumab is common (up to 5% in bevacizumab-treated patients). 
 
Laboratory Abnormalities: Decreased absolute neutrophil count (ANC), decreased white blood 
count (WBC) and presence of urine protein may be associated with bevacizumab treatment. 
Across clinical trials, the following Grade 3 and 4 laboratory abnormalities were seen with an 
increased (≥2%) incidence in patients treated with bevacizumab compared to those in the control 
groups: hyperglycemia, decreased hemoglobin, hypokalemia, hyponatremia, decreased white 
blood cell count, increased prothrombin time (PT), normalized ratio. 
 
Additional Adverse Events: See the bevacizumab drug package insert for additional details 
regarding the safety experience with bevacizumab. 
 
2.3 Atezolizumab (MPDL3280A) 
Atezolizumab is a human immunoglobulin (Ig) G1 monoclonal antibody consisting of two heavy 
chains (448 amino acids) and two light chains (214 amino acids) and is produced in Chinese 
hamster ovary cells. Atezolizumab was engineered to eliminate Fc-effector function via a single 
amino acid substitution (asparagine to alanine) at position 298 on the heavy chain, which results 
in a non-glycosylated antibody that has minimal binding to Fc receptors and prevents Fc-effector 
function at expected concentrations in humans. Atezolizumab targets human PD-L1 and inhibits 
its interaction with its receptor, programmed death-1 (PD-1). Atezolizumab also blocks the 
binding of PD-L1 to B7.1, an interaction that is reported to provide additional inhibitory signals 
to T cells. Atezolizumab is being investigated as a potential therapy against solid tumors and 
hematologic malignancies in humans. 
 
2.3.1 
Summary of Non-Clinical Experience 
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and in vivo 
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activity, to determine in vivo pharmacokinetic (PK) behavior, to demonstrate an acceptable 
safety profile, and to identify a Phase I starting dose. Comprehensive pharmacology, PK, and 
toxicology evaluations were thus undertaken with atezolizumab. 
 
The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in mice and 
cynomolgus monkeys to support IV administration and to aid in projecting the appropriate 
starting dose in humans. Given the similar binding of atezolizumab for cynomolgus monkey and 
human PD-L1, the cynomolgus monkey was selected as the primary and relevant nonclinical 
model for understanding the safety, pharmacokinetics, and toxicokinetics of atezolizumab. 
 
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for atezolizumab 
supported entry into clinical studies, including providing adequate safety factors for the proposed 
Phase I starting doses.  The results of the toxicology program were consistent with the 
anticipated pharmacologic activity of down-modulating the PD-L1/PD-1 pathway and supported 
entry into clinical trials in patients. Refer to the atezolizumab Investigator’s Brochure for details 
on the nonclinical studies. 
 
2.3.2 
Clinical Experience in RCC and Clinical Activity 
Ongoing Phase II Study WO29074 is evaluating the safety and efficacy of atezolizumab 
monotherapy or the combination of atezolizumab and bevacizumab versus sunitinib in treatment- 
naïve patients with RCC.  Safety and efficacy data are not yet available for this study. 
 
As of the data cutoff of 1 January 2014, efficacy analyses were performed on 386 efficacy 
evaluable patients who were defined as those patients, with measurable disease at baseline, 
treated by 1 July 2013 in Study PCD4989g (to ensure that each patient had a minimum of 6 
months follow-up). Patients with multiple tumor types were included in the study, with the 
largest cohorts consisting of patients with non-small cell lung cancer (NSCLC), RCC, and 
bladder cancer. Objective responses with atezolizumab monotherapy were observed in a broad 
range of malignancies, including NSCLC, RCC, melanoma, bladder cancer, colorectal cancer, 
head and neck cancer, gastric cancer, breast cancer and sarcoma. Altogether, there were 47 
patients with responses with a median duration of response of 75.7 weeks (range: 11.7+ to 85.9+ 
weeks, where “+” denotes censored value). The majority of these responses have been durable, 
with 72.3% (34/47) of responses ongoing as of the clinical cutoff date. 
 
Analyses of tumor-infiltrating immune cells for PD-L1 expression on baseline tumor tissue have 
been performed for Study PCD4989g. Preliminary results from Study PCD4989g suggest that 
PD-L1 expression in tumor infiltrating immune cells is likely to be associated with response to 
atezolizumab. 
 
2.3.3 
Clinical Pharmacokinetics and Immunogenicity 
The fixed dose of 1200 mg (equivalent to an average body weight-based dose of 15 mg/kg) was 
selected on the basis of both nonclinical studies and available clinical data. On the basis of 
available preliminary PK data (0.03-20 mg/kg), atezolizumab appeared to show linear 
pharmacokinetics at doses ≥1 mg/kg. For the 1-mg/kg and 20-mg/kg dose groups, the mean 
clearance (CL) and the mean volume at steady state (Vss) had a range of 3.20-4.43 mL/kg and 
48.1-64.1 mL/kg, respectively, which is consistent with the expected profile of an IgG1 antibody 
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in humans. 
 
The development of anti-therapeutic antibodies (ATAs) has been observed in patients in all dose 
cohorts and was associated with changes in pharmacokinetics for some patients in the lower dose 
cohorts (0.3, 1, and 3 mg/kg). The development of detectable ATAs has not had a significant 
impact on pharmacokinetics for doses from 10-20 mg/kg. Patients dosed at the 10-, 15-, and 20- 
mg/kg dose levels have maintained the expected target trough levels of drug despite the detection 
of ATAs. To date, no clear relationship between detection of ATAs and adverse events (AEs) or 
infusion related reactions (IRRs) has been observed. 
 
2.3.4 
Clinical Safety 
The presented safety data for atezolizumab have been derived mainly from the treatment of 
patients in Phase Ia Study PCD4989g. As of 10 May 2014, atezolizumab has been administered 
to approximately 775 patients with solid and hematologic malignancies. No dose-limiting 
toxicities (DLTs) have been observed at any dose level, and no maximum tolerated dose (MTD) 
was established.  Fatigue was the most frequently reported AE. 
 
The following safety data are from PCD4989g, in which atezolizumab is being used as single- 
agent therapy in patients with locally advanced or metastatic solid tumors or hematologic 
malignancies. In 412 treated patients, 97.1% reported an AE while on study. Of these AEs, 
48.8% were Grade 1 or 2 in maximum severity on the basis of NCI-CTCAE version 4.0. The 
most frequently observed AEs (occurring in ≥10% of treated patients) included fatigue, nausea, 
decreased appetite, pyrexia, dyspnea, diarrhea, constipation, cough, headache, back pain, 
vomiting, anemia, arthralgia, rash, insomnia, asthenia, abdominal pain, chills, pruritus, and upper 
respiratory tract infection. 
 
Grade ≥3 AEs were reported by 199 of 412 patients (48.3%). There were 51 patients (12.4%) 
who reported Grade ≥3 AEs that were assessed as related to study drug by the investigators. The 
most frequently reported related Grade ≥3 AEs included fatigue (5 patients [1.2%]), increased 
alanine aminotransferase (ALT) and increased aspartate aminotransferase (AST) (each reported 
in 4 patients [1.0%]); and asthenia, autoimmune hepatitis, and hypoxia (each reported in 3 
patients [0.7%]). 
 
Given the mechanism of action of atezolizumab, events associated with inflammation and/or 
immune-mediated AEs have been closely monitored during the atezolizumab clinical program. 
These include potential dermatologic, hepatic, endocrine, and respiratory events as well as events 
of hepatitis/elevated liver function tests (LFTs) and influenza-like illness.Expected adverse drug 
reactions associated with atezolizumab include the following: hepatitis/transaminitis, 
hypothyroidism, IRRs, pneumonitis, influenza-like illness, and dermatologic reactions. Potential 
adverse drug reactions include the following: ATAs, colitis, endocrine disorders, 
hypersensitivity, neurologic disorders, and pericardial effusion. For further details, see the 
atezolizumab Investigator’s Brochure. 
 
2.4 Rationale 
There is no established high-level evidence for a standard of care for patients with nccRCC. 
Current approved agents in RCC have limited activity in nccRCC compared to ccRCC and there 
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is a need to actively investigate new therapies in this setting. 
 
VEGF blocking agents including bevacizumab have been investigated for the treatment of 
patient with nccRCC. A phase II trial investigating the efficacy of bevacizumab, specifically in 
patients with papillary RCC was conducted, however was closed to slow accrual, demonstrated 
safety, and modest activity. For patients who were on this study, individual PFS ranged from 6- 
25 months.9 
 
The rationale for including all nccRCC patients stems from historic and currently ongoing trials 
in nccRCC which include all non-clear cell histologies. A phase II trial (ESPN) investigated 
outcomes of first-line everolimus compared to sunitinib in nccRCC patients.10 Patients were 
stratified by histology (papillary vs. others), MSKCC risk groups, and Kaplan-Meier curves were 
used to estimate unadjusted TTE distributions between groups. Accrual was terminated due to 
futility analysis of PFS and inferior OS with everolimus compared to sunitinib in first-line 
(median OS with everolimus was 10.5 months (95% CI), and median OS with sunitinib was not 
reached). Another phase II trial investigated the efficacy of everolumus versus sunitinib in the 
first-line setting in patients with metastatic nccRCC, with papillary, chromophobe, or any 
unclassified histology (ASPEN).11 Patients were stratified by histology and risk group, with the 
primary endpoint as radiographic PFS. Sunitinib was found to prolong PFS as compared with 
everolimus in patients with nccRCC. This trial is the largest trial to date in nccRCC and first to 
demonstrate an mTOR-sensitive subgroup of nccRCC patients as compared with VEGF 
inhibition in the first-line setting, including chromophobe and poor risk RCC patients. 
 
Given the small size of this study and the limited nccRCC patient population of only 20%, we 
will allow patients have received both first and second line therapies as this is an exploratory 
study evaluating for a signal of efficacy in this patient population. If a signal of efficacy is 
observed, a larger study in a more homogenous patient population can be considered in the 
future. 
 
Immunotherapy strategies have been used for decades in patients with advanced RCC with 
prolonged survival being seen in a very small proportion of patients treated with IFN-α or high- 
dose interleukin-2 therapy. The past several years has witnessed a resurgence in interest in 
immunotherapy with the developed of blocking antibodies against the inhibitory PD-1 pathway. 
PD-L1 is broadly expressed on tumor cells and tumor infiltrating mononuclear cells (TIMC). We 
have previously demonstrated that PD-L1 expression in tumor (10.9%) and TIMC (56.4%) 
occurs in patients with nccRCC and PD-L1 positivity on tumor cell membrane was associated 
with aggressive clinicopathological features.12 Single agent atezolizumab, a monoclonal anti- 
PD-L1 antibody, has been investigated in metastatic ccRCC as detailed in section 2.3.2. 
 
There is rationale for combining VEGF inhibition with immunotherapy. VEGF has profound 
effects on immune regulatory cell function, specifically inhibiting dendritic cell maturation and 
antigen presentation.13,14 Additionally, there is increasing evidence for the role angiogenic 
factors play in influencing lymphocyte trafficking across endothelia in tumor deposits.15 
 
The combination of bevacizumab (15 mg/kg every 3 weeks) and ipilimumab has been 
investigated in melanoma.16  Therapy with these agents revealed that VEFG blockade influences 
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inflammation, lymphocyte trafficking, and immune regulation based on data from on treatment 
tumor biopsies and peripheral blood analysis. Clinically, 8 patients had a partial response (PR) 
and 22 patients stable disease (SD) for disease control rate of 67.4%. Median survival was 25.1 
months. 
 
There is precedence to combining VEGF inhibition with immunotherapy in RCC, however this 
data mainly exits for ccRCC. Two large phase III trials combine bevacizumab with IFN-α.4,5 A 
phase II study explored the immunomodulatory effects of bevacizumab and low-dose 
interleukin-2 in patients with metastatic RCC.17 In this study, the combination demonstrated 
modest activity with PFS 9.6 months and ORR 15%. Biological data indicated that inhibition of 
VEGF levels increased immunosuppressive regulatory T cells. Furthermore, the combination of 
nivolumab with sunitinib or pazopanib in patients with metastatic RCC is being explored in a 
phase 1 study.18  Preliminary data demonstrated that the ORR was 52% (17/33) in patients treated 
with sunitinib and 45% (9/20) in patients treated with pazopanib. SD rate was 33% in the 
sunitinib arm and 35% in the pazopanib arm. 24 week PFS was 78% in the sunitinib arm and 
55% in the pazopanib arm. 
 
A phase 1b study evaluated atezolizumab in combination with bevacizumab in patients with 
metastatic ccRCC.19  Patients were treated with bevacizumab 15 mg/kg alone on cycle 1/day 1 
and atezolizumab 20 mg/kg every 3 weeks thereafter. Preliminary data demonstrated that among 
first-line metastatic RCC patients with one tumor assessment (n = 10), the ORR was 40%. An 
additional 4/5 patients with best response as SD had prolonged AD at ≥ 24 weeks. On treatment 
tumor biopsies demonstrated increases in tumor-infiltrating CD8+ cells. 
 
A phase II study evaluating atezolizumab as monotherapy or in combination with bevacizumab 
compared to sunitinib is currently ongoing but closed to accrual. Patients with previously 
untreated locally advanced or metastatic renal cell carcinoma with a component of clear cell 
and/or sarcomatoid histology were enrolled. In this study, patients receive either 1200 mg of 
atezolizumab every 3 weeks until disease progression, atezolizumab in combination with 15 
mg/kg of bevacizumab every 3 weeks until disease progression, or the active comparator, 
sunitinib administered as 50 mg each day orally, followed by 2 weeks of rest, until disease 
progression. Patients starting on atezolizumab alone or sunitinib may crossover to the 
combination arm following disease progression. The primary objective is progression-free 
survival per RECIST v1.1 via central IRC assessment. 
 
Lastly, a phase III study of atezolizumab in combination with bevacizumab versus sunitinib in 
patients with untreated inoperable locally advanced or metastatic renal cell carcinoma who have 
not received prior systemic active or experimental therapy, either in the adjuvant or metastatic 
setting, is currently ongoing and recruiting patients. Patients must have a definitive diagnosis of 
unresectable advanced or metastatic RCC with clear-cell histology and/or sarcomatoid carcinoma 
in order to be eligible. Patients assigned to the experimental dual regimen of atezolizumab plus 
bevacizumab receive a fixed-dose of 1200 mg of atezolizumab on days 1 and 22 of 42-day cycles 
until loss of clinical benefit, unacceptable toxicity, symptomatic deterioration attributed to 
disease progression, or death. Participants assigned to receive single-agent sunitinib are 
administered 50 mg of sunitinib orally once daily on days 1 through 28. The primary outcome 
measure, like the phase II, is progression-free survival as determined by RECIST v1.1. 
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Given the immunomodulatory properties of VEGF, we hypothesize that the combination of 
atezolizumab and bevacizumab will be synergistic and result in improved response in patients 
with metastatic nccRCC. In this study, we propose to evaluate the efficacy and safety of the 
combination of bevacizumab and atezolizumab in patients with non-ccRCC. 
 
2.5 Correlative Studies Background 
Immunotherapy has historically had a significant role in the management of metastatic RCC. 
Treatment using IFNα and interleukin-2 (IL-2) results in objective responses in approximately 
5% of patients with RCC and 10% of patients treated with IL-2 exhibit durable disease 
stabilization. Atezolizumab blocks the inhibitor receptors expressed on tumor cells called PD-L1, 
resulting in enhanced tumor activity. Studies suggest that this compound derives effect from 
enhancement of immune function by targeting the PD-L1 axis which may be of critical 
importance in RCC. 
 
PD-L1 is an extracellular protein that downregulates immune responses primarily in peripheral 
tissues through binding to its two receptors: PD-1 and B7-1. Many human tumors have been 
found to overexpress PD-L1, which acts to suppress anti-tumor immunity. PD-1 is an inhibitor 
receptor expressed on T-cells following T-cell activation, which is sustained in states of chronic 
stimulation, such as chronic infection or chance.20 Ligation of PD-L1 and PD-1 inhibits T-cell 
proliferation, cytokine production, and cytolytic activity, leading to the function inactivation or 
exhaustion of T-cells. B7-1 is a molecular expressed on antigen-presenting cells (APC) and 
activated T-cells. PD-L1 binding to B7-1 on T cells and APCs can mediate the downregulation 
of immune response, including inhibition of T-cell activation and cytokine production.21,22 
 
Aberrant expression of PD-L1 on tumor cells has been reported to impede anti-tumor immunity, 
resulting in immune evasion.23 Therefore the interruption of the PD-L1/PD-1 pathway represents 
an attractive strategy to reinvigorate tumor-specific T-Cell immunity. In addition, VEGF is 
known to play a significant role in the pathogenesis of RCC and recent data suggests that VEGF 
may have an effect on immune function including antigen presentation and T-cell activation. 
 
In this study, we will evaluate the immunomodulatory properties of atezolizumab in combination 
with bevacizumab and correlate findings with outcomes. In addition, we will evaluate tumor 
tissue and TIMC for expression of PD-L1 and correlates with outcomes. 
 
2.5.1 
Rationale for Collection of Blood Biomarkers 
Changes in biomarkers in the blood may provide evidence for the biological activity of 
atezolizumab in humans and may allow for the developed of a blood based biomarker to help 
predict which patients may benefit from atezolizumab. A secondary objective is to assess the 
immunomodulatory properties of atezolizumab in combination with bevacizumab by evaluating 
baseline levels and changes in levels upon treatment of surrogate pharmacodynamic markers in 
the blood. In addition, we will correlate levels with the anti-tumor activity of the combination of 
these agents. 
 
2.5.2 
Rationale for Collection of Archival and Fresh Tumor Specimens 
PD-L1/PD-1 pathway activation in tumors, as determined by PD-L1 levels, may be an important 
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predictive diagnostic for atezolizumab. Published results suggest that expression of PD-L1 in 
tumors correlates with response to anti-PD-1 therapy.24 This correlation is also observed with 
atezolizumab in preliminary data from Study PCD4989g such that patients with PD-L expression 
appear to derive he most benefit from atezolizumab. Tumor specimens (collected from baseline 
fresh tumor specimens) from patients meeting eligibility criteria will be tested for PD-L1 
expression and other markers of immunogenicity and angiogenesis. In addition, PD-L1 status (as 
defined by expression of PD-L1 on tumor cells or TIMC) will be correlated with outcomes. 
Because the expression of PD-L1 on the surface of both tumor cells and TIMC can be a dynamic 
process and because PD-L1 expression on these cells may vary between primary and metastatic 
sites, mandatory fresh tumor specimens will be collected. Additionally, to investigate 
mechanisms of acquired resistance to therapy, patients who experience relapse after an initial 
response will be required to undergo a mandatory fresh tumor biopsy if medically safe.  
 
3. PARTICIPANT SELECTION 
 
3.1 Eligibility Criteria 
• Age ≥ 18 years. 
 
• Unresectable advanced or metastatic non-clear cell RCC to include but not limited to: 
o Papillary RCC, any type 
o Unclassified RCC 
o Translocation RCC 
o Chromophobe RCC 
o Collecting duct RCC 
o Medullary RCC 
o Clear cell RCC or any histology with > 20% sarcomatoid features will be eligible  
• 
If a patient has not had a nephrectomy, then a patient that has a metastatic 
biopsy showing sarcomatoid will still be eligible.  
o Other non-clear cell histologies that are not included above need to be discussed 
with the PI. 
 
• Request for formalin-fixed, paraffin-embedded (FFPE) archival tumor specimens if 
available and willingness of the participant to undergo mandatory fresh tumor biopsy 
unless determined medically unsafe or not feasible. A note from the study team should be 
provided documenting availability of tissue. If a target lesion is biopsied at screening, this 
lesion must be followed as non-target lesion after the biopsy unless it is the patient’s only 
target lesion. If there is only one target lesion, it should be followed as a target lesion 
regardless. 
o The archival specimen should contain adequate viable tumor tissue. 
o The specimen may consist of a tissue block (preferred and should contain the 
highest grade of tumor) or at least 30 unstained serial sections. Fine-needle 
aspiration, brushings, cell pellet from pleural effusion, bone marrow 
aspirate/biopsy are not acceptable. 
o Fresh tumor biopsy at progression will be required in cases where patients 
experience relapse after an initial response if medically safe. 
 
• Measurable disease as defined by Response Evaluation Criteria In Solid Tumors 
(RECIST) version 1.1. 
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• ECOG performance status ≤ 2 (See Appendix A). 
 
• Adequate hematologic and end-organ function as defined by the following laboratory 
results obtained within 28 days prior to the first study treatment: 
o Absolute neutrophil count (ANC) ≥ 1500 cells/uL. 
o Platelet count ≥ 100,000/uL. 
o Hemoglobin ≥ 9 g/dL (patients may be transfused to meet this criterion).  
o Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x 
upper limit of normal (ULN) with the following exceptions: Patients with 
documented liver metastases should have AST and ALT ≤ 5 x ULN.  
o Serum bilirubin ≤ 2.0 x ULN with the following exception: Patients with 
known Gilbert’s disease should have a serum bilirubin ≤ 3 x ULN. 
o Creatinine clearance ≥ 30 mL/min as calculated by Cockcroft-Gault equation. 
 
• For female patients of childbearing potential and male patients with partners of 
childbearing potential, agreement (by patient and/or partner) to use highly effective forms 
of contraception and to continue its use 6 months after the last dose of atezolizumab or 
bevacizumab. 
 
• Signed informed consent form. 
 
• Ability and capacity to comply with study and follow-up procedures. 
 
3.2 Exclusion Criteria 
• Prior treatment with CD137 agonists, anti- cytotoxic T-lymphocyte-associated protein 4, 
anti-PD-1, or anti-PDL1 therapeutic antibody or pathway targeting agents. Prior IFNα or 
IL-2 is allowed following 4 week washout from treatment end date. 
 
• Receipt of any type of small molecule kinase inhibitor (including investigational kinase 
inhibitors) within 2 weeks of enrollment or receipt of any anti-cancer therapy (including 
investigational therapy, monoclonal antibodies, cytokine therapy) within 4 weeks of 
enrollment. 
 
• Prior therapy with bevacizumab. 
 
• Thrombologic event within 3 weeks of treatment start date, unless stable on 
anticoagulation with LMWH or Factor Xa inhibitor for at least 2 weeks.   
 
• Treatment with systemic immunosuppressive medications including but not limited to: 
prednisone, dexamethasone, cyclosporin, azathioprine, methotrexate, thalidomide, anti- 
tumor necrosis factor (TNF) agents, hydroxychloroquine within 2 weeks of first study 
dose. 
o Patients who have received acute, low-dose systemic immunosuppressant 
medications may be enrolled. 
o Patients with adrenal insufficiency on physiologic replacement doses of steroids 
may be enrolled. 
o The use of inhaled, topical intraocular, or intra articular corticosteroids or, 
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mineralocorticoids are allowed. 
 
• 
Radiotherapy for RCC within 14 days of first study treatment with the exception of a 
single fraction of radiation administered for palliation of symptoms. 
 
• 
Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks prior to the 
initiation of study treatment. Stability must be confirmed by magnetic resonance 
imaging (MRI) or computed tomography (CT) imaging and/or treating investigator 
determination.  
 
• 
Malignancies other than RCC within 2 years of first study treatment with the 
exception of those with negligible risk of metastases or death (included but not 
limited to carcinoma in situ of the cervix, basal or squamous cell skin cancer, 
localized prostate cancer, ductal carcinoma in situ of the breast, non-muscle invasive 
urothelial carcinoma, or other malignancy not deemed to impact that patients 5-year 
life expectancy). 
 
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion protein. 
 
• Known hypersensitivity to any component of the atezolizumab product. 
 
• History of autoimmune disease including: myasthenia gravis, myositis, autoimmune 
hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, 
vascular 
thrombosis 
associated 
with 
anti-phospholipid 
syndrome, 
Wegner’s 
granulomatosis, Sjogren’s syndrome, Guillain-Barre syndrome, multiple sclerosis, type I 
diabetes mellitus, vasculitis, or glomerulonephritis. Patients with a history of autoimmune-
related hypothyroidism on thyroid replacement hormone or those with autoimmune 
dermatologic conditions not requiring the use of prednisone > 10 mg or equivalent are 
eligible. 
 
• History of idiopathic pulmonary fibrosis, organized pneumonia, or evidence of active 
pneumonitis on screening imaging CT of the chest. History of radiation pneumonitis in the 
radiation field is permitted. 
 
• Positive test for HIV (test to be performed within 28 days of first treatment start). 
 
• 
Patients with active or chronic hepatitis B (defined as having a positive hepatitis B surface 
antigen [HBsAg] test at screening). Patients with past/resolved HBV infection (defined as 
having negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] 
antibody test) are eligible. A negative HBA DNA test must be obtained in patients with 
positive hepatitis B core antibody prior to Cycle 1 Day 1. 
• Active hepatitis C infection. Patients positive hepatitis C antibody test are eligible if PCR 
is negative for hepatitis C viral DNA. 
 
• Infection requiring receipt of therapeutic oral or IV anti-microbials within 2 weeks of first 
study treatment. Patients receiving routine anti-microbial prophylaxis (for dental 
extractions/procedures) are eligible. 
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• Significant cardiovascular disease such as New York Heart Association (NYHA) class II 
or greater, myocardial infarction within the previous 3 months of first study treatment, 
unstable arrhythmias, unstable angina. Patients with known coronary artery disease, 
congestive heart failure not meeting the above criteria, or left ventricular ejection fraction 
< 50% must be on a stable regimen that is optimized in the opinion of the treating 
physician, in consultation with a cardiologist when appropriate. 
 
• Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg  
and/or diastolic blood pressure > 100 mmHg). Anti-hypertensive therapy to achieve 
these parameters is allowed. 
 
• Prior history of hypertensive crisis or hypertensive encephalopathy within the previous 3 
months of first study treatment. 
 
• History of stroke or transient ischemic attack within 3 months of first study dose. 
 
• Significant vascular disease (such as aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months of first study dose. Evidence of bleeding 
diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation). 
 
• Current or recent use of dipyramidole, ticlopidine, clopidogrel, cilostazol is excluded. 
Aspirin (≤ 325 mg per day) is allowed. Prophylactic anticoagulation with oral or 
parenteral anticoagulants for the patency of venous access devices or other indications is 
allowed. Therapeutic use of low-molecular weight heparin (such as enoxaparin), and 
factor Xa inhibitors are allowed. Use of warfarin is prohibited.  
 
• Use of plaquenil must be discontinued two weeks prior to first study treatment. 
 
• History of abdominal or tracheoesophageal fistula or GI perforation within 6 months of 
first study treatment. 
 
• Clinical signs or symptoms of active GI obstruction or requirement of routine parenteral 
nutrition or tube feedings. 
 
• Evidence of abdominal free air not explained by paracentesis or recent surgical 
procedure. 
 
• Serious, non-healing or dehiscing wound or active ulcer. 
 
• Proteinuria, as demonstrated by > 1.5 gram of protein in a 24-hour urine collection. All 
patients with ≥ 2+ protein on dipstick urinalysis at baseline must undergo 24-hour urine 
collection for protein. 
 
• Major surgical procedure within 21 days of first study treatment. 
 
• Prior allogenic stem cell or solid organ transplant. 
 
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• Administration of a live, attenuated vaccine within 4 weeks for first study treatment. 
 
• Pregnant or lactating women. 
 
3.3 Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
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4. REGISTRATION PROCEDURES 
 
4.1 General Guidelines for Dana-Farber/Harvard Cancer Center (DF/HCC) and Dana- 
Farber/Partners Cancer Care (DF/PCC) Institutions 
Institutions will register eligible participants with the DF/HCC Office of Data Quality (ODQ) 
central registration system. Registrations must occur prior to the initiation of protocol therapy. 
Any participant not registered to the protocol before protocol therapy begins will be considered 
ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
ODQ protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Notify the ODQ Registrar of registration cancellations as soon as 
possible. 
 
4.2 Registration Process for DF/HCC and DF/PCC Institutions 
The ODQ registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Standard Time. In emergency situations when a participant must begin protocol therapy 
during off-hours or holidays, call the ODQ registration line
and follow the 
instructions for registering participants after hours. 
 
The registration procedures are as follows: 
 
• Obtain written informed consent from the participant prior to the performance of any 
protocol specific procedures or assessments. 
 
• Complete the ODQ protocol-specific eligibility checklist using the eligibility assessment 
documented in the participant’s medical record and/or research chart. To be eligible for 
registration to the protocol, the participant must meet all inclusion and exclusion 
criterion as described in the protocol and reflected on the eligibility checklist. 
 
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for a 
treatment protocol. Registration to both treatment and ancillary protocols will not be 
completed if eligibility requirements are not met for all studies. 
 
• Fax the eligibility checklist(s) and all pages of the consent form(s) to the ODQ
 
For Phase I protocols, attach participant dose level assignment confirmation 
from the sponsor. 
 
• The ODQ Registrar will (a) review the eligibility checklist, (b) register the participant on 
the protocol, and (c) randomize the participant when applicable. 
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• An email confirmation of the registration and/or randomization will be sent to the Overall 
PI, study coordinator(s) from the Lead Site, treating investigator and registering person 
immediately following the registration and/or randomization. 
 
4.3 General Guidelines for Other Investigative Sites 
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute 
(DFCI) by the Study Coordinator. All sites should call the Study Coordinator
 to 
verify dose level availabilities. The required forms will be provided to all participating 
institutions by the DFCI study coordination. 
 
Following registration, participants should begin protocol therapy within 7 days or as soon as 
possible. Issues that would cause treatment delays should be discussed with the Overall PI. If a 
participant does not receive protocol therapy following registration, the participant’s registration 
on the study must be canceled. The Study Coordinator should be notified of cancellations as soon 
as possible. 
 
4.4 Registration Process for Other Investigative Sites 
To register a participant, the documents listed in Appendix B should be completed by the 
research nurse or data manager and faxed
 or emailed to the DFCI study 
coordination. 
 
The research nurse or data manager at the participating site will then call
 or email 
the DFCI Study Coordinator to verify eligibility. To complete the registration process, the 
Coordinator will: 
• Register the participant on the protocol with the ODQ. 
• Fax or e-mail the participant study number, and if applicable the dose treatment level to 
the participating site. 
• Call the research nurse or data manager at the participating site and verbally confirm 
registration. 
 
NOTE: Registration and randomization with the ODQ can only be conducted during the 
business hours of 8:00 AM and 5:00 PM Eastern Standard Time Monday through Friday. 
Same day treatment registrations will only be accepted with prior notice and discussion with the 
DF/HCC Lead Institution. 
 
5. TREATMENT PLAN 
 
5.1 Treatment Regimen 
The participant will then undergo screening procedures and will enter the trial after successful 
screening. The participant must be willing to undergo a mandatory fresh tumor biopsy at 
baseline unless the investigator deems the procedure medically unsafe. Participants with no 
available archival tumor tissue will be required to undergo a fresh tumor biopsy at baseline. 
 
Eligible patients will be enrolled and will treatment with bevacizumab 15 mg/kg IV every 3 
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weeks and atezolizumab 1200 mg IV every 3 weeks. Each cycle will be 3 weeks in duration. 
Patients will be evaluated clinically every 3 weeks and will undergo disease assessments with 
imaging every 6 weeks. 
 
Participants will be continued on therapy until radiographic progression or withdrawal for some 
other reason as detailed in section 5.6. Participants who experience a response to therapy and 
then subsequently progress will be required to undergo a mandatory tumor biopsy at the time of 
progression if medically safe. Reported adverse events, potential risks, and dose modifications 
are described in Section 6. No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the participant’s malignancy. 
 
Regimen Description 
Agent 
Premedications; 
Precautions** 
Dose 
Route 
Schedule 
Cycle 
Length 
Atezolizumab* 
None (may be 
administered for 
Cycles ≥2 at the 
discretion of the 
treating 
physician) 
1200 mg 
IV before 
bevacizumab 
*** 
Every 3 
weeks (21 
[+/-3] days) 
3 weeks 
(21 [+/-3] 
days) 
Bevacizumab 
None (See 
Section 5.4) 
15 
mg/kg*** 
* 
IV***** 
Every 3 
weeks (21 
[+/-3] days) 
* Atezolizumab will be administered first followed by bevacizumab, with a minimum of 5 
minutes between dosing. 
**Observation should be for at least 2 hours after the first administration of the combination. 
*** The initial dose of atezolizumab will be delivered over 60 (+/-15) minutes. If the first 
infusion is tolerated without infusion associated AEs, the second infusion may be delivered over 
30 (+/-10) minutes. If the 30 minute infusion is well tolerated, all subsequent infusions may be 
delivered over 30 (+/-10) minutes. 
****Bevacizumab doses will be calculated based on C1D1 weight unless there is a >5% weight 
change in subsequent cycles. If a patient has a change of weight that is >5% from C1D1 weight, 
this value will become the new baseline.  
*****The initial dose will be delivered over 90 (+/-15) minutes. If the first infusion is tolerated 
without infusion associated adverse events (fever and/or chills), the second infusion may be 
delivered over 60 (+/-10) minutes. If the 60 minute infusion is well tolerated, all subsequent 
infusions may be delivered over 30 (+/-10) minutes. 
 
5.2 Pre-Treatment Criteria 
 
5.2.1 Cycle 1, Day 1 
 
Prior to cycle 1, day 1, the following parameters must be met: 
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• ANC ≥ 1500/mm3. 
• Platelet count ≥ 100,000/uL. 
• Hemoglobin ≥ 9 g/dL (transfusions allowed). 
 
Cycle 1, day 1 laboratory assessments do not need to re-meet eligibility criteria. For subsequent 
cycles, labs should be reviewed and CTC grading for toxicities should be done prior to treatment. 
Dose modifications should be followed per the protocol as necessary. 
 
5.3 Atezolizumab 
The dose level of atezolizumab to be tested in this study is 1200 mg (equivalent to an average 
body weight-based dose of 15 mg/kg) administered by IV infusion every 3 weeks (21 [+/-3] 
days). Atezolizumab will be delivered in infusion bags with IV infusion lines that have product 
contacting surfaces of polyvinyl chloride (PVC) or polyolefin and 0.2 um in-line filters (filter 
membrane of polyethersulfone [PES]). No incompatibilities have been observed between 
atezolizumab and PVC or polyolefin infusion materials (bags or infusion lines). 
 
Atezolizumab dose preparation will be done on the day atezolizumab is administered. 
Atezolizumab should be allowed to reach room temperature prior to removal from the vials. The 
product should be administered only using 250 mL 0.9% sodium chloride saline IV bags. The 
required volume of atezolizumab for the patient is 20 mL. Dose solutions are prepared by 
removing 20 mL of saline solution from the IV bag prior to the addition of 20 mL of 
atezolizumab. The total volume of NS for the final product isThe IV bags containing 
atezolizumab should be mixed and handled gently. The study drug must be diluted under 
appropriate aseptic conditions, as it does not contain antimicrobial preservatives. Once the 
atezolizumab dose solution is prepared, it may be stored at 2°C–8°C (36°F–46°F) and/or at room 
temperature for up to 8 hours prior to the start of infusion. However, if the infusion is interrupted 
and the combined storage and dose hold time of the diluted IV bags exceeds the 8-hour limit, 
prepare a new dose solution to resume the infusion. 
If the dose solution is stored at 2°C–8°C (36°F–46°F), it should be removed from refrigeration 
and allowed to reach room temperature prior to administration. Protect dose solutions from 
intense light and heat. 
 
Administration of atezolizumab will be performed in a setting with emergency medical facilities 
and staff who are trained to monitor for and respond to medical emergencies. 
 
Atezolizumab will be administered first, followed by bevacizumab, with a minimum of 5 
minutes between dosing. The initial dose of atezolizumab will be delivered over 60 (+/-15) 
minutes. If the first infusion is tolerated without infusion associated AEs, the second infusion 
may be delivered over 30 (+/-10) minutes. If the 30 minute infusion is well tolerated, all 
subsequent infusions may be delivered over 30 (+/-10) minutes. For the first infusion, the 
patient’s vital signs (heart rate, respiratory rate, blood pressure, and temperature) should be 
determined within 60 minutes before, during (every 15 [+/-5] minutes), and 30 (+/-10) minutes 
after the infusion. For subsequent infusions, vital signs will be collected within 60 minutes 
before and within 30 minutes after the infusion. Vital signs should be collected during the 
infusion only if clinically indicated. Patients will be informed about the possibility of delayed 
post-infusion symptoms and instructed to contact their study physician if they develop such 
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symptoms. Observation should be for at least 2 hours after the first administration of the 
combination. 
 
No premedication will be allowed for the first dose of atezolizumab. Premedication may be 
administered for Cycles ≥2 at the discretion of the treating physician. The management of IRRs 
will be according to severity as follows: 
• In the event that a patient experiences a mild (NCI CTCAE Grade 1) IRR, the infusion 
rate should be reduced to half the rate being given at the time of event onset. Once the 
event has resolved, the investigator should wait for 30 minutes while delivering the 
infusion at the reduced rate. If tolerated, the infusion rate may then be increased to the 
original rate. 
• In the event that a patient experiences a moderate IRR (NCI CTCAE Grade 2) or 
flushing, fever, or throat pain, the infusion should be immediately interrupted and the 
patient should receive aggressive symptomatic treatment. The infusion should be 
restarted only after the symptoms have adequately resolved to baseline grade. The 
infusion rate at restart should be half of the infusion rate that was in progress at the time 
of the onset of the IRR. 
• For severe or life-threatening IRRs (NCI CTCAE Grade 3 or 4), the infusion should be 
stopped immediately, and aggressive resuscitation and supportive measures should be 
initiated. Patients experiencing severe or life threatening IRRs will not receive further 
infusion and will be further managed as clinically indicated until the event resolves. 
 
If bevacizumab is being held atezolizumab can still be administered unless the participant is 
experiencing treatment-emergent toxicities for which the etiology could be related to both 
agents. In this case, both drugs should be held. If one or both study agents are being held, study 
assessments (e.g. scans, laboratory assessments, etc.) will remain on schedule as per the study 
calendar. 
 
5.4 Bevacizumab 
Bevacizumab should be prepared using aseptic technique. Withdraw the necessary amount of 
bevacizumab and dilute to the required administration volume with 0.9% Sodium Chloride 
Injection, USP. Bevacizumab preparation should be conducted as per the USPI. Administration 
will be as a continuous IV infusion. Anaphylaxis precautions should be observed during study 
drug administration. 
 
The initial dose will be delivered over 90 (+/-15) minutes. If the first infusion is tolerated without 
infusion associated adverse events (fever and/or chills), the second infusion may be delivered 
over 60 (+/-10) minutes. If the 60 minute infusion is well tolerated, all subsequent infusions may 
be delivered over 30 (+/-10) minutes. 
 
If a subject experiences an infusion–associated AE, he or she may be premedicated for the next 
study drug infusion; however, the infusion time may not be decreased for the subsequent 
infusion. If the next infusion is well tolerated with premedication, the subsequent infusion time 
may then be decreased by 30 (+/-10) minutes as long as the subject continues to be 
premedicated. If a subject experiences an infusion associated adverse event with the 60 minute 
infusion, all subsequent doses should be given over 90 (+/-15) minutes.  Similarly, if a subject 
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experiences an infusion associated adverse event with the 30 minute infusion, all subsequent 
doses should be given over 60 (+/-10) minutes. 
 
If atezolizumab is being held bevacizumab can still be administered unless the participant is 
experiencing treatment-emergent toxicities for which the etiology could be related to both 
agents. In this case, both drugs should be held. If one or both study agents are being held, study 
assessments (e.g. scans, laboratory assessments, etc.) will remain on schedule as per the study 
calendar. 
 
5.5 General Concomitant Medication and Supportive Care Guidelines 
 
5.5.1 
Permitted Therapy 
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a patient after 7 days preceding the screening evaluation and prior to the end of 
treatment visit or the date of RECIST version 1.1 progression, whichever is later. All 
concomitant medications administered within 14 days preceding Cycle 1, Day 1 and throughout 
the study until the treatment termination visit will be collected on study-specific electronic Case- 
Report Forms (eCRFs). The reason(s) for treatment and dates of treatment should be reported to 
the investigator and recorded as instructed on the study-specific eCRFs. 
 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, anti-emetics, etc., when appropriate. Prophylactic anticoagulation for patency of 
device with oral or parenteral anticoagulants is allowed. Patients who require therapeutic 
anticoagulation can be maintained on low molecular weight heparin (LMWH) (e.g., enoxaparin 
and tinzaparin) or fondaparinux. In addition, patients requiring therapeutic anticoagulation with 
LMWH during study participation will be allowed to remain on study therapy. Therapeutic 
warfarin is not allowed on study. 
 
Patients who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or famotidine or another H2 receptor 
antagonist, as per standard practice. Serious infusion-associated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory 
distress should be managed with supportive therapies as clinically indicated. 
 
Systemic corticosteroids, TNF-α inhibitors, and hydroxychloroquinemay attenuate potential 
beneficial immunologic effects of treatment with atezolizumab but may be administered at the 
discretion of the treating physician after consultation with the PI. If feasible, alternatives to 
corticosteroids should be considered. Premedication may be administered for Cycles ≥ 2 at the 
discretion of the treating physician after consultation with the PI. The use of inhaled, topical 
intraocular or intraarticular corticosteroids, or mineralocorticoids are allowed. Megestrol 
administered as an appetite stimulant is acceptable while the patient is enrolled in the study. 
Mineralocorticoids for orthostatic hypotension or adrenalcortical insufficiency are acceptable. 
 
Influenza vaccination should be given during influenza season only (approximately October to 
March). Patients must not receive live attenuated influenza vaccine within 4 weeks prior to Cycle 
1, Day 1 or at any time during the study but may receive inactivated influenza vaccines. 
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Patients who use hormonal therapy with GnRH agonists or antagonists for prostate cancer, oral 
contraceptives, hormone-replacement therapyshould continue their use. 
 
Males and females of reproductive potential should use highly effective means of contraception. 
 
All concomitant medications should be reported to the investigator and recorded on the 
appropriate eCRF. 
 
5.5.2 
Prohibited Therapy 
Any concomitant therapy intended for the treatment of kidney cancer, whether health 
authority−approved or experimental, is prohibited. This includes but is not limited to the 
following: 
• Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational agents, 
or herbal therapy. After Cycle 2, certain forms of radiotherapy may be considered for 
pain palliation if patients are deriving benefit (such as treatment of known bony 
metastases). 
• Patients experiencing a mixed response requiring local therapy (such as surgery, 
stereotactic radiosurgery, radiotherapy, radiofrequency ablation) for control of three or 
fewer lesions may still be eligible to continue study treatment. Patients who receive local 
therapy directed at a target lesion will no longer be evaluable for radiographic response 
but will remain evaluable for progression. Such cases must be discussed with and 
approved by the PI. 
 
Traditional herbal medicines should not be administered because the ingredients of many herbal 
medicines are not fully studied and their use may result in unanticipated drug-drug interactions 
that may cause or confound assessment of toxicity. 
 
Patients who are receiving a RANKL inhibitor (denosumab) prior to enrollment must be willing 
and eligible to receive a bisphosphonate instead while on study; denosumab could potentially 
alter the activity and the safety of atezolizumab. 
 
Initiation or increased dose of granulocyte colony-stimulating factors (such as granulocyte 
colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, and/or 
pegfilgrastim) is prohibited. 
 
Patients are not allowed to receive immunostimulatory agents, including but not limited to IFNα 
or IL-2, during the entire study. These agents, in combination with atezolizumab, could 
potentially increase the risk for autoimmune conditions. 
 
Patients should also not receive immunosuppressive medications, including but not limited to 
cyclophosphamide, azathioprine, methotrexate, and thalidomide. These agents could potentially 
alter the activity and the safety of atezolizumab. Systemic corticosteroids and anti-TNF-α agents 
may attenuate potential beneficial immunologic effects of treatment with atezolizumab but may 
be administered at the discretion of the treating physician after consultation with the PI. If 
feasible, alternatives to these agents should be considered. In addition, all patients (including 
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those who discontinue the study early) should not receive other immunostimulatory agents for 10 
weeks after the last dose of atezolizumab. 
 
Use of full-dose warfarin will not be allowed during the study. Because bevacizumab has a half- 
life of approximately 21 days, elective major surgery should be delayed whenever possible. No 
data are available to define a safe interval. Re-initiation of bevacizumab following surgery 
requires documented approval from the PI. 
 
5.6 Treatment Beyond Disease Progression 
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of disease progression. Subjects will be permitted to 
continue treatment beyond site investigator assessed progression as long as they meet the following 
criteria: 
• Site investigator-assessed clinical benefit 
AND 
• Subject is tolerating study drug(s). 
 
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. All decisions to 
continue treatment beyond progression should be discussed with the sponsor-investigator and 
documented in the study records. 
 
Subjects should discontinue study therapy upon evidence of further progression, defined as an 
additional 10% or greater increase in tumor burden volume from time of initial progression 
(including all target lesions and new measurable lesions). 
 
New lesions are considered measurable at the time of progression if the longest diameter is at least 
10 mm (except for pathological lymph nodes, which must have a short axis of at least 15 mm). Any 
new lesion considered non-measurable at the time of initial progression may become measurable 
and therefore included in the tumor burden measurement if the longest diameter increases to at 
least 10 mm (except for pathological lymph nodes, which must have an increase in short axis to at 
least 15 mm). 
 
5.7 Criteria for Taking a Participant off Protocol Therapy 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies: 
 
• 
Disease progression. 
 
• 
Intercurrent illness that prevents further administration of treatment. 
 
• 
Unacceptable AE(s) requiring discontinuation of both agents. 
 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements. 
 
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• 
Participant decides to withdraw from the protocol therapy. 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator. 
 
• 
Pregnancy. 
 
Participants will be removed from the protocol therapy when any of these criteria apply but 
continue to be followed according to protocol. The reason for removal from protocol therapy, 
and the date the participant was removed, must be documented in the eCRF. Alternative care 
options will be discussed with the participant. 
 
Participants will be permitted to continue study treatment with atezolizumab and bevacizumab 
after RECIST v1.1 criteria for investigator-assessed progressive disease are met, at the discretion 
of the investigator, if they meet all of the following criteria: 
 
• 
Evidence of clinical benefit as assessed by the investigator 
 
• 
Absence of symptoms and signs (including worsening of laboratory values [e.g., new 
or worsening hypercalcemia]) indicating unequivocal progression of disease 
 
• 
No decline in KPS  
• 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be readily managed and stabilized by protocol-allowed medical 
interventions prior to repeat dosing 
 
• 
Patients must provide written consent to acknowledge deferring any standard 
treatment options that may exist in favor of continuing atezolizumab treatment at the 
time of initial progression. 
 
• 
Patients who demonstrate confirmed radiographic disease progression may be 
considered for continued study treatment at the discretion of the investigator, 
provided they continue to meet all the criteria above. 
 
An ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the ODQ website or obtained from the ODQ 
registration staff. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI. 
 
5.8 Duration of Follow Up 
Patients will be followed for safety for 90 days following the last dose of study treatment or until 
receipt of another anticancer therapy, whichever comes first. Patients who have an ongoing study 
treatment-related AE upon study completion or at discontinuation from the study will be 
followed until the event has resolved to baseline grade, the event is assessed by the investigator 
as stable, new anticancer treatment is initiated, the patient is lost to follow-up, the patient 
withdraws consent, or until it has been determined that study treatment or participation is not the 
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cause of the AE. 
 
After progression/treatment discontinuation, participants will be followed for survival and 
receipt of next line therapies every 6 months until death or 2 years after treatment 
discontinuation Follow-up will be via phone calls and through review of medical records. 
 
5.9 Criteria for Taking a Participant off Study 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the eCRF. 
 
An ODQ Treatment Ended/Off Study Form will be filled out when a participant comes off study. 
This form can be found on the ODQ website or obtained from the ODQ registration staff. 
 
5.10 Replacement 
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already been assigned to treatment or administered at least one dose 
of the study drug. Subjects who have dropped out but have not received at least one dose of 
treatment will be replaced. Subjects that have not received at least one dose of treatment will not 
be included in data analysis and thus will not require data entry. 
 
5.11 
Study and Site Discontinuation 
The PI has the right to terminate this study at any time. Reasons for terminating the study may 
include, but are not limited to, the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients. 
• Patient enrollment is unsatisfactory. 
 
The PI will notify the investigators if the PI decides to discontinue the study. 
The PI has the right to close a site at any time. Reasons for closing a site may include, but are 
not limited to, the following: 
• Excessively slow recruitment 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• Non-compliance with the International Conference on Harmonisation (ICH) guideline for 
Good Clinical Practice (GCP) 
• No study activity (i.e., all patients have completed and all obligations have been fulfilled) 
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6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Measures will be taken to ensure the safety of patients participating in this trial, including the use 
of stringent inclusion and exclusion criteria and close monitoring. Eligibility criteria were 
selected to guard the safety of patients in this trial. Safety will be evaluated in this study through 
the monitoring of all serious and non-serious AEs, defined and graded according to NCI CTCAE 
v4.0. Patients will be assessed for safety (including laboratory values). General safety 
assessments will include serial interval histories, physical examinations, and specific laboratory 
studies, including serum chemistries and blood counts all serious adverse events (SAEs) and 
protocol-defined events of special interest will be reported in an expedited fashion. In addition, 
the investigators will review and evaluate observed AEs on a regular basis. 
 
There will be no dose reductions for either atezolizumab or bevacizumab on this study however 
dose delays will be permitted as detailed below for each agent. The descriptions and grading 
scales found in the revised NCI CTCAE version 4.0 will be utilized for dose delays. A copy of 
the CTCAE version 4.0 can be downloaded from the Cancer Therapy Evaluation Program 
(CTEP) website 
 
 
6.1 Atezolizumab Dose Modifications 
 
There will be no dose reduction for atezolizumab in this study. Patients may temporarily suspend 
study treatment for up to 42 days beyond the scheduled date of delayed infusion if study drug- 
related toxicity requiring dose suspension is experienced. The decision to temporarily suspend 
treatment beyond 42 days will be based on a discussion between the treating investigator and 
Sponsor-Investigator. If atezolizumab is held because of AEs for >42 days beyond the scheduled 
date of infusion, the patient will be discontinued from atezolizumab and will be followed for 
safety and efficacy as previously defined in Section 5.7. If, in judgment of the treating 
investigator, the patient is likely to derive clinical benefit from resuming atezolizumab after >42 
days, the study drug may be restarted with the approval of the Sponsor-Investigator. 
 
If a patient must be tapered off steroids used to treat AEs, atezolizumab may be held for 
additional time beyond 42 days from the scheduled dose until steroids are discontinued or 
reduced to a prednisone dose (or dose equivalent) of ≤10 mg/day. The acceptable length of 
interruption will be at the discretion of the investigator. 
 
Dose interruptions for reasons other than toxicity, such as surgical procedures, may be allowed. 
The acceptable length of interruption will be at the discretion of the Sponsor. 
 
Any toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice. Additional tests, such as autoimmune serology or 
biopsies, may be used to determine a possible immunogenic etiology. Although most irAEs 
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 there is no 
available antidote for atezolizumab. In severe cases, immune related toxicities may be acutely 
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managed with topical corticosteroids, systemic corticosteroids, mycophenolate, or TNF-α 
inhibitors. 
 
Patients should be assessed clinically (including review of laboratory values) for toxicity prior to, 
during, and after each infusion. If unmanageable toxicity due to atezolizumab occurs at any time 
during the study, treatment with atezolizumab should be discontinued. 
 
Management of hepatitis/transaminitis, colitis, rash, and hypothyroidism are presented in this 
section as they have been observed in this study and are potentially immune related. 
 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice. 
 
6.1.1 
Immune-Related Adverse Event (irAEs) 
Although most irAEs 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 there is no available antidote for atezolizumab. In severe cases, immune-related toxicities 
may be acutely managed with topical corticosteroids, systemic corticosteroids, mycophenolate, 
or TNF-α inhibitors. 
 
The primary approach to Grade 1 to 2 irAEs is supportive and symptomatic care with continued 
treatment with atezolizumab; for higher-grade irAEs, atezolizumab should be withheld and oral 
and/or parenteral steroids administered. Recurrent Grade 2 irAEs may also mandate withholding 
atezolizumab or the use of steroids. Assessment of the benefit risk balance should be made by 
the investigator, with consideration of the totality of information as it pertains to the nature of the 
toxicity and the degree of clinical benefit a given patient may be experiencing prior to further 
administration of atezolizumab. Atezolizumab should be permanently discontinued in patients 
with life threatening irAEs. 
 
6.1.2 
Gastrointestinal Toxicity 
Immune-mediated colitis has been associated with the administration of atezolizumab. 
Patients should be advised to inform the investigator if any diarrhea occurs, even if it is mild. 
If the event is of significant duration or magnitude, or is associated with signs of systemic 
inflammation or acute phase reactants (e.g., increased c-reactive protein or platelet count or 
bandemia), it is recommended that sigmoidoscopy (or colonoscopy, if appropriate) with colonic 
biopsy with three to five specimens for standard paraffin block be performed. If possible, one or 
two biopsy specimens should be snap frozen and stored. 
 
Treatment may be restarted following the resolution of colitis. In addition, if the patient is being 
managed with corticosteroids, treatment should not be restarted until the steroids have been 
tapered down to a prednisone dose ≤10 mg/day. Patients who resume treatment should be 
monitored closely for signs of renewed diarrhea. Table 1 provides a summary of dose 
modification guidelines for GI toxicities. 
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Table 1. Dose Modification Guidelines for Gastrointestinal Toxicity 
Toxicity 
Description 
Management 
Diarrhea 
Grade 2 (4-6 stools per day 
over baseline) < 5 days 
Hold atezolizumab and 
discontinue NSAIDS (or 
other medications known to 
exacerbate colitis). 
Investigate for etiology. 
Restart atezolizumab once at 
baseline stool frequency. 
Grade 2(4-6 stools per day 
over baseline) > 5 days 
Hold atezolizumab and 
discontinue NSAIDS (or 
other medications known to 
exacerbate colitis) while 
etiology is being investigated. 
Consider referral to a 
gastroenterologist. 
Administer anti-diarrheal 
agent (e.g., Imodium). 
Consider oral budesonide, 
mesalamine, or 10 mg oral 
prednisone equivalent per 
day. 
Restart atezolizumab once at 
baseline stool frequency. 
Abdominal pain 
Blood or mucus in stool 
OR 
Grade ≥3 (≥7 stools/day over 
baseline) with peritoneal 
signs, ileus, or fever 
Hold atezolizumab and 
discontinue NSAIDS (or 
other medications known to 
exacerbate colitis). 
Rule out bowel perforation. 
Consider administering 
prednisone 60 mg/day or 
equivalent. 
Taper steroids over 1 month. 
Restart atezolizumab if 
diarrhea is resolved and 
systemic steroid dose is  10 
mg oral prednisone equivalent 
per day. 
Permanently discontinue 
atezolizumab for 
life-threatening, 
immune-related diarrhea or 
colitis. 
NSAID = nonsteroidal anti-inflammatory drug. 
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6.1.3 
Hepatotoxicity 
Immune-mediated hepatitis has been associated with the administration of atezolizumab. 
 
While in this study, patients presenting with right upper-quadrant abdominal pain and/or 
unexplained nausea or vomiting should have LFTs performed immediately, and LFTs should be 
reviewed before administration of the next dose of study drug. 
 
If LFTs increase, neoplastic, concurrent medications, viral hepatitis, and toxic etiologies should 
be considered and addressed, as appropriate. Imaging of the liver, gall bladder, and biliary tree 
should be performed to rule out neoplastic or other causes of increased LFTs. Anti nuclear 
antibody, perinuclear anti-neutrophil cytoplasmic antibody, anti-liver kidney microsomal, and 
anti-smooth muscle antibody tests should be performed if an autoimmune etiology is considered. 
Patients with LFT abnormalities should be managed according to the guidelines in Table 2. 
 
Table 2. Dose Modification Guidelines for Hepatoxicity 
Toxicity 
Description 
Management 
LFT abnormalities 
AST/ALT ( ULN to 
3  ULN) with total bilirubin 
 2  ULN 
Continue with the standard 
monitoring plan (e.g., LFTs 
every 3 weeks before dosing). 
AST/ALT ( 3  ULN to 
 10  ULN) with total 
bilirubin  2  ULN 
Continue atezolizumab. 
Monitor LFTs at least 
weekly. 
Consider referral to a 
hepatologist. 
AST/ALT  10  ULN 
Hold atezolizumab. 
Consider administering IV 
steroids for 24-48 hours 
(prednisone 60 mg/day 
equivalent) followed by an 
oral prednisone (or 
equivalent) taper over 2-4 
weeks. If LFT results do not 
decrease within 48 hours after 
initiation of systemic steroids, 
addition of an alternative 
immunosuppressive agent 
(e.g., mycophenolate or TNF- 
α antagonist) to the 
corticosteroid regimen may 
be considered. Monitor LFTs 
every 48-72 hours until 
decreasing and then follow 
weekly. 
Restart atezolizumab if 
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AST/ALT ≤3 x ULN with 
bilirubin <2 x ULN and 
steroid dose is ≤10 mg oral 
prednisone equivalent per 
day. 
Permanently discontinue 
atezolizumab for life- 
threatening, immune-related 
hepatic events. 
AST/ALT  3  ULN with 
bilirubin  2  ULN 
Hold atezolizumab. 
Consult a hepatologist. 
Consider administering IV 
steroids for 24-48 hours 
(prednisone 60 mg/day 
equivalent) followed by oral 
taper over 1 month. If LFTs 
results do not decrease within 
48 hours after initiation of 
systemic steroids, addition of 
an alternative 
immunosuppressive agent 
(e.g., mycophenolate or 
TNF antagonist) to the 
corticosteroid regimen may 
be considered. Monitor LFTs 
every 48-72 hours until 
decreasing and then follow 
weekly. Restart atezolizumab 
if AST/ALT  3 x ULN with 
bilirubin  2 x ULN and 
steroid dose is 10 mg oral 
prednisone equivalent per 
day. 
IV = intravenous; LFT = liver function test; TNF- = tumor necrosis factor alpha; ULN = upper 
limit of normal. 
 
6.1.4 
Dermatologic Toxicity 
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 
performed unless contraindicated. Low-grade rash and pruritus irAEs have been treated with 
symptomatic therapy (e.g., antihistamines). Topical or parenteral corticosteroids may be required 
for more severe symptoms. 
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Dermatologic toxicity and rash should be managed according to the guidelines in Table 3. 
 
Table 3. Dose Modification Guidelines for Dermatologic Toxicity 
Toxicity 
Description 
Management 
Dermatologic toxicity/rash 
(e.g., maculopapular or 
purpura) 
Grade 1: Mild 
 10% BSA 
Continue atezolizumab 
symptomatic therapy with 
antihistamine PRN. 
Consider topical steroids 
and/or other symptomatic 
therapy (e.g., antihistamines). 
Grade 2: Moderate 
10%−30% BSA 
Continue atezolizumab. 
Consider dermatologist 
referral. 
Administer topical steroids. 
Consider higher potency 
topical steroids if rash is 
unresolved. 
Grade 3: Severe 
>30% BSA 
Hold atezolizumab. 
Consult dermatologist. 
Administer oral prednisone 
10 mg or equivalent.  If the 
rash is unresolved after 48-72 
hours, administer oral 
prednisone 60 mg or 
equivalent. 
Restart MPDL3280A if rash 
is resolved and systemic dose 
is 10 mg oral prednisone 
equivalent per day. 
Permanently discontinue 
atezolizumab for 
life-threatening, 
immune-related dermatologic 
toxicity. 
BSA = body surface area; PRN = as needed. 
 
6.1.5 
Endocrine Toxicity 
Hypothyroidism has been associated with the administration of atezolizumab. 
 
Patients 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, as well as for hyponatremia or hyperkalemia. An endocrinologist should be 
consulted if an endocrinopathy is suspected. Thyroid stimulating hormone (TSH) and free T4 
levels should be obtained to determine whether thyroid abnormalities are present. TSH, 
prolactin, and a morning cortisol level will help to differentiate primary adrenal insufficiency 
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from primary pituitary insufficiency. 
 
Hypothyroidism should be managed according to the guidelines in Table 4. 
 
Table 4. Dose Modification Guidelines for Endocrine Toxicity 
Toxicity 
Description 
Management 
Hypothyroidism 
TSH <10, asymptomatic 
Continue atezolizumab. 
Monitor according to 
Sponsor-Investigator 
discretion. 
TSH >10, asymptomatic 
Continue  atezolizumab. 
Start thyroid-replacement 
hormone. Monitor according 
to Sponsor-Investigator 
discretion. 
TSH >10, symptomatic 
Hold atezolizumab. 
Consider referral to an 
endocrinologist. Restart 
atezolizumab when 
symptoms are controlled by 
thyroid replacement and 
TSH levels are decreasing. 
Monitor according to 
Sponsor-Investigator 
discretion. 
 
6.1.6 
Pulmonary Toxicity 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab and have primarily been observed in patients with 
underlying NSCLC. 
 
Mild-to-moderate events of pneumonitis have been reported with atezolizumab. All pulmonary 
events should be thoroughly evaluated for other commonly reported etiologies such as 
pneumonia/infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, chronic 
obstructive pulmonary disease (COPD), or pulmonary hypertension and the following should be 
performed: 
• Measurement of oxygen saturation (i.e., arterial blood gas) 
• High-resolution CT scan of the chest 
• Bronchoscopy with bronchoalveolar lavage and biopsy 
• Pulmonary function tests (with diffusion capacity of the lung for carbon monoxide 
[DLCO]) 
 
Patients will be assessed for pulmonary signs and symptoms throughout the study. Patients will 
also have CT scans of the chest at every tumor assessment. 
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Pulmonary toxicity should be managed according to the guidelines in Table 5. 
 
 
Table 5. Dose Modification Guidelines for Pulmonary Toxicity 
Toxicity 
Description 
Management 
Pulmonary Toxicity 
GGO or non-infectious 
infiltrate in absence of 
hypoxia, or dyspnea 
Hold treatment with 
atezolizumab. 
Re-evaluate after 1 week. 
If no worsening in 
GGO/infiltrates and patient 
still asymptomatic, resume 
treatment with atezolizumab. 
If GGO/infiltrates worsen and 
patient is still asymptomatic, 
continue to hold atezolizumab 
and refer for bronchoscopy. 
Consider starting low-dose 
oral prednisone 10 mg or 
equivalent. 
Re-evaluate after 1 week. 
Resume atezolizumab if 
GGO/infiltrates improving. 
Hypoxia or dyspnea in 
presence of GGO or infiltrate 
without alternative etiology 
Hold atezolizumab. 
Consult a pulmonologist. 
Investigate for other 
etiologies 
and consider 
bronchoscopy. If 
bronchoscopy is consistent 
with immune-related etiology, 
start 60 mg prednisone 
equivalent per day followed 
by taper over 2 weeks. 
Restart atezolizumab if 
symptomatically improved, 
infiltrates are resolved, and 
steroid use is 10 mg 
prednisone equivalent per 
day. 
Permanently discontinue 
atezolizumab for 
life-threatening, 
immune-related pulmonary 
events. 
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GGO = ground glass opacities. 
 
 
6.1.7 
Pancreatic Toxicity 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with administration of other immunomodulatory agents. The 
differential diagnosis of acute abdominal pain should include pancreatitis. Appropriate workup 
should include an evaluation for obstruction, as well as serum amylase and lipase tests. 
 
6.1.8 
Eye Toxicity 
An ophthalmologist should evaluate visual complaints. Uveitis or episcleritis may be treated with 
topical corticosteroid eye drops. Atezolizumab should be permanently discontinued for immune- 
mediated ocular disease that is unresponsive to local immunosuppressive therapy. 
 
Ocular toxicity should be managed according to the guidelines in Table 6. 
 
Table 6. Dose Modification Guidelines for Eye Toxicity 
Toxicity 
Description 
Management 
Eye toxicity (autoimmune 
uveitis, iritis, or episcleritis) 
Symptomatic 
Hold atezolizumab. 
Consult ophthalmologist and 
start topical corticosteroid eye 
drops. 
Atezolizumab may be 
restarted following resolution 
of the events. 
Permanently discontinue 
atezolizumab for 
immune-mediated ocular 
disease that is unresponsive to 
local immunosuppressive 
therapy. 
 
6.2 Bevacizumab Dose Modifications 
Bevacizumab dose will not be reduced for reasons other than a >5% change in weight from 
baseline. Bevacizumab treatment may be either temporarily or permanently suspended in the 
case of bevacizumab-related events such as fistulae, GI perforation, hypertension, proteinuria, 
thrombosis/embolism, hemorrhage, CHF, wound healing complications, PRES and 
hypersensitivity/allergic reactions in addition to any other serious bevacizumab-related toxicity 
(grade 3 or 4). If bevacizumab is held because of related adverse events for >42 days beyond 
when the next dose would have been given, then the patient will be discontinued from 
bevacizumab and be followed for safety according to Section 5.7. If, in judgment of the treating 
investigator, the patient is likely to derive clinical benefit from resuming bevacizumab after >42 
days, the study drug may be restarted with the approval of the Sponsor-Investigator. 
 
In addition, bevacizumab should be temporarily withheld in the event of febrile grade 4 
neutropenia and/or grade 4 thrombocytopenia (regardless of the relationship to treatment), since 
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these conditions are predisposing factors for an increased bleeding tendency. 
 
To summarize, bevacizumab should be held temporarily or permanently discontinued in patients 
(as per the clinical judgment of the treating physician) experiencing any of the following events: 
• Febrile grade 4 neutropenia and/or grade 4 thrombocytopenia regardless of the 
relationship to treatment (hold treatment temporarily) 
• Grade ≥2 fistula (hold temporarily or permanently discontinue) 
• GI perforation (permanently discontinue) 
• Major surgery or wound healing complications (hold temporarily or permanently 
discontinue) 
• Medically significant hypertension not controlled with antihypertensive therapy, 
hypertensive crisis or hypertensive encephalopathy (permanently discontinue) 
• Grade ≥3 left ventricular dysfunction (CHF) (permanently discontinue) 
• Nephrotic syndrome (permanently discontinue) 
• Arterial thrombosis/embolism (any grade) (permanently discontinue) 
• Grade ≥3 venous thrombosis/embolism (hold temporarily or permanently discontinue for 
grade 4) 
• CNS bleeding (any grade) or  ≥grade 3 bleeding of any kind (permanently discontinue) 
• Grade ≥2 hemoptysis (hold temporarily or permanently discontinue) 
• Hypersensitivity/allergic reactions related to bevacizumab (permanently discontinue) 
• PRES (permanently discontinue) 
 
6.2.1 
Posterior Reversible Encephalopathy Syndrome (PRES) 
There have been rare reports of patients treated with bevacizumab developing signs and 
symptoms that are consistent with PRES, a rare neurological disorder. PRES is also known as 
reversible posterior leukoencephalopathy syndrome or RPLS. PRES can present with following 
signs and symptoms among others: seizures, headache, altered mental status, visual disturbance 
or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires 
confirmation by brain imaging. In patients developing PRES, treatment of specific symptoms 
including control of hypertension is recommended along with discontinuation of bevacizumab. 
The safety of reinitiating bevacizumab therapy in patients previously experiencing PRES is not 
known. Adequate brain imaging using MRI must be performed as a follow-up measurement for 
patients with PRES. 
 
6.2.2 
Gastrointestinal Perforation and Fistula 
Bevacizumab has been associated with serious cases of gastrointestinal perforation in patients 
with metastatic colorectal cancer and a few reports of gallbladder perforation have been reported 
from the post-marketing experience. The presentation of these events has varied in type and 
severity, ranging from free air seen only on the plain abdominal X-ray, which resolved without 
treatment, to a colonic perforation with abdominal abscess and fatal outcome. The common 
feature among these cases was intra abdominal inflammation, either from gastric ulcer disease, 
tumor necrosis, diverticulitis or chemotherapy-associated colitis. Nevertheless, a causal 
association of an intra-abdominal inflammatory process and GI perforation to treatment with 
bevacizumab has not been established. However, caution should be exercised when treating 
patients with intra-abdominal inflammatory process with bevacizumab. 
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Bevacizumab should be permanently discontinued in patients who develop GI perforation. 
 
Bevacizumab use has been associated with serious cases of fistulae including events resulting in 
death. Fistulae within the GI tract or GI tract and skin are common in patients with metastatic 
colorectal cancer and ovarian cancer, but are uncommon or rare in other indications. Other 
fistulae (e.g. tracheoesophageal, bronchopleural, urogenital, biliary) have been reported 
uncommonly in bevacizumab clinical trials patients and in post-marketing reports. 
 
Temporarily discontinue bevacizumab in patients with grade 2 or 3 non- tracheoesophageal 
fistula until resolution to ≤ grade 1. 
 
Permanently discontinue bevacizumab in patients with tracheoesophageal fistula or any grade 4 
fistula. Limited information is available on the continued use of bevacizumab in patients with 
other fistulae. In cases of internal fistula not arising in the GI tract, discontinuation of 
bevacizumab should be considered. 
 
6.2.3 
Wound Healing Complications 
Increased incidences of post-operative bleeding or wound healing complications have been 
observed in clinical trials of bevacizumab in relapsed glioma and metastatic colorectal and breast 
cancer. 
 
Bevacizumab therapy should not be initiated for at least 28 days following major surgery or until 
the surgical wound is fully healed as bevacizumab may adversely impact wound healing. 
 
In patients who experience wound healing complications during bevacizumab treatment, 
bevacizumab should be withheld until the wound is fully healed. If the wound does not fully heal 
despite withholding treatment, should be permanently discontinued. 
 
Bevacizumab therapy should be withheld for an interval of at least two half-lives (approximately 
six weeks) before conducting major elective surgery. Emergency surgery should be performed as 
appropriate without delay after a careful risk-benefit assessment. 
 
6.2.4 
Hypertension 
An increased incidence of hypertension has been observed in patients treated with bevacizumab. 
Clinical safety data suggest the incidence of hypertension is likely to be dose-dependent. 
 
Pre-existing hypertension should be adequately controlled before starting bevacizumab 
treatment. There is no information on the effect of bevacizumab in patients with uncontrolled 
hypertension at the time of initiating therapy. 
 
Blood pressure must be assessed before each bevacizumab administration. 
 
In most cases hypertension is controlled adequately using standard antihypertensive treatment 
appropriate for the individual situation of the affected patient. Bevacizumab should be 
permanently discontinued if medically significant hypertension cannot be adequately controlled 
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with antihypertensive therapy, or if the patient develops hypertensive crisis or hypertensive 
encephalopathy. 
 
6.2.5 
Congestive Heart Failure (CHF) 
Events consistent with CHF were reported in clinical trials. The findings ranged from 
asymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiring 
treatment or hospitalization. Most of the patients who experienced CHF had metastatic breast 
cancer and had received previous treatment with anthracyclines, prior radiotherapy to the left 
chest wall or other risk factors for CHF were present. 
 
Caution should be exercised when treating patients with clinically significant cardiovascular 
disease such as pre-existing coronary artery disease, concomitant cardiotoxic therapy or CHF 
with bevacizumab. 
Bevacizumab should be permanently discontinued in patients with ≥ grade 3 CHF. 
 
6.2.6 
Proteinuria 
In clinical studies, the incidence of proteinuria was higher in patients receiving bevacizumab in 
combination with chemotherapy compared to those who received chemotherapy alone. 
Proteinuria reported as an AE with bevacizumab treatment has ranged in severity from clinically 
asymptomatic, transient, trace proteinuria to nephrotic syndrome with the great majority as grade 
1 proteinuria. The proteinuria seen in bevacizumab clinical trials was not associated with renal 
dysfunction and rarely required permanent discontinuation of bevacizumab therapy. Patients 
with a history of hypertension may be at increased risk for the development of proteinuria when 
treated with bevacizumab. 
 
Proteinuria must be assessed by dipstick before each bevacizumab administration unless 
proteinuria has been determined by 24-hour urine collection. 
 
Table 7. Bevacizumab Treatment Management for Proteinuria. 
Grade 
Urinalysis 
Treatment Actions 
Grade 1 
1+ proteinuria OR 
urinary protein < 1.0 g/24 hrs 
No bevacizumab dose 
modification 
Grade 2 
2+ proteinuria OR 
urinary protein 1.0-3.4 g/24 
hrs 
For 2+ dipstick: may 
administer bevacizumab 
without dose modification 
and collect 24-hour urine 
prior to subsequent 
bevacizumab administration. 
For 3+ dipstick: must obtain 
24-hour urine prior to 
administering bevacizumab 
Suspend bevacizumab for 
urinary protein ≥2 g/24 hrs. 
Resume bevacizumab when 
proteinuria is < 2 g/24 hrs. 
Grade 3 
urinary protein ≥3.5 g/24 hrs 
Suspend bevacizumab. 
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Resume bevacizumab when 
proteinuria is < 2 g/24 hrs. 
Nephrotic syndrome 
Permanently discontinue 
bevacizumab. 
 
6.2.7 
Arterial thrombosis/embolism 
Bevacizumab should be discontinued in patients who develop arterial thromboembolic events. 
A history of arterial thromboembolic events or age greater than 65 years has been associated 
with an increased risk of arterial thromboembolic events during bevacizumab therapy. Patients 
receiving bevacizumab plus chemotherapy with a history of arterial thromboembolism and age 
greater than 65 years have a higher risk. Caution should be taken when treating these patients 
with bevacizumab. 
 
6.2.8 
Venous thrombosis/embolism 
Bevacizumab should be held in patients developing a grade 3 thrombosis/embolism. 
Bevacizumab may be resumed once the patient is adequately anti-coagulated and on a stable 
level of anticoagulation for at least 2 weeks prior to restarting study drug treatment. Patients on 
full dose low molecular weight heparins should receive the appropriate dose based on the weight 
of the patient according to package insert. 
 
An increased risk of venous thromboembolic events and bleeding in patients receiving anti- 
coagulation therapy after first venous thromboembolic event while receiving bevacizumab has 
been observed. 
 
In the event of recurrent grade 3 thrombosis/embolism, the patient should be discontinued from 
bevacizumab. 
 
Bevacizumab should be discontinued in patients with life-threatening (grade 4) pulmonary 
embolism. 
 
6.2.9 
Hemorrhage 
An increased incidence of bleeding events was observed in study patients treated with 
bevacizumab as compared to control treatment arms. The hemorrhagic events observed in 
bevacizumab studies were predominantly tumor-associated hemorrhage and minor 
mucocutaneous hemorrhage. 
 
Patients with untreated CNS metastases were routinely excluded from clinical trials with 
bevacizumab, based on imaging procedures or signs and symptoms. Therefore, the risk of CNS 
hemorrhage in such patient has not been prospectively evaluated in randomized clinical studies. 
 
Bevacizumab should be permanently discontinued for: 
• Grade 3 or 4 bleeding of any kind. 
• Any grade of CNS bleeding. Patients should be monitored for signs and symptoms of 
CNS bleeding. 
 
Bevacizumab should be temporarily held or permanently discontinued for grade ≥ 2 haemoptysis 
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(defined as ≥ 2.5 mL bright red blood per episode). The safety of re-initiating bevacizumab in 
patients previously experiencing grade ≥ 2 haemoptysis has not been evaluated. 
 
If hemorrhagic complications occur in patients on full dose anti-coagulation therapy, 
permanently discontinue bevacizumab treatment and follow guidelines of the treating institution. 
Standard procedures such as antagonisation with protamin or vitamin K and infusion of vitamin 
K dependent factors should be considered dependent on the severity of the bleeding. 
 
6.2.10 Hypersensitivity/Allergic Reactions and Infusion-Associated Reactions 
Bevacizumab should be permanently discontinued in patients exhibiting hypersensitivity/allergic 
reactions. 
 
The NCI CTCAE distinguishes between hypersensitivity reactions and acute infusion reactions 
induced by cytokine release. Despite the different possible mechanisms underlying 
hypersensitivity and infusion reactions, the clinical signs and symptoms associated with these 
reactions overlap. 
 
Patients may be at risk of developing infusion reactions to bevacizumab. Close observation of 
the patient during and following the administration of bevacizumab is recommended as expected 
for any infusion of a therapeutic humanized monoclonal antibody. If an infusion reaction occurs, 
the infusion should be discontinued and appropriate medical therapies should be administered. A 
systematic premedication is not warranted. 
 
6.2.11 Osteonecrosis of the Jaw 
Osteonecrosis of the jaw was reported in patients receiving bevacizumab mainly in combination 
with bisphosphonates in the post-marketing setting. The pathogenesis of the osteonecrosis is 
unclear.  For further information, please refer to the bevacizumab Investigator’s Brochure. 
 
6.2.12 Ovarian Failure 
Ovarian failure has been reported more frequently in patients receiving bevacizumab. Ovarian 
function recovered in the majority of women after bevacizumab discontinuation. For further 
information, please refer to the bevacizumab Investigator’s Brochure. 
Dana Farber
IRB NUMBER: 15-592
IRB APPROVAL DATE: 04/17/2020


NCI Protocol #: N/A 
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Protocol Version Date: November 4, 2019
48 
 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) per protocol. This includes all events of death, and any study specific 
issue of concern. AE monitoring and reporting is a routine part of every clinical trial. Adverse 
events associated with atezolizumab and bevacizumab are detailed in Section 2. 
 
7.1 Adverse Events 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational medicinal product 
(IMP) or other protocol imposed intervention, regardless of attribution. 
This includes the following: 
− AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with Advanced Non-Clear Cell 
Renal Cell Carcinoma 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 
− Pre-existing medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period 
 
 
7.2 Serious Adverse Event 
An AE should be classified as an SAE if the following criteria are met: 
− It results in death (i.e., the AE actually causes or leads to death) 
− It is life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death.) 
− It requires or prolongs inpatient hospitalization 
− It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
− It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP 
− It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the patient or may require medical/surgical intervention to 
prevent one of the outcomes listed above) 
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IRB NUMBER: 15-592
IRB APPROVAL DATE: 04/17/2020


NCI Protocol #: N/A 
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Protocol Version Date: November 4, 2019
49 
 
 
 
7.3 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 U.S. Food and Drug Administration (FDA), 
appropriate Institutional Review Boards (IRBs), and Genentech, Inc., in accordance with CFR 
312.32 (Investigational New Drug [IND] Safety Reports). 
 
7.3.1 
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed consent 
is obtained and initiation of study treatment and ends 30 days following the last administration of 
study treatment or study discontinuation/termination, whichever is earlier. After this period, 
investigators should only report SAEs that are attributed to prior study treatment. 
 
7.3.2 
Assessment of Adverse Events 
All AEs and SAEs, whether volunteered by the patient, 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 study drug 
(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 or bevacizumab, and the AE cannot be readily explained 
by the patient’s clinical state, intercurrent illness, or concomitant therapies; and/or the AE 
follows a known pattern of response to atezolizumab or bevacizumab or with similar 
treatments; and/or the AE abates or resolves upon discontinuation of atezolizumab or 
bevacizumab or dose reduction and, if applicable, reappears upon re-challenge. 
− No: Evidence exists that the AE has an etiology other than atezolizumab or bevacizumab 
(e.g., pre existing medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship to 
atezolizumab or bevacizumab administration (e.g., cancer diagnosed 2 days after first 
dose of study drug). 
 
Expected AEs are those AEs that are listed or characterized in the Package Insert (PI) or current 
Investigator’s Brochure. 
 
Unexpected AEs are those not listed in the PI or current Investigator’s Brochure or not identified. 
This includes AEs for which the specificity or severity is not consistent with the description in 
the PI or Investigator’s Brochure. For example, under this definition, hepatic necrosis would be 
unexpected if the PI or Investigator’s Brochure only referred to elevated hepatic enzymes or 
hepatitis. 
 
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy. 
 
 
7.4 Procedures for Eliciting, Recording, and Reporting Adverse Events 
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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?” 
 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations. 
 
7.4.1 
Diagnosis versus 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. 
 
7.4.2 
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.” 
 
7.4.3 
Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A pre-existing 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 pre existing condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
 
7.4.4 
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 patient 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 patient 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 pre-existing 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. 
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IRB NUMBER: 15-592
IRB APPROVAL DATE: 04/17/2020


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Protocol Version Date: November 4, 2019
51 
 
 
 
 
7.4.5 Assessment of Severity of Adverse Events 
 
 
  
The adverse event severity grading scale for the NCI CTCAE (V4.0 Update current versions) will 
be used for assessing adverse event severity. 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 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events. 
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
 
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  
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IRB NUMBER: 15-592
IRB APPROVAL DATE: 04/17/2020


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Protocol Version Date: November 4, 2019
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7.4.6 
Pregnancies 
If a female subject or female partner of the male study subject becomes pregnant while receiving 
the study drug or within 6 months after the last dose of study drugs,a report should be completed 
and expeditiously submitted to Genentech, Inc. Follow-up to obtain the outcome of the 
pregnancy should also occur. 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 atezolizumab and/or 
bevacizumab should be reported as an SAE. 
 
 
7.4.7 
Case Transmission Verification of Single Case Reports / Reconciliation 
The Sponsor-Investigator agrees to conduct reconciliation for the product(s) to ensure that all 
single case reports have been adequately received by Genentech via sponsor emailing 
Genentech a Quarterly line-listing documenting single case reports sent by Sponsor to 
Genentech in the preceding time period. Genentech and the Sponsor will agree to the 
reconciliation periodicity and format, but agree at minimum to exchange quarterly line listings 
of cases received by the other party. 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 Genentech 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 sponsor shall receive reconciliation guidance 
documents within the ‘Activation Package’. 
 
Following reconciliation, sponsor-investigator shall forward single case reports, which have 
not been received by Genentech, to Genentech within five (5) calendar days from request by 
Genentech. 
 
At the end of the study, a final cumulative reconciliation (Case Transmission Verification) 
report will be sent to Genentech. 
 
 
7.4.8 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a patient has completed or 
discontinued study participation if attributed to prior atezolizumab and/or bevacizumab 
exposure. If the investigator should become aware of the development of cancer or a congenital 
anomaly in a subsequently conceived offspring of a female patient who participated in the study, 
this should be reported as an SAE. 
 
7.4.9 
Adverse Events of Special Interest 
 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern 
specific to the product, for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor is required. Such an event might require 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., Regulatory Authorities) may also be 
warranted. 
Dana Farber
IRB NUMBER: 15-592
IRB APPROVAL DATE: 04/17/2020


NCI Protocol #: N/A 
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Protocol Version Date: November 4, 2019
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• Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law: 
• Treatment-emergent ALT or AST  3  ULN in combination with total 
bilirubin  2  ULN 
• Treatment-emergent ALT or AST  3  ULN in combination with 
clinical jaundice 
Data related to a suspected transmission of an infectious agent by the study drug (STIAMP), as 
defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent.  
A transmission of an infectious agent may be suspected from clinical symptoms or laboratory 
findings that indicate an infection in a patient exposed to a medicinal product.  This term 
applies only when a contamination of the study drug is suspected 
 
Atezolizumab specific AESIs: 
 
• Pneumonitis 
• Colitis 
• Endocrinopathies: diabetes mellitus, pancreatitis, hyperthyroidism,  adrenal 
insufficiency and hypophysitis 
• Hepatitis, including AST or ALT > 10 x 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 
influenza-like illness and systemic inflammatory response syndrome syndrome.  
• Nephritis. 
• Ocular toxicities (e.g., uveitis, retinitis, optic neuritis). 
• Myositis  
• Myopathies, including rhabdomyolysis. 
• Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis). 
• Vasculitis. 
• Autoimmune hemolytic anemia. 
• Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis) 
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IRB NUMBER: 15-592
IRB APPROVAL DATE: 04/17/2020


NCI Protocol #: N/A 
DF/HCC Protocol #: 15-592 
Protocol Version Date: November 4, 2019
54 
 
 
 
Bevacizumab specific AESIs: 
 
• Haemorrhage ≥ grade 3 (any grade CNS bleeding; ≥ grade 2 haemoptysis) 
• Hypertension ≥ grade 3 
• GI perforation, abscesses and fistulae (any grade) 
• Wound healing complication/wound dehiscence ≥ grade 3 
• Arterial thromboembolic events (any grade) 
• Venous thromboembolic events ≥ grade 3 
• Posterior Reversible encephalopathy syndrome (PRES) [or  RPLS; any grade] 
• Non-GI fistula or abscess ≥ grade 2 
• Proteinuria ≥ grade 3 
• Congestive heart failure/cardiomyopathy ≥ grade 3 
Dana Farber
IRB NUMBER: 15-592
IRB APPROVAL DATE: 04/17/2020


NCI Protocol #: N/A 
DF/HCC Protocol #: 15-592 
Protocol Version Date: November 4, 2019
55 
 
 
 
7.4.10 Adverse Event Reporting to Genentech Inc  
Investigators will be responsible for collecting all protocol-defined Adverse Events (AEs)/Serious 
Adverse Events (SAEs), AEs of Special Interest (AESIs), Special Situation Reports (including 
pregnancy reports) and Product Complaints (with or without an AE) originating from the Study 
for the Product(s).  
 
Investigators must report all the above-mentioned single case reports adequately to Genentech 
within the timelines described below. The completed MedWatch forms should be faxed/emailed 
immediately upon completion to Genentech at the following contacts: 
 
All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including pregnancy reports) 
and Product Complaints with an AE should be sent to: 
 
 
 
All Product Complaints without an AE should be sent to: 
                     
 
 
It is understood and agreed that the Sponsor will be responsible for the evaluation of AEs/SAEs, 
AESIs, Special Situation Reports (including pregnancy reports) and Product Complaints (with or 
without an AE) originating from the study.  
 
These single case reports will be exchanged between the parties as outlined below so that 
regulatory obligations are met. 
 
Serious adverse events (SAEs), AEs of Special Interest (AESIs), pregnancy reports (including 
pregnancy occurring in the partner of a male study subject), other Special Situation Reports and 
Product Complaints (with or without an AE), where the patient has been exposed to the Genentech 
Product, will be sent on a MedWatch form or CIOMS I form or on Genentech approved reporting 
forms to  Genentech Drug Safety. Transmission of these reports (initial and follow-up) will be 
either electronically or by fax and within the timelines specified below: 
 
Serious Adverse Drug Reactions: 
Serious AE reports that are related to the Product shall be transmitted to Genentech 
within fifteen (15) calendar days of the awareness date. 
 
• Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech 
within thirty (30) calendar days of the awareness date. 
 
• AESIs 
AESIs shall be forwarded to Genentech within fifteen (15) calendar days of the 
awareness date. 
 
• Special Situation Reports 
Pregnancy reports 
While such reports are not serious AEs or Adverse Drug Reactions (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 within thirty (30) calendar days of the awareness date. 
Dana Farber
IRB NUMBER: 15-592
IRB APPROVAL DATE: 04/17/2020


NCI Protocol #: N/A 
DF/HCC Protocol #: 15-592 
Protocol Version Date: November 4, 2019
56 
 
 
Pregnancies will be followed up until the outcome of the pregnancy is known, whenever 
possible, based upon due diligence taken to obtain the follow-up information. 
 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately inform 
the investigator if their partner becomes pregnant during the study or within 30 days after 
the last dose of study drug. A Clinical Trial Pregnancy Reporting Form should be completed 
and submitted to Genentech within thirty (30) calendar days of the awareness date. 
• Other Special Situation Reports 
In addition to all SAEs, pregnancy reports and AESIs, the following other Special 
Situations Reports should be collected even in the absence of an Adverse Event and 
transmitted to Genentech within thirty (30) calendar days: 
• Data related to the Product usage during breastfeeding 
• Data related to overdose, abuse, misuse or medication error (including 
potentially exposed or intercepted medication errors) 
• 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 
• Product Complaints  
All Product Complaints (with or without an AE) shall be forwarded to Genentech within 
fifteen (15) calendar days of the awareness date. 
 
A Product Complaint is defined as 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. 
 
 
 
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 AE 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., date of birth, initial, patient number), protocol description and number, if 
assigned, brief AE description, and notation that additional or follow-up information is 
being submitted. (The patient identifiers are important so that the new information is 
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added to the correct initial report.) 
 
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the patient for whom and AE was reported. For questions regarding SAE 
reporting, you may contact the Genentech Drug Safety representative noted above or the Medical 
Science Liaison assigned to the study. Relevant follow-up information should be submitted to 
Genentech Drug Safety as soon as it becomes available and/or upon request. 
 
 
  
 
 
7.4.11 Reporting to Regulatory Authorities, Ethics Committees and Investigators 
 
Sponsor-Investigator, 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.  
 
 
Sponsor-Investigator will be responsible for the distribution of safety information to its own 
investigators, where relevant, in accordance with local regulations. 
 
7.4.12 Additional Reporting Requirements for IND 
For investigator-sponsored IND 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 FDA as expedited IND Safety 
Reports according to the following guidance and timelines: 
 
7 Calendar Day Telephone or Fax Report: 
The investigator is required to notify the FDA of any fatal or life-threatening AE that is 
unexpected and assessed by the investigator to be possibly related to the use of atezolizumab 
and/or bevacizumab. An unexpected AE is one that is not already described in the atezolizumab 
and/or bevacizumab Investigator’s Brochure as applicable. Such reports are to be telephoned or 
faxed to the FDA and Genentech within 7 calendar days of first learning of the event. 
 
15 Calendar Day Written Report: 
The Investigator is also required to notify the FDA and all participating investigators, in a written 
IND Safety Report, of any serious, unexpected AE that is considered reasonably or possibly 
related to the use of atezolizumab. An unexpected AE is one that is not already described in the 
atezolizumab Investigator’s Brochure. 
 
Written IND 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 IND 
concerning similar events should be analyzed and the significance of the new report in light of 
the previous, similar reports commented on. 
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IRB NUMBER: 15-592
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Protocol Version Date: November 4, 2019
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Written IND safety reports with analysis of similar events are to be submitted to the FDA, 
Genentech, and 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). 
 
 
 
All written IND safety reports submitted to the FDA by the investigator must also be faxed 
to the following: 
 
 
Sponsor will be responsible for the distribution of safety information to Site IRB when an event 
meets reporting requirements.  
 
 
 
 
 
 
 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
 
 
 
7.4.13 IND Annual Reports 
Copies of all IND annual reports submitted to the FDA by the Sponsor-investigator should be 
emailed to Genentech
  
 
7.4.14Other Reports  
 
Sponsor-Investigator will forward a copy of the Final Study Report to Genentech upon completion 
of the Study.  
 
7.4.15 Study Close Out 
Any study report submitted to the FDA by the Sponsor-investigator should be copied to 
Genentech. This includes all IND 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. Copies of such reports should be mailed to the assigned Clinical Operations contact 
for the study: 
Atezolizumab Protocols 
 
  
 
 
 
QUERIES 
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IRB NUMBER: 15-592
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Protocol Version Date: November 4, 2019
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Queries related to the Study will be answered by Sponsor-Investigator. 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 shall have the final say and control over 
safety queries relating to the Product. Sponsor-Investigator 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. 
 
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 shall have the final say and control over safety crisis management 
issues relating to the Product. Sponsor-Investigator agrees that it shall not answer such queries 
from media and other sources relating to the Product but shall redirect such queries.  
7.5 Expedited Adverse Event Reporting 
For multi-institution studies where a DF/HCC investigator is serving as the Overall PI, each 
participating institution must abide by the reporting requirements set by the DF/HCC. This 
applies to any medical event equivalent to an unexpected grade 2 or 3 with a possible, probable 
or definite attribution, unexpected grade 4 toxicities, and grade 5 (death) regardless of study 
phase or attribution. 
 
7.5.1 
DF/HCC Expedited Reporting Guidelines 
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy. 
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IRB NUMBER: 15-592
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Other investigative sites will report SAEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional SAE form should be forwarded to the Overall PI within the timeframes detailed 
in the table below. 
 
Table 8. DF/HCC Reportable AEs 
Attribution 
DF/HCC Reportable AEs 
Grade 2 & 3 
AE 
Expected 
Grade 2 & 3 
AE 
Unexpected 
Grade 4 AE 
Expected 
Grade 4 AE 
Unexpected 
Grade 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar 
days# 
5 calendar 
days 
24 hours* 
Possible 
Probable 
Definite 
Not required 
5 calendar 
days 
5 calendar 
days# 
5 calendar 
days 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to 
be reported. 
* For participants enrolled and actively participating in the study or for AEs occurring within 
30 days of the last intervention, the AE should be reported within 24 business hours of learning 
of the event. 
 
The Overall PI will submit SAE reports from outside institutions to the DFCI OHRS 
according to DFCI IRB policies and procedures in reporting adverse events. 
 
7.6 Expedited Reporting to the FDA 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. 
The Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse 
event that meets the FDA’s criteria for expedited reporting following the reporting 
requirements and timelines set by the FDA. 
 
7.7 Expedited Reporting to Hospital Risk Management 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy. 
 
7.8 Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions to the Overall PI on 
the toxicity case report forms. AEs reported through expedited processes (e.g., reported to 
the IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 
 
 
 
 
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Protocol Version Date: November 4, 2019
61 
 
 
 
8. PHARMACEUTICAL INFORMATION 
 
8.1 Atezolizumab     
8.1.1 Description 
Atezolizumab is a human immunoglobulin (Ig) G1 monoclonal antibody consisting of two heavy 
chains (448 amino acids) and two light chains (214 amino acids) and is produced in Chinese 
hamster ovary cells. Atezolizumab was engineered to eliminate Fc-effector function via a single 
amino acid substitution (asparagine to alanine) at position 298 on the heavy chain, which results 
in a non-glycosylated antibody that has minimal binding to Fc receptors and prevents Fc-effector 
function at expected concentrations in humans. Atezolizumab targets human programmed death- 
ligand 1 (PD-L1) and inhibits its interaction with its receptor, programmed death-1 (PD-1). 
Atezolizumab also blocks the binding of PD-L1 to B7.1, an interaction that is reported to provide 
additional inhibitory signals to T cells. 
 
8.1.2 Form 
The atezolizumab drug product is provided in a single-use, 20 cc USP/Ph. Eur. Type 1 glass vial 
as a colorless-to-slightly-yellow, sterile, preservative-free clear liquid solution intended for IV 
administration. The vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution but 
may contain more than the stated volume to enable delivery of the entire 20 mL volume. The 
Atezolizumab drug product is formulated as 60 mg/mL atezolizumab in 20 mM histidine acetate, 
120 mM sucrose, 0.04% polysorbate 20, pH 5.8. 
 
8.1.3 Storage and Stability 
Atezolizumab must be refrigerated at 2°C-8°C (36°F-46°F) upon receipt until use. Atezolizumab 
vials should not be used beyond the expiration date provided by the manufacturer. No 
preservative is used in the atezolizumab drug product; therefore, each vial is intended for single 
use only. Discard any unused portion of drug left in a vial. Vial contents should not be frozen or 
shaken and should be protected from direct sunlight. 
 
8.1.4 Compatibility 
No incompatibilities between the bevacizumab and atezolizumab have been observed. 
 
8.1.5 Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
 
8.1.6 Availability 
Genentech/Roche will supply atezolizumab. 
 
8.1.7 Preparation 
See section 5.3. 
 
8.1.8 Administration 
See section 5.3. 
 
8.1.9 Ordering 
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62 
 
 
Genentech/Roche will supply atezolizumab and ordering will take place through 
Genentech/Roche. The study team will complete the Drug Request Form, which is kept as  
separate document. All Drug Request Forms should be sent to the following email
 
 
 
8.1.10 Accountability 
Accountability for investigational product is the responsibility of the investigator. The research 
pharmacy will maintain a careful record of the inventory and disposition of the agent using the 
NCI Drug Accountability Record Form (DARF) or another comparable drug accountability 
form. 
 
8.1.11 Destruction and Return 
Drug should be destroyed at the site, after the investigator approves the drug destruction policy at 
the site. Drug will not be returned to Genentech/Roche. Destruction will be documented in the 
Drug Accountability Record Form. 
 
8.2 Bevacizumab 
 
8.2.1 Description 
Bevacizumab is a recombinant, humanized monoclonal antibody which binds to, and neutralizes, 
VEGF. 
 
8.2.2 Form 
Bevacizumab is manufactured by recombinant DNA technology, using a genetically engineered 
Chinese hamster ovary (CHO) cell line. The protein is purified from the cell culture medium by 
routine methods of column chromatography and filtration. The final product is tested for quality, 
identity, safety, purity, potency, strength, and excipient/chemical composition according to 
International Conference on Harmonisation (ICH) guidelines. The purity of bevacizumab is 
>95%. 
 
Bevacizumab may be supplied in 6-cc (100-mg) and 20-cc (400-mg) glass vials containing 4 mL 
or 16 mL of bevacizumab, respectively (all at 25 mg/mL). Vials contain 
bevacizumab with phosphate, trehalose, polysorbate 20, and sterile water for injection (SWFI). 
Vials contain no preservative and are suitable for single use only. 
 
8.2.3 Storage and Stability 
Upon receipt of the study drug, vials are to be refrigerated at 2C-8C (36F-46F) and should 
remain refrigerated until just prior to use. DO NOT FREEZE. DO NOT SHAKE. Keep vial in 
the outer carton due to light sensitivity. 
 
VIALS ARE FOR SINGLE USE ONLY. Vials used for 1 subject may not be used for any other 
subject. Chemical and physical in-use stability has been demonstrated for 48 hours at 2C-30C 
in 0.9% Sodium Chloride solution. If not used immediately, in-use storage times and conditions 
are the responsibility of the user and would normally not be longer than 24 hours at 2C-8C, 
unless dilution has taken place in controlled and validated aseptic conditions. 
 
8.2.4 Compatibility 
No incompatibilities between the bevacizumab and atezolizumab have been observed. 
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63 
 
 
 
 
8.2.5 Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
 
8.2.6 Availability 
Genentech/Roche will supply bevacizumab. 
 
8.2.7 Preparation 
See section 5.4. 
 
8.2.8 Administration 
See section 5.4. 
 
8.2.9 Ordering 
Genentech/Roche will supply bevacizumab from its commercial supply. Bevacizumab will be 
ordered using the Drug Request Form, which is kept as a separate document. All Drug Request 
Forms should be sent to the following email:
 
 
8.2.10 Accountability 
Accountability for investigational product is the responsibility of the investigator. The 
investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form. 
 
8.2.11 Destruction and Return 
Drug should be destroyed at the site, after the investigator approves the drug destruction policy at 
the site. Drug will not be returned to Genentech/Roche. Destruction will be documented in the 
Drug Accountability Record Form. 
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IRB NUMBER: 15-592
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NCI Protocol #: N/A 
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Protocol Version Date: November 4, 2019
64 
 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Correlative studies will be exploratory in nature. In this study, we will evaluate the 
immunomodulatory properties of atezolizumab in combination with bevacizumab and correlate 
findings with outcomes. In addition, we will evaluate tumor tissue and TIMC for expression of 
PD-L1 in mandatory baseline biopsies and progression biopsies (mandatory in patients who have 
a response to treatment as per RECIST 1.1 and then subsequently progress) and correlate with 
outcomes. Lastly, we will evaluate mechanisms of resistance to therapy in progression biopsy 
specimens. 
 
Whole blood for germline DNA and cfDNA plasma samples will be analyzed by investigators at   
collaborating institutions, such as the Broad Institute, for all patients enrolled on this trial. From  
these samples, the data will be submitted to the National Institutes of Health’s Database for  
Genotypes and Phenotypes (dbGaP) and other public databases. Samples and data will be de-
identified.  
 
9.1 Blood Studies 
Biomarker Analysis 
Serum plasma will be collected for flow cytometry studies to analyze peripheral blood 
mononuclear cells. Additionally, plasma will be collected to analyze soluble biomarkers to 
include cytokines/chemokines and angiogenic/growth factors. 
 
For DF/HCC participating sites, 30 mL of blood will be collected as per the Laboratory Manual 
and couriered within 6 hours of collection to The Center of Immunooncology Laboratory. 
 
For non-DF/HCC participating sites, 30 mL of blood will be collected and stored as per the 
Laboratory Manual and batch shipped at the end of study to The Center of Immunooncology 
Laboratory. 
 
Germline DNA 
Whole blood for Germline DNA for cfDNA will be collected as per the Laboratory Manual and 
stored until the end of study at which time the sample will be shipped overnight to the Broad 
Institute. 
 
Whole blood for Germline DNA for tissue will be collected as per the Laboratory Manual and 
stored until the end of study at which time the sample will be shipped overnight to the Signoretti 
Laboratory. 
 
cfDNA Plasma 
As an exploratory endpoint, plasma will be collected at baseline, every two cycles, and at the end 
of study for genomic analysis of circulating free DNA (cfDNA). 
 
Blood for cfDNA will be collected as per the Laboratory Manual and shipped at the end of study 
to the Broad Institute. 
 
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9.2 Tissue Studies 
 
Tissue will be collected to assess the immunomodulatory properties of atezolizumab in 
combination with bevacizumab, assess PD-L1 tumor and TIMC expression, and evaluate 
mechanisms of acquired resistance to therapy. Mutation profiling will be performed using 
massively parallel sequencing technology (Oncopanel) and/or whole exome and transcriptome 
sequencing. 
 
Mutational profiling of molecular mechanisms of response and resistance will be analyzed via 
whole exome or whole genome sequencing and via RNA-sequencing. If fresh tissue is available, 
the specimen will be collected, as stated in this protocol and according to institutional guidelines, 
and put on ice to be transported to the processing laboratory. A portion of fresh tissue will be 
dissociated into a single cell suspension and frozen for future studies, including single cell 
transcriptome studies and cell line creation. 
 
Archived Tumor Tissue 
Archived tumor tissue will be collected pre-study as per the Laboratory Manual and stored at 
ambient temperature until the end of study at which time the specimens will be shipped to the 
Signoretti Laboratory. 
 
Fresh Tumor Tissue 
Fresh tumor biopsy will be conducted pre-study as per the Laboratory Manual. Fresh tumor 
biopsy may be conducted at the end of study on patients who experience a response as per 
RECIST 1.1 and then subsequently progress if medically safe. Frozen specimens should be 
stored at -80°C and specimens fixed in formalin should be stored at 4°C until shipping. At the 
end of study, the tumor specimens will be shipped to the Signoretti Laboratory. 
 
9.3 
Radiology Imaging Studies 
Images of all radiologic assessments at baseline, on study, and at treatment discontinuation with 
corresponding imaging reports for non-DFCI patients need to be placed on a CD and sent to the 
DFCI for central review of exploratory imaging response assessment by irRC. Images and 
reports should be sent on all patients once they discontinue study treatment. Reference the 
Laboratory Manual for additional information. 
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Protocol Version Date: November 4, 2019
66 
 
 
 
10. STUDY CALENDAR 
 
Pre- Study1 
Day 1 of Each Cycle 
(+/- 3 days)2 
Every 6 weeks 
(+/- 7 days)3 
Treatment 
Discontinuation Visit 
(within 30 days of last 
treatment)20 
Follow up4 
Informed Consent 
X 
Demographics 
X 
History and Physical5 
X 
X 
X 
ECOG Performance 
Status 
X 
X 
X 
Vital Signs6 
X 
X 
X 
Weight 
X 
X 
X 
Height 
X 
X 
X 
Hematology7 
X 
X 
X 
Serum Chemistry8 
X 
X 
X 
Liver Function Tests9 
X 
X 
X 
TSH/fT3/fT4 
X 
X 
X 
Urinalysis10 
X 
X 
X 
Coagulation Factors11 
X 
Pregnancy Test12 
X 
Viral Serologies13 
X 
C-Reactive Protein 
X 
X 
EKG 
X 
ECHO 
X 
MRI or CT Brain14 
X 
Imaging15 
X 
X 
FKSI-19 
X 
X 
X 
BFI 
X 
X 
Concomitant 
Medications 
X 
X 
X 
Adverse Events 
X 
Atezolizumab 
Administration 
X21 
Bevacizumab 
Administration 
X21 
Germline DNA16 
X 
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Plasma cfDNA17 
X 
X 
X 
Blood Biomarkers17 
X 
X 
X 
Archival Tumor Tissue18 
X 
Tumor Biopsy19 
X 
X22 
1: Baseline evaluations are to be conducted within 28 days prior to registration. Scans must be done within 28 days of registration. All 
baseline screening should be done prior to registration. 
2: A cycle will be defined as 21 days (+/- 3 days). 
3: Imaging assessments and quality of life assessments will take place every 6 weeks (2 cycles) for the first 24 weeks (6 months). After 6 
months, imaging assessments and quality of life assessments can take place every 12 weeks (+/- 7-10 days) 
4: After progression/treatment discontinuation, participants will be followed for survival and receipt of next line therapies every 6 months 
until death or 2 years after treatment discontinuation. 
5: Physical examination should include general description of participant, head, eyes, ears, nose, and throat, chest, abdominal, extremities, 
neurologic, skin, and lymph node examination. Any other evaluation is up to the discretion of the practitioner. It will not be considered a 
violation if the exam is not described as outlined here. 
6: Vital signs include blood pressure, heart rate, respiratory rate, and body temperature. 
7: Hematology testing to include full CBC with WBC, ANC, hemoglobin, and platelet count and differential. 
8: Serum chemistry to include full comprehensive metabolic panel with sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, calcium, albumin, magnesium, and LDH. 
9: Liver function tests to include AST, ALT, , total bilirubin, and direct bilirubin.  
10: Patients with ≥ 2+ protein on dipstick urinalysis at baseline must undergo 24-hour urine collection for protein. 
11: Coagulation factors to include PT, aPTT, and INR. 
12: Pregnancy test only needs to be obtained in childbearing women. 
13: Hepatitis B virus (HBV) serology (HBsAg, , hepatitis B core antibody), and HCV serology (anti-HCV). HBV DNA test is required 
for patients who have known positive serology for hepatitis B core antibody. HCV RNA test is required for patients who have known 
positive serology for anti HCV. HIV testing is also required. 
14: MRI of the brain with and without contrast is preferred. If a patient is not able to obtain an MRI, CT imaging with contrast is 
acceptable. If a patient is no able to receive contrast, CT head without contrast is acceptable. 
15: Diagnostic CT chest and CT or MRI of the abdomen and pelvis should be obtained at baseline and at every 6 week imaging 
assessment. All baseline scans used to determine disease burden should be continued during restaging scans. In instances when providers 
would like to follow with bone scans they can be followed at 6 or 12 weeks by provider discretion. Actual images and imaging reports at 
all time points including baseline, on study, and at treatment discontinuation must be sent to DFCI for central review once a patient has 
discontinued treatment. 
16: Blood for germline DNA analysis will be collected once at Cycle 1 Day 1. 
17: Research plasma cfDNA analysis and blood biomarkers to be collected at baseline, every 6 weeks on treatment for the first 24 weeks 
(6 months). After 6 months, research plasma if cfDNA and blood biomarkers can be collected every 12 weeks (+/- 7-10 days), and at the 
time of progression. If off treatment collection is within 2 weeks of prior collection, research samples do not need to be collected. 
18: Archival tissue should to be requested and availability confirmed prior to therapy initiation. A note from the study team should be 
provided documenting availability of tissue. 
19: Baseline fresh tumor biopsies are not optional, and must occur at least 7 days prior to the first dose of bevacizumab if medically 
feasible and safe. 
20: Patients who discontinue from treatment will be asked to return to the clinic no more than 30 days after the last treatment for a 
treatment discontinuation visit. The visit at which a response assessment shows progressive disease may be used as the treatment 
discontinuation visit. 
21: Atezolizumab and bevacizumab are to be administered +/-3 days of Day 1 of each cycle. Each cycle should be calculated from the last 
dose of study drug or last study visit if both study drugs were skipped  (either single agent Atezolizumab or bevacizumab or drug 
combination).  
22: Progression tumor biopsies are mandatory in a subset of participants who demonstrate a tumor response to therapy and then 
subsequently develop tumor progression if medically safe. The progression tumor biopsy must be at least 2 weeks after the participants’ 
last dose of bevacizumab. 
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Protocol Version Date: November 4, 2019
68 
 
 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, participants should be re-evaluated for response every 6 weeks. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the RECIST guideline (version 1.1).25 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. 
 
11.1.1 Definitions 
Evaluable for Target Disease response. Only those participants who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease re- 
evaluated will be considered evaluable for target disease response. These participants will have 
their response classified according to the definitions stated below. (Note: Participants who 
exhibit objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response. Participants 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. 
 
11.1.2 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 or ≥10 mm 
with CT scan, MRI, or 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 are not considered 
measurable. 
 
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. Leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all considered 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. 
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‘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 participant, these are preferred for selection as target lesions. 
 
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. If a target 
lesion is biopsied at screening, this lesion must be followed as non-target lesions after the biopsy 
unless it is the patients only target lesion. If there is only one target lesion, it should be followed 
as a target lesion regardless. 
 
11.1.3 Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation using a ruler, calipers, or a 
digital measurement tool. 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 in 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. 
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT thickness is 5mm or less. If CT scans have slice thickness greater than 
5 mm, the minimum size of a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans). 
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70 
 
 
 
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. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
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, 
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 progression). 
 
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. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. For patients who demonstrate PD at the first on-treatment imaging assessment, patients 
will be allowed to remain on study until confirmatory imaging at the next imaging assessment at 
the discretion of the treating investigator if it appears that the patients is clinically benefiting 
from treatment. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
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treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
11.1.4.3 
Evaluation of New Lesions 
The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning 
technique, imaging modality, or findings thought to represent something other than tumor (for 
example, some ‘new’ bone lesions may be simply healing or flare of pre-existing lesions). 
However, a lesion identified on a follow-up scan in an anatomical location that was not scanned 
at baseline is considered new and will indicate PD. If a new lesion is equivocal (because of small 
size etc.), follow-up evaluation will clarify if it truly represents new disease and if PD is 
confirmed, progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
 
11.1.4.4 
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. 
 
Table 9. For Participants with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non- 
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
 In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
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72 
 
 
 
 
 
 
Table 10. For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘SD’ for non-target disease since SD is increasingly 
used as an endpoint for assessment of efficacy in some trials so to assign this category 
when no lesions can be measured is not advised 
11.1.5 Duration of Response 
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, or death due to any 
cause. Participants without events reported are censored at the last disease evaluation). 
Duration of overall CR: 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, 
or death due to any cause. Participants without events reported are censored at the last disease 
evaluation. 
Duration of SD: SD 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. 
11.1.6 Immune-Related Response Criteria (irRC) 
The sum of the products of the two largest perpendicular diameters of lesions (SPD; 5 lesions per 
organ, up to 10 visceral lesions) at tumor assessment using the immune related response criteria 
(irRC) for progressive disease incorporates the contribution of new measurable lesions (up to 5 
new lesions per organ: 10 new visceral lesions).26 Each net Percentage Change in Tumor Burden 
per assessment using irRC criteria accounts for the size and growth kinetics of both old and new 
lesions as they appear. 
11.1.6.1 
Definition of  IndexLesions Response Using irRC 
• irComplete Response (irCR): Complete disappearance of all target lesions in two 
consecutive observations not less than 4 weeks apart. This category encompasses exactly 
the same subjects as “CR” by the mWHO criteria. 
• irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum of 
the products of the two largest perpendicular diameters of all target and all new 
measurable lesions in two consecutive observations not less than 4 weeks apart. 
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(i.e., Percentage Change in Tumor Burden). Note: the appearance of new measurable 
lesions is factored into the overall tumor burden, but does not automatically qualify as 
progressive disease until the SPD increases by > 25% when compared to SPD at nadir. 
• irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of 
progressive disease. 
• irProgressive Disease (irPD): At least 25% increase in the percentage change in tumor 
burden (i.e., taking SPD of all target lesions and any new lesions) when compared to SPD 
at nadir, in two consecutive observations at least 4 weeks apart, in the absence of rapid 
clinical deterioration. 
 
11.1.6.2 
Definition of Non-Index Lesions Response Using irRC 
• irComplete Response (irCR): Complete disappearance of all non-index lesions. This 
category encompasses exactly the same subjects as “CR” by the mWHO criteria. 
• irPartial Response (irPR): Non-index lesion(s) are not considered in the definition of PR; 
this term does not apply. 
• irStable Disease (irSD): Does not meet the criteria for irCR or irPD. 
• irProgressive Disease (irPD): Increases in number or size of non-index lesion(s) does not 
constitute progressive disease unless/until the Percentage Change in Tumor Burden 
increases by 25% (i.e., the SPD at nadir of the target lesions increases by the required 
amount). 
 
11.1.6.3 
Impact of New Lesions on irRC 
New lesions in and by themselves do not qualify as progressive disease. However their 
contribution to total tumor burden is included in the SPD which in turn feeds into the irRC 
criteria for tumor response. Therefore, new non-measurable lesions will not discontinue any 
subject from the study. 
 
11.1.6.4 
Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria: 
• Immune-Related Complete Response (irCR): Complete disappearance of all tumor 
lesions (index and non-index together with no new measurable/unmeasurable lesions) for 
at least 4 weeks from the date of documentation of complete response. 
• Immune-Related Partial Response (irPR): The sum of the products of the two largest 
perpendicular diameters of all index lesions is measured and captured as the SPD 
baseline. At each subsequent tumor assessment, the SPD of the two largest perpendicular 
diameters of all index lesions and of new measurable lesions are added together to 
provide the Immune Response Sum of Product Diameters (irSPD). A decrease, relative to 
baseline of the irSPD compared to the previous SPD baseline, of 50% or greater is 
considered an immune Partial Response (irPR). 
• Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria for 
immune complete response or immune partial response, in the absence of progressive 
disease. 
• Immune-Related Progressive Disease (irPD): It is recommended to confirm PD by serial 
imaging. Any of the following will constitute progressive disease: 
− At least 25% increase in the SPD of all target lesions over nadir SPD calculated 
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for the index lesions. 
− At least a 25% increase in the SPD of all index lesions and new measurable 
lesions (irSPD) over the nadir SPD calculated for the target lesions. 
 
 
Table 11. Immune-Related Response Criteria Definitions 
Target 
Lesion 
Definition 
Non-Target 
Lesion 
Definition 
New 
Measurable 
Lesions 
New  
Unmeasurable 
Lesions 
Percent Change 
in Tumor 
Burden 
(including 
measurable 
new lesions 
when present) 
Overall 
irRC 
Response 
Complete 
Response 
Complete 
Response 
No 
No 
-100% 
irCR 
Partial 
Response 
Any 
Any 
Any 
≥-50% 
irPR 
<-50% to 
<+25% 
irSD 
>+25% 
irPD 
Stable 
Disease 
Any 
Any 
Any 
<-50% to 
<+25% 
irSD 
>+25% 
irPD 
Progressive 
Disease 
Any 
Any 
Any 
≥+25% 
irPD 
 
11.1.6.5 
Immune-Related Best Overall Response Using irRC (irBOR) 
irBOR is the best confirmed irRC overall response over the study as a whole, recorded between 
the date of first dose until the last tumor assessment before subsequent therapy (except for local 
palliative radiotherapy for painful bone lesions) for the individual subject in the study. For the 
assessment of irBOR, all available assessments per subject are considered. irCR or irPR 
determinations included in the irBOR assessment must be confirmed by a second (confirmatory) 
evaluation meeting the criteria for response and performed no less than 4 weeks after the criteria 
for response are first met. 
 
11.1.7 Response Review 
Tumors will be assessed for response and progression by RECIST version 1.1 by central 
radiology review. 
 
11.1.8 Progression-Free Survival 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive. 
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Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease evaluation. 
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12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
The ODQ will collect, manage, and perform quality checks on the data for this study. 
 
12.1.2 Responsibility for Data Submission 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to the ODQ according to the schedule set by the ODQ. 
 
12.2 
Data Safety Monitoring 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; all grade 2 or higher unexpected adverse events that have been reported; , 
summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other information (e.g. 
scans, laboratory values) will be provided upon request. 
 
12.3 
Multicenter Guidelines 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan. The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix C. 
 
• The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters 
or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required. 
 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site. 
 
• Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from supplier. A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center. 
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13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
This is a multi-center, open-label, single-arm phase II study of the combination of the human 
immunoglobulin (Ig) G1 monoclonal antibody (atezolizumab) with bevacizumab in patients with 
advanced non-clear cell renal cell carcinoma (nccRCC). 
 
The primary objective is to evaluate the efficacy of the drug combination. 
 
Primary Endpoints: 
 
− Objective Response Rate: Confirmed CR or PR as best overall response according 
to RECIST version 1.1 as defined in section 11.1.4 by central review. 
 
Secondary/exploratory Endpoints: 
 
− ORR by histologic subtype (papillary, sarcomatoid RCC, and other nccRCC) 
 
− Duration of ORR 
 
− Safety and tolerability according to NCI CTCAE version 4.0. 
 
− Immune Related Objective Response Rate as defined according to Immune- 
Related Response Criteria26  and detailed in section 11.1.6. 
 
− PFS defined as the time from trial treatment start to the earlier of progression or 
death due to any cause. Participants alive without disease progression are 
censored at date of last disease evaluation. 
 
− OS defined as the time from trial treatment start to death due to any cause, or 
censored at date last known alive. 
 
− Quality of life assessments include FKSI-19 and BFI. The FKSI-19 is a 19 item 
questionnaire with each item scored on a scale of 0-4 for a total score of 0-76 with 
higher scores indicating fewer symptoms (Appendix D).27 The BFI is a 9 item 
questionnaire with each item scored on a scale of 0-10.28   Scores are categorized 
as mild (1-3), moderate (4-6), or severe (7-10). A global fatigue score can be 
found by averaging the score obtained on each test item completed (Appendix E). 
 
− Immunomodulatory properties: Blood based biomarkers representing 
immunomodulatory properties of combination treatment with atezolizumab and 
bevacizumab at baseline, on treatment and at disease progression 
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− Tumor expression for PD-L1 at pre-treatment and post treatment/ radiographic 
progression. 
− Resistance to therapy measured by somatic mutation, insertions and deletions, 
copy number alterations, overexpressed genes, and chimeric transcripts and a 
complete set of potential driver alterations 
 
13.2 
Sample Size, Accrual Rate and Study Duration 
A single arm design was used to estimate the sample size for this phase II trial. Evaluable 
patients who receive at least one combination therapy of bevacizumab and atezolizumab will be 
included in the sample size. 
 
The null hypothesis (Ho) of a true objective response rate (ORR) of 6%-10% were seen from 
reported with sunitinib and data of targeted therapy in patients with nccRCC from the IMDC.2,3 
The following table shows that a corresponding alternative hypothesis (Ha) of objective response 
rate to be detected under the scenario with the adequate statistical power. Specifically, assuming 
a hypothesis test of Ho: ORR=0.1 versus Ha: ORR=0.25 (bold in table), there is a 90% 
statistical power with the minimum sample size of 40 for an exact one-sided one-sample 
binomial test with a type I error rate=0.1 and beta (type II error =0.1) to assess the efficacy 
(ORR) of the bevacizumab and atezolizumab combination, i.e., if at least 7 responses out of 40 
patients are observed, then the treatments are considered to be efficacious or the null hypothesis 
of 10% ORR is rejected. 
 
Type I error 
(one-sided) 
Ho:  
ORR (%) 
Ha: 
ORR 
Sample 
size 
# of 
responses 
required to 
reject Ho 
Corresponding 
80% 
confidence 
interval (CI) 
Power 
(%) 
0.1 
6 
15 
77 
>7 
(6,16) 
91 
0.1 
10 
25 
40 
>6 
(10, 28) 
90 
0.1 
15 
30 
53 
>11 
(15,32) 
90 
The accrual is expected to be 3 patients every month for a duration of 20 months to complete 
enrollment. 
 
As of April 28, 2017, the sample size will be increased from n=40 to 60 patients. The increased 
sample size to n=60 patients will allow for better efficacy analysis according to histology 
subtypes. Specifically, an exploratory objective has been added to estimate the ORR according to 
histology subtypes. 
 
Justification of sample size increase:  It is estimated that among the targeted patient 
population, 50% would be papillary RCC, 20% would be other nccRCC, and 30% RCC with > 
20% sarcomatoid features.  With the assumed/expected sample size in each histology subtype 
and the targeted ORR rate, the following table provides the ORR estimate precision (the width of 
a confidence interval (CI)) to be achieved based on the unknown targeted ORR rate. The 
precision of ORR estimate uses 80% CI, to be consistent with the original study design, which 
was based on 90% power for a one-sided type I error of 10% for a hypothesis test of Ho: 
ORR=0.05 vs. Ha: ORR=0.25. 
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For example, if the targeted ORR is 0.25, with a sample size of n=30 with papillary RCC (bold), 
the width of 80% CI for a ORR estimate would be 0.24 (precision), and with the maximum width 
of 80% CI to be .26 (corresponding to a  ORR of 0.5) 
 
ORR estimate 
Histology subtypes 
N 
Targeted 
ORR 
80% CI 
Width of 80% 
CI 
Papillary RCC (50%) 
30 
0.2 
(0.11,0.32) 
0.21 
30 
0.25 
(0.16,0.4) 
0.24 
30 
0.5 
(0.37,0.63) 
0.26* 
RCC with >20% 
sarcomatoid features 
(30%) 
18 
0.2 
(0.1,0.4) 
0.3 
18 
0.25 
(0.1,0.4) 
0.3 
18 
0.5 
(0.33,0.67) 
0.34* 
Other nccRCC (20%) 
12 
0.2 
(0.05,0.39) 
0.34 
12 
0.25 
(0.1,0.48) 
0.38 
12 
0.5 
(0.29,0.71) 
0.42* 
* The maximum width of a 80%CI for a ORR estimate. 
 
13.3 
Definition of Study Population /Stratification Factors 
Safety/Evaluable population: All patients receiving at least one dose of bevacizumab and 
atezolizumab will be included in analyses unless otherwise specified. 
 
No stratification factors are used in enrolling patients. 
 
IMDC risk group (favorable, intermediate, versus poor risk as previously defined),29 prior 
systemic treatment for RCC (yes versus no), histology (papillary versus other) will be used in 
subset analysis. IMDC risk factors include ECOG < 1, time from original diagnosis to treatment 
less than one year, hemoglobin less than the lower limit of normal, and serum calcium, 
neutrophil count, or platelet count greater than the upper limit of normal. 
 
13.4 
Analysis of Demographics/Baseline Characteristics 
Demographic and other baseline characteristics will be summarized for all patients by study 
population. Demographic and baseline characteristics of patients who are replaced will be 
summarized in a separate category. Summaries of continuous demographic/baseline variables, 
including age, weight, and vital signs, will be presented as N, mean, standard deviation, median, 
quartiles and minimum and maximum values. For categorical variables, such as histology type, 
the number and percentage of patients will be used. 
13.5 
Efficacy Analysis 
Primary Analysis 
Tumor assessment will be performed every 6 weeks (every 2 cycles). At the time of each 
restaging, patients will be classified as achieving complete response (CR), partial response (PR), 
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stable disease (SD), progressive disease (PD), or non-evaluable for response according to 
RECIST (Version 1.1) criteria. Objective response will be determined by the best overall 
confirmed response designation recorded between the date of first dose of trial therapy and the 
date of objectively documented disease progression or cessation of trial therapy, whichever 
occurs first. For patients without documented progression or cessation of trial therapy, all 
available response designations will contribute to the objective response determination. The 
proportion of patients with an objective response will be presented with a two-sided 80% 
confidence interval (CI) using exact binominal method. Based on a sample size of 40 patients, 
the confidence interval will be no wider than 0.22. For the targeted ORR=25%, the estimated 
ORR precision (two sided 80%CI) would be 0.20. 
 
Secondary Analyses 
Safety and Tolerability: All adverse events recorded during the trial will be summarized for the 
safety population. The incidence of events that are new or worsening from the time of first dose 
of treatment will be summarized according to system organ class and/or preferred term, severity 
(based on CTCAE version 4.0 grade), type of adverse event, and relation to study treatment. 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by primary system organ class, and type of adverse event. 
 
Immune Related Objective Response Rate: The proportion of patients with immune ORR (as 
defined in section 11.1.6) will be presented with two-sided 90% confidence interval estimated 
using exact binomial methods. 
 
PFS and OS: PFS and OS will each be summarized using the product-limit method of Kaplan- 
Meier. Median times for each endpoint will be presented with two-sided 90% confidence 
intervals estimated using log(-log(survival)) methodology. Kaplan-Meier estimates of PFS at 6 
or 12 months after treatment initiation may also be presented with two-sided 90% confidence 
intervals. 
 
Quality of Life Assessment: 
The quality of life assessments use the FKSI-1 comprising of 19 items (each has score range 
from 0 to 4) with a possible maximum total score of 76. The BFI is a 9 items questionnaire 
(each score ranging from 0-10) with possible maximum score of 90. Patients will be asked to 
complete FKSI-19 and BFI Forms at baseline (prior to randomization), at every 6 week visits or 
time of treatment termination (only FKSI-19). 
• 
The estimated differences in quality of life measurements (total scores) between baseline 
(pre-treatment) and the subsequent timepoints while patients receiving treatment will be 
summarized with 90% CI. 
• Each of the 19 (FKSI) items will also be summarized descriptively over time as the 
proportion of patients with “clinically significant” symptoms (those scoring 3 or 4). Two 
sided 90% CI for the difference in the proportion will also be assessed. 
• Missing assessments may be due to stopping treatment, not completing the FKSI or BFI 
assessments, and other reasons. Information on reasons why the patient did not complete 
the FKSI or BFI Form will be collected. 
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13.6 
Exploratory/Correlative Analysis 
 
We anticipate that 15-20% of tumors (of the 40s patients) will not be evaluable for the analyses 
given issue with biopsy/staining/ etc. The evaluable samples for the analysis will be 32 (80% of 
40 patients). 
 
We anticipate that 15-20% of tumors (of the 40s patients) will not be evaluable for the analyses 
given issue with biopsy/staining/ etc. The evaluable samples will be 32 (80% of 40 patients). 
 
Tumor infiltrating lymphocytes (TILs) (biomarkers of immunomodulatory properties) 
 
The relationship between tumor-infiltrating lymphocytes (TILs) and outcomes will be explored 
according to pre-treatment TIL percentages. It is hypothesized that higher levels of lymphocytic 
infiltration will be associated with better outcomes. To examine responses according to levels of 
TILs, the evaluable samples will be divided retrospectively according to objective response or 
non-response. Pre-treatment percentages of stromal infiltrating lymphocytes will be summarized 
descriptively for the two response groups and compared using Wilcoxon rank-sum tests. Assume 
a targeted ORR of 25% (our primary study alternative hypothesis), if there are 8 responses (25% 
of 32 patients) and 24 non-responses, a Wilcoxon rank-sum test with a two-sided, 10% type I 
error will have 88% power to detect a difference in baseline TILs between the two response 
groups that is 1.2 times the common standard deviation. 
 
Kaplan-Meier estimates will be used to visualize the relationship between PFS or OS and 
lymphocyte predominant breast cancer (LPBC) phenotype or median of the distribution of 
intratumoral or stromal percentages. The LPBC phenotype is defined as 50% or higher 
infiltration (baseline TIL) of either stromal or intratumoral lymphocytic infiltration. Medians of 
the time-to-event endpoints will be calculated with two-sided 90% confidence intervals 
according to the LPBC groups. 
 
Changes in TILs between baseline and progression/treatment discontinuation will be calculated 
(post-pre) for each patient and summarized descriptively. In addition, the correlation of TIL 
changes with measures of peripheral blood markers/cytokines (including a panel of markers IL1, 
2, 4, 6, 8, 19, 12, IFN, TNFa, GMCSF) will be explored graphically, or by appropriate statistical 
methods based on data availability, to assess associations. 
 
PD-L1 Expression Levels 
 
The PD-L1 expression will be evaluated by IHC in both tumor cell membrane and TIMC. The 
association between pre-treatment PD-L1 expression (percentages) and outcomes will be 
explored. It is hypothesized that higher expression levels of PD-L1 will be associated with poor 
outcomes, due to the fact that upregulation of PD-L1 may allow cancers to evade the immune 
system. 
 
To examine responses according to PD-L1 expression, the evaluable samples will be divided 
retrospectively according to objective response or non-response. Pre-treatment 
PD-L1 expression will be summarized descriptively for the two response groups. 
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In order to assess the association of PD-L1 positivity with objective response, given the limited 
sample size, the study could only detect large difference. Based on our experience in a cohort 
of nccRCC patients [ref], the observed PD-L1 positivity is 11% in tumor cell membrane, and 
56% in TIMC, respectively. The following table displays the detectable differences in PD-L1 
positivity (PD-L1>5%) between the response groups (yes vs. no) with reasonable statistical 
power in TIMC samples, assuming an overall expected % PD-L1+ of 50%-60%, i.e., only large 
differences in % of PD-L1 positivity (56% in responder vs. 6% in non-responders) could be 
detected with 81% power. 
 
[ref]: T.K. Choueiri et al. PD-L1 expression in nonclear-cell renal cell carcinoma. Annals of 
Oncology 25: 2178–2184, 2014 
 
 
Responder 
Non-responder 
% PD-L1 + in 
TIMC 
# samples 
% PD-L1 + in 
TIMC 
# samples 
Exact Power of 
Fisher’s test 
50% 
8 
3% 
24 
82% 
56% 
8 
6% 
24 
81% 
60% 
8 
9% 
24 
80% 
 
 
Therefore, no formal inference will be made. The proportion of patients with objective response 
according to pre-treatment (baseline) PD-L1 positivity (PD-L1 ≥5% tumor cell membrane 
staining) will be summarized with two-sided 90% exact binomial CI. Kaplan-Meier estimates 
will be used to describe the distribution of PFS according to baseline PD-L1 expression 
positivity. Medians of time to event endpoints will be shown with two-sided 90% CIs. 
 
Mechanism of Resistance to Therapy 
We will analyze mechanisms of resistance to therapy via serial tumor biopsies (pre-treatment and 
post treatment/progression). Mutation profiling will be performed using massively parallel 
sequencing technology (Oncopanel) and/or whole exome and transcriptome sequencing. The 
sequencing data will be analyzed for somatic mutations, insertions and deletions, copy number 
alterations, overexpressed genes, and chimeric transcripts and a complete set of potential driver 
alterations will be compiled at baseline and progression. 
 
Changes in the aforementioned mutation measures of resistance between baseline and 
progression/treatment discontinuation will be calculated (post-pre) for each patient and 
summarized descriptively. In addition, the correlation among the resistance (marker changes 
post-pre) measures will be explored graphically, or by appropriate statistical methods based on 
data availability, to potentially assess associations. 
 
13.7 
Safety Monitoring 
No formal stopping rule regarding the primary efficacy endpoints is planned. Adverse event 
reports are to be submitted within 28 days of each clinic visit. All relevant adverse events will be 
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reviewed by the DSMC for up to 4 times each year. The DSMC will make recommendation to 
the study management team if it notes any concerns regarding patient safety or if further action 
needs to be taken based on the safety monitoring review results. Formal assessment of (targeted) 
adverse events will also be included in statistical analysis for secondary objectives as detailed in 
section 13.5. 
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14. ETHICAL CONSIDERATIONS 
 
14.1 
Compliance with Laws and Regulations 
Patients who comply with the requirements of the protocol, are tolerating study treatment, and 
may be receiving benefit will be offered dosing beyond Cycle 1 at the investigator’s discretion 
after a careful assessment and thorough discussion of the potential risks and benefits of 
continued treatment with the patient. Such patients may have the option to receive atezolizumab 
treatment as long as they continue to experience clinical benefit in the opinion of the investigator 
until the earlier of unacceptable toxicity, symptomatic deterioration attributed to disease 
progression, or any of the other reasons for treatment discontinuation listed in Section 5.6. 
 
14.2 
Informed Consent 
The informed consent document must be signed by the subject or the subject’s legally authorized 
representative before his or her participation in the study. The case history for each subject shall 
document that informed consent was obtained prior to participation in the study. A copy of the 
informed consent document must be provided to the subject or the subject's legally authorized 
representative.  If applicable, it will be provided in a certified translation of the local language. 
Signed consent forms must remain in each subject’s study file and must be available for 
verification by study monitors at any time. 
 
14.3 
Institutional Review Board or Ethics Committee Approval 
This protocol, the informed consent document, and relevant supporting information must be 
submitted to the IRB for review and must be approved before the study is initiated. The study 
will be conducted in accordance with FDA, applicable national and local health authorities, and 
IRB requirements. 
 
The Principal Investigator is responsible for keeping the IRB apprised of the progress of the 
study and of any changes made to the protocol as deemed appropriate, but in any case, the IRB 
must be updated at least once a year. The Principal Investigator must also keep the IRB 
informed of any significant AEs. 
 
Investigators are required to promptly notify their respective IRB of all adverse drug reactions 
that are both serious and unexpected.  This generally refers to SAEs that are not already 
identified in the Investigator’s Brochure and that are considered possibly or probably related to 
the molecule or study drug by the investigator. Some IRBs may have other specific AE 
requirements to which investigators are expected to adhere. Investigators must immediately 
forward to their IRB any written safety report or update provided by Genentech (e.g., IND safety 
report, Investigator’s Brochure, safety amendments and updates, etc.). 
 
14.4 
Confidentiality 
Patient medical information obtained by this study is confidential and may be disclosed to third 
parties only as permitted by the ICF (or separate authorization to use and disclose personal health 
information) signed by the patient or unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes. 
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Data generated by this study must be available for inspection upon request by representatives of 
the FDA and other regulatory agencies, national and local health authorities, Genentech 
representatives and collaborators, and the IRB/Ethics Committee (EC) for each study site, if 
appropriate. 
 
14.5 
Study Medical Monitoring Requirements 
This clinical research study will be monitored both internally by the PI and externally by the 
IRB.  In terms of internal review, the PI will continuously monitor and tabulate AEs. 
Appropriate reporting to the IRB will be made. The PI of this study will also continuously 
monitor the conduct, data, and safety of this study to ensure that: 
− Interim analyses occur as scheduled, 
− Stopping rules for toxicity and/or response are met, 
− Risk/benefit ratio is not altered to the detriment of the subjects, 
− Appropriate internal monitoring of AEs and outcomes is done, 
− Over-accrual does not occur, 
− Under-accrual is addressed with appropriate amendments or actions, and 
− Data are being appropriately collected in a reasonably timely manner. 
 
Routine monitoring will be carried out via a periodic team conference among investigators 
during which toxicity data, including all SAEs, will be reviewed and other issues relevant to the 
study such as interim assessment of accrual, outcome, and compliance with study guidelines, will 
be discussed. Monitoring will be carried out on an ongoing basis. The severity, relatedness, and 
whether or not the event is expected will be reviewed. 
 
14.6 
Study Medication Accountability 
If study drug will be provided by Genentech, the recipient will acknowledge receipt of the drug 
by returning the INDRR 1 form indicating shipment content and condition. Damaged supplies 
will be replaced. 
 
Accurate records of all study drug dispensed from and returned to the study site should be 
recorded by using the institution’s drug inventory log or the National Cancer Institute drug 
accountability log. 
 
All partially used or empty containers should be disposed of at the study site according to 
institutional standard operating procedure. Return unopened, expired, or unused study drug with 
the Inventory of Returned Clinical Material form as directed by Genentech. 
 
14.7 
Data Collection 
The study coordinator and investigators are responsible for ensuring that the eligibility checklist 
is completed in a legible and timely manner for every patient enrolled in the study, and that data 
are recorded on the appropriate forms and in a timely manner. Any errors on source data should 
be lined through, but not obliterated, with the correction inserted, initialed, and dated by the 
study coordinator or PI. All source documents will be available for inspection by the FDA and 
the DFCI IRB. 
 
 
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Before trial completion, it is possible to report data on a subset of patients for safety reasons or in 
case a later cohort was added mainly for correlatives purposes or a specific cohort within the trial 
finished accrual.  
 
14.8 
Retention of Records 
FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see Section 4.9 of the 
guideline) require that records and documents pertaining to the conduct of clinical trials and the 
distribution of investigational drug, patient records, consent forms, laboratory test results, and 
medication inventory records, must be retained for 2 years after the last marketing application 
approval in an ICH region or after at least 2 years have elapsed since formal discontinuation of 
clinical development of the investigational product. All state and local laws for retention of 
records also apply. 
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15. PUBLICATION PLAN 
 
The data will be collected by the Principal Investigator and analyzed by the Principal 
Investigator and the statistical team at DFCI. It is anticipated that the results will be made public 
within 12 months of the end of data collection. A report is planned to be published in a peer- 
reviewed journal, however initial release may be an abstract that meets the requirements of the 
International Committee of Medical Journal Editors. 
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16. REFERENCES 
 
1. 
Dutcher JP, de Souza P, McDermott D, et al. Effect of temsirolimus versus interferon- 
alpha on outcome of patients with advanced renal cell carcinoma of different tumor 
histologies. Med Oncol. 2009;26(2):202-209. 
2. 
Tannir NM, Plimack E, Ng C, et al. A phase 2 trial of sunitinib in patients with advanced 
non-clear cell renal cell carcinoma. Eur Urol. Dec 2012;62(6):1013-1019. 
3. 
Kroeger N, Xie W, Lee JL, et al. Metastatic non-clear cell renal cell carcinoma treated 
with targeted therapy agents: characterization of survival outcome and application of the 
International mRCC Database Consortium criteria. Cancer. Aug 15 2013;119(16):2999- 
3006. 
4. 
Escudier B, Bellmunt J, Negrier S, et al. Phase III trial of bevacizumab plus interferon 
alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of 
overall survival. J Clin Oncol. May 1 2010;28(13):2144-2150. 
5. 
Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for 
treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. 
Lancet. Dec 22 2007;370(9605):2103-2111. 
6. 
Melichar B, Koralewski P, Ravaud A, et al. First-line bevacizumab combined with 
reduced dose interferon-alpha2a is active in patients with metastatic renal cell carcinoma. 
Ann Oncol. Aug 2008;19(8):1470-1476. 
7. 
Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with 
interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 
90206. J Clin Oncol. Nov 20 2008;26(33):5422-5428. 
8. 
Rini BI, Halabi S, Rosenberg JE, et al. Phase III trial of bevacizumab plus interferon alfa 
versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final 
results of CALGB 90206. J Clin Oncol. May 1 2010;28(13):2137-2143. 
9. 
Irshad T, Olencki T, Zynger DL, Coston A, Mortazavi A, Monk JP. Bevacizumab in 
metastatic papillary renal cell carcinoma (PRCC). ASCO Meeting Abstracts. June 9, 2011 
2011;29(15_suppl):e15158. 
10. 
Tannir NM, Jonasch E, Altinmakas E, et al. Everolimus versus sunitinib prospective 
evaluation in metastatic non-clear cell renal cell carcinoma (The ESPN Trial): A 
multicenter randomized phase 2 trial. ASCO Meeting Abstracts. June 11, 2014 
2014;32(15_suppl):4505. 
11. 
Armstrong AJ, Broderick S, Eisen T, et al. Final clinical results of a randomized phase II 
international trial of everolimus vs. sunitinib in patients with metastatic non-clear cell 
renal cell carcinoma (ASPEN). ASCO Meeting Abstracts. May 18, 2015 
2015;33(15_suppl):4507. 
12. 
Choueiri TK, Fay AP, Gray KP, et al. PD-L1 expression in nonclear-cell renal cell 
carcinoma. Ann Oncol. Nov 2014;25(11):2178-2184. 
13. 
Ohm JE, Carbone DP. VEGF as a mediator of tumor-associated immunodeficiency. 
Immunol Res. 2001;23(2-3):263-272. 
14. 
Oyama T, Ran S, Ishida T, et al. Vascular endothelial growth factor affects dendritic cell 
maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic 
progenitor cells. J Immunol. Feb 1 1998;160(3):1224-1232. 
15. 
Kandalaft LE, Motz GT, Busch J, Coukos G. Angiogenesis and the tumor vasculature as 
antitumor immune modulators: the role of vascular endothelial growth factor and 
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endothelin. Curr Top Microbiol Immunol. 2011;344:129-148. 
16. 
Hodi FS, Lawrence D, Lezcano C, et al. Bevacizumab plus ipilimumab in patients with 
metastatic melanoma. Cancer Immunol Res. Jul 2014;2(7):632-642. 
17. 
Garcia JA, Mekhail T, Elson P, et al. Clinical and immunomodulatory effects of 
bevacizumab and low-dose interleukin-2 in patients with metastatic renal cell carcinoma: 
results from a phase II trial. BJU Int. Feb 2011;107(4):562-570. 
18. 
Amin A, Plimack ER, Infante JR, et al. Nivolumab (anti-PD-1; BMS-936558, ONO- 
4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal 
cell carcinoma (mRCC). ASCO Meeting Abstracts. June 11, 2014 
2014;32(15_suppl):5010. 
19. 
Sznol M, McDermott DF, Jones SF, et al. Phase Ib evaluation of MPDL3280A (anti- 
PDL1) in combination with bevacizumab (bev) in patients (pts) with metastatic renal cell 
carcinoma (mRCC). ASCO Meeting Abstracts.33(7_suppl):410. 
20. 
Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on 
tumor-specific T cells as a mechanism of immune evasion: implications for tumor 
immunotherapy. Cancer Immunol Immunother. Apr 2005;54(4):307-314. 
21. 
Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 
1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. 
Immunity. Jul 2007;27(1):111-122. 
22. 
Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy-- 
inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. Dec 
15 2012;18(24):6580-6587. 
23. 
Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: 
an update on implications for chronic infections and tumor evasion. Cancer Immunol 
Immunother. May 2007;56(5):739-745. 
24. 
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti- 
PD-1 antibody in cancer. N Engl J Med. Jun 28 2012;366(26):2443-2454. 
25. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. Jan 2009;45(2):228-247. 
26. 
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res. Dec 1 
2009;15(23):7412-7420. 
27. 
Rao D, Butt Z, Rosenbloom S, et al. A Comparison of the Renal Cell Carcinoma- 
Symptom Index (RCC-SI) and the Functional Assessment of Cancer Therapy-Kidney 
Symptom Index (FKSI). J Pain Symptom Manage. Aug 2009;38(2):291-298. 
28. 
Mendoza TR, Wang XS, Cleeland CS, et al. The rapid assessment of fatigue severity in 
cancer patients: use of the Brief Fatigue Inventory. Cancer. Mar 1 1999;85(5):1186-1196. 
29. 
Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients 
with metastatic renal cell carcinoma treated with vascular endothelial growth factor- 
targeted agents: results from a large, multicenter study. J Clin Oncol. Dec 1 
2009;27(34):5794-5799. 
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17. APPENDIX A: 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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18. APPENDIX B: REQUIRED FORMS FOR REGISTRATION 
 
Please notify the lead clinical research coordinator at the time a participant is identified or 
consented to the study. The DFCI coordinator will register the participant once the below 
documentation is finalized using the DFCI OnCore registration system. Non-DF/HCC 
participating sites will send the documents to the DFCI research coordinator to complete 
registration. Please allow a one-week turn-a-round time for the DFCI research team to determine 
participant eligibility. The following documentation is required prior to participant registration: 
 
• Current IRB approved consent form signed by participant and Investigator (MD 
only) 
• HIPAA authorization form (if separate from the informed consent document) 
• Signed and dated DFCI eligibility checklist (signed by MD and RN) 
• The following source documentation is typically required: 
• Please note: Additional documentation may be required by the lead institution. 
o Documentation of prior treatments/procedures performed to treat RCC 
o Reports documenting disease status 
▪ MRI or CT Brain 
▪ Chest CT 
▪ CT or MRI Abdomen and Pelvis 
▪ Bone Scan if applicable 
▪ PET/CT 
o Pathology Report 
o Concomitant medication list 
o Progress note or equivalent documentation of consenting visit 
o Progress note documenting medical history and oncologic history 
o Screening Labs 
▪ Complete blood count with differential 
▪ Electrolytes 
▪ Liver Function Tests 
▪ TSH/fT3/fT4 
▪ Urinalysis 
▪ Coagulation factors 
▪ Pregnancy test 
o Screening visit note with vital signs, weight, height, ECOG performance 
status, physical examination 
o Screening ECG, ECHO 
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19. APPENDIX C: MULTICENTER MONTIORING PLAN 
 
 
 
DFCI IRB Protocol #: 15-592 
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan 
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TABLE OF CONTENTS 
1. 
INTRODUCTION 
 
1.1 Purpose 
1.2 Multi-Center Data and Safety Monitoring Plan Definitions 
2. 
GENERAL ROLES AND RESPONSIBILITIES 
2.1 DF/HCC Sponsor 
2.2 Coordinating Center 
2.3 Participating Institution 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
3.1 Protocol Distribution 
3.2 Protocol Revisions and Closures 
3.3 Informed Consent Requirements 
3.4 IRB Documentation 
3.5 IRB Re-Approval 
3.6 Participant Confidentiality and Authorization Statement 
3.7 
DF/HCC Multi-Center Protocol Registration Policy 
3.8 DF/HCC Protocol Case Number 
3.9 Safety Assessments and Toxicity Monitoring 
3.10 Data Management 
4. 
REQUISITIONING INVESTIGATIONAL DRUG 
5. 
MONITORING: QUALITY CONTROL 
5.1 Ongoing Monitoring of Protocol Compliance 
5.2 Monitoring Reports 
5.3 Accrual Monitoring 
6. 
AUDITING: QUALITY ASSURANCE 
6.1 DF/HCC Internal Audits 
6.2 Audit Notifications 
6.3 Audit Reports 
6.4 Participating Institution Performance 
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1. 
INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP serves as a reference for any sites external to DF/HCC that 
are participating in a DF/HCC clinical trial. 
 
1.1 Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi- 
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating 
Procedures. 
 
1.2 Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-Center Protocol: A research protocol in which one or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC 
investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) 
Network Clinical Trial Affiliates. 
 
Lead Institution: One of the Dana-Farber/Harvard Cancer Center consortium members 
(Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel 
Deaconess Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham and 
Women’s Hospital (BWH) responsible for the coordination, development, submission, and 
approval of a protocol as well as its subsequent amendments per the DFCI IRB and applicable 
regulatory guidelines (CTEP, Food and Drug Administration (FDA), Office of 
Biotechnology Activities (OBA) etc.). The Lead Institution is typically the home of the 
DF/HCC Sponsor. The Lead Institution also typically serves as the Coordinating Center for 
the DF/HCC Multi-Center Protocol. 
 
DF/HCC Sponsor: The person sponsoring the submitted Multi-Center protocol who takes 
responsibility for initiation, management and conduct of the protocol at all research locations. 
In applicable protocols, the DF/HCC Sponsor will serve as the single liaison with any 
regulatory agencies The DF/HCC Sponsor has ultimate authority over the protocol and is 
responsible for the conduct of the study at DF/HCC and all Participating Institutions. In most 
cases the DF/HCC Sponsor is the same person as the DF/HCC Overall Principal Investigator; 
however, both roles can be filled by two different people. 
 
Participating Institution: An institution that is outside the DF/HCC and DF/PCC 
consortium that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC 
Investigator. The Participating Institution acknowledges the DF/HCC Sponsor as having the 
ultimate authority and responsibility for the overall conduct of the study. 
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research 
Organization (CRO), etc) that provides administrative support to the DF/HCC Sponsor in 
order that he/she may fulfill the responsibilities outlined in the protocol document and 
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DSMP, and as specified in applicable regulatory guidelines. In general, the Lead Institution 
is the Coordinating Center for the DF/HCC Multi-Center Protocol. 
 
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring 
high-quality standards are used for data collection and the ongoing management of clinical 
trials, auditing, and data and safety monitoring. ODQ also coordinates quality assurance 
efforts related to multi-center clinical research. 
 
DF/HCC Clinical Trials Research Informatics Office (CTRIO): A group within DF/HCC 
responsible for providing a comprehensive data management platform for managing clinical 
trial data. 
 
2. 
GENERAL ROLES AND RESPONSIBILITIES 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general responsibilities: 
 
2.1 DF/HCC Sponsor 
 
The DF/HCC Sponsor, 
 will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to: 
• Oversee the coordination, development, submission, and approval of the protocol as 
well as subsequent amendments. 
• Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol. 
• Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team member receives adequate 
protocol training (and/or a Site Initiation Visit prior to enrolling participants) and 
throughout the trials conduct as needed. 
• Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary 
language. 
• Monitor progress and overall conduct of the study at all Participating Institutions. 
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable (i.e., 
FDA,) reporting requirements are met. 
• Review data and maintain timely submission of data for study analysis. 
• Act as the single liaison with the FDA, as applicable. 
• Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol. 
• Commit to the provision that the protocol will not be rewritten or modified by anyone 
other than the DF/HCC Sponsor. 
• Identify and qualify Participating Institutions and obtain accrual commitments prior to 
extending the protocol to that site. 
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• Monitor accrual and address Participating Institutions that are not meeting their accrual 
requirements. 
 
2.2 Coordinating Center 
 
The general responsibilities of the Coordinating Center may include but are not limited to: 
• Assist in protocol development. 
• Maintain FDA correspondence, as applicable. 
• Review registration materials for eligibility and register participants from Participating 
Institutions in the DF/HCC clinical trial management system (CTMS). 
• Distribute protocol and informed consent document updates to Participating 
Institutions as needed. 
• Oversee the data collection process from Participating Institutions. 
• Maintain 
documentation 
of 
Serious 
Adverse 
Event 
(SAE) 
reports 
and 
deviations/violation submitted by Participating Institutions and provide to the DF/HCC 
Sponsor for timely review and submission to the DFCI IRB, as necessary. 
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under the 
DFCI IRB Adverse Event Reporting Policy to all Participating Institutions. 
• Provide Participating Institutions with information regarding DF/HCC requirements 
that they will be expected to comply with. 
• Carry out plan to monitor Participating Institutions either by on-site or remote 
monitoring. 
• Maintain Regulatory documents of all Participating Institutions which includes but is 
not limited to the following: local IRB approvals/notifications from all Participating 
Institutions, confirmation of Federalwide Assurances (FWAs) for all sites, all SAE 
submissions, Screening Logs for all sites, IRB approved consents for all sites 
• Conduct regular communications with all Participating Institutions (conference calls, 
emails, etc) and maintain documentation all relevant communications. 
 
2.3 Participating Institution 
 
Each Participating Institution is expected to comply with all applicable federal regulations 
and DF/HCC requirements, the protocol and HIPAA requirements. 
 
The general responsibilities for each Participating Institution may include but are not limited 
to: 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain regulatory files as per sponsor requirements. 
• Provide the Coordinating Center with regulatory documents or source documents as 
requested. 
• Participate in protocol training prior to enrolling participants and throughout the trial 
as required (i.e. teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
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• Register participants through the Coordinating Center prior to beginning research 
related activities. 
• Submit Serious Adverse Event (SAE) reports to local IRB per institutional 
requirements and to the Coordinating Center, in accordance with DF/HCC 
requirements. 
• Submit protocol deviations and violations to local IRB per institutional requirements 
and to the DF/HCC Sponsor in accordance with DF/HCC requirements. 
• Order, store and dispense investigational agents and/or other protocol mandated drugs 
per federal guidelines and protocol requirements. 
• Have office space, office equipment, and internet access that meet HIPAA standards. 
• Participate in any quality assurance activities and meet with monitors or auditors at the 
conclusion of a visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring queries 
or audit findings. 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
The following section will clarify DF/HCC Requirements and further detail the expectations 
for participating in a DF/HCC Multi-Center protocol. 
 
3.1 Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions. 
 
3.2 Protocol Revisions and Closures 
The Participating Institutions will receive notification of protocol revisions and closures from 
the Coordinating Center. It is the individual Participating Institution’s responsibility to notify 
its IRB of these revisions. 
• Non-life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non-life-threatening events from the 
Coordinating Center. Non-life-threatening protocol revisions must be IRB approved 
and implemented within 90 days from receipt of the notification. 
 
• Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 
required to protect lives with follow-up by fax, mail, e-mail, etc. Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval. 
 
• Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating Center. 
Closures and holds will be effective immediately. In addition, the Coordinating Center, 
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will update the Participating Institutions on an ongoing basis about protocol accrual 
data so that they will be aware of imminent protocol closures. 
 
3.3 Informed Consent Requirements 
The DF/HCC approved informed consent document will serve as a template for the informed 
consent for Participating Institutions. The Participating Institution consent form must follow 
the consent template as closely as possible and should adhere to specifications outlined in 
the DF/HCC Guidance Document on Model Consent Language for PI-Initiated Multi-Center 
Protocols. This document will be provided separately to each Participating Institution upon 
request. 
Participating Institutions are to send their version of the informed consent document and 
HIPAA authorization, if a separate document, to the Coordinating Center for review and 
approval prior to submission to their local IRB. The approved consent form must also be 
submitted to the Coordinating Center after approval by the local IRB for all consent versions. 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form for 
therapeutic protocols. Participating institutions must follow the DF/HCC requirement that 
only attending physicians obtain informed consent and re-consent for all interventional drug, 
biologic, or device research. 
 
3.4 IRB Documentation 
The following must be on file with the Coordinating Center: 
• Initial approval letter of the Participating Institution's IRB. 
• Copy of the Informed Consent Form(s) approved by the Participating Institution’s IRB. 
• Participating Institution’s IRB approval for all amendments. 
• Annual approval letters by the Participating Institution's IRB. 
3.5 IRB Re-Approval 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received 
from the Participating Institution on or before the anniversary of the previous approval date. 
 
 
 
3.6 Participant Confidentiality and Authorization Statement 
In 1996, congress passed the first federal law covering the privacy of health information 
known as the Health Insurance Portability and Accountability Act (HIPPA). Any 
information, related to the physical or mental health of an individual is called Protected 
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Protocol Version Date: November 4, 2019
 
 
 
Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be 
used or disclosed. 
In order for covered entities to use or disclose protected health information during the course 
of a study, the study participant must sign an authorization statement. This authorization 
statement may or may not be separate from the informed consent document. The 
Coordinating Center, with the approval from the DFCI IRB will provide a consent template, 
with information regarding authorization for the disclosure of protected health information. 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in 
its trials. However, because of the nature of these trials, certain protected health information 
must be collected. DF/HCC has chosen to use authorizations, signed by the participant in the 
trial, rather than limited data sets with data use agreements. 
 
3.6.1     DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should 
be de-identified. It is recommended that the assigned protocol case number (as described 
below) be used for all participant specific documents. Participant initials may be included or 
retained for cross verification of identification. 
 
3.7 
DF/HCC Multi-Center Protocol Registration Policy 
3.7.1 
Participant Registration and Randomization 
To register a participant, the following documents should be completed by the Participating 
Institution and faxed or e-mailed to the Coordinating Center at Dana-Farber Cancer Institute 
at
or e-mailed to the DFCI Clinical Research Manager and Clinical Research 
Coordinator. Please notify the DFCI team in advance that a registration packet is to be 
expected with the following items: 
• Current IRB approved informed consent document signed by participant and 
investigator. Participant name and MRN must be redacted. Please ensure the 
participant’s initials are written on each page of the informed consent document. 
 HIPAA authorization form (if separate from the informed consent document) 
 Signed and dated DFCI eligibility checklist 
 The following source documentation is typically required. Please note additional 
documentation may be required by the lead institution: 
 Lab values used to determine eligibility 
 Imaging reports 
 Pathology Report 
 Concomitant medication list 
 Progress note or equivalent documentation of consenting visit 
 Progress note documenting medical history and oncologic history 
 Screening visit note, with BP, vital signs, ECOG Performance status 
 Screening EKG 
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 ECHO 
 Other screening assessments 
The Coordinating Center will review the submitted documents in order to verify eligibility 
and consent. To complete the registration process, the Coordinating Center will: 
 Register the participant on the study with the DF/HCC Clinical Trial Management 
System (CTMS). 
 Upon receiving confirmation of registration, the Coordinating Center will inform the 
Participating Institution and provide the study specific participant case number, and, if 
applicable, assigned treatment and/or dose level. 
 
Treatment may not begin without confirmation from the Coordinating Center that the 
participant has been registered. 
Randomization can only occur during normal business hours, Monday through Friday 
from 8:00 AM to 5:00 PM Eastern Standard Time. 
3.7.2 
Initiation of Therapy 
Participants must be registered with the DF/HCC CTMS before the initiation of treatment or 
other protocol-specific interventions. Treatment and other protocol-specific interventions 
may not be initiated until the Participating Institution receives confirmation of the 
participant’s registration from the Coordinating Center. The DF/HCC Sponsor and DFCI 
IRB must be notified of any violations to this policy. 
3.7.3 
Eligibility Exceptions 
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval will 
be permitted. All Participating Institutions are required to fully comply with this requirement. 
The process for requesting an eligibility exception is defined below. 
 
3.8 DF/HCC Protocol Case Number 
At the time of registration, the following identifiers are required for all subjects: initials, date 
of birth, gender, race and ethnicity. Once eligibility has been established and the participant 
successfully registered, the participant is assigned a unique protocol case number. 
Participating Institutions should submit all de-identified subsequent communication and 
documents to the Coordinating Center, using this case number to identify the subject. 
 
3.8.1 
Protocol Deviations, Exceptions and Violations 
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review and 
approval, except when necessary to eliminate apparent immediate hazards to the participant. 
DF/HCC requires all departures from the defined procedures set forth in the IRB approved 
protocol to be reported to the DF/HCC Sponsor, who in turn is responsible for reporting to 
the DFCI IRB. 
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For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” to 
describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy 
for reporting to their local IRB. 
 
3.8.2 
Definitions 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved 
protocol which is prospectively approved prior to its implementation. 
Protocol Exception: Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
Protocol Violation: Any protocol departure that was not prospectively approved by the IRB 
prior to its initiation or implementation. 
3.8.3 
Reporting Procedures 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations 
and violations. The DF/HCC Sponsor will also be responsible for ensuring that all protocol 
violations/deviations are promptly reported per DFCI IRB guidelines. 
Participating Institutions: Protocol deviations require prospective approval from the DFCI 
IRB. The Participating Institution must submit the deviation request to the Coordinating 
Center who will then submit the deviation request to the DFCI IRB. Upon DFCI IRB 
approval the deviation is submitted to the Participating Institution IRB, per institutional 
policy. A copy of the Participating Institution’s IRB report and determination will be 
forwarded to the Coordinating Center within 10 business days after the original submission. 
The deviation may not be implemented without all required approvals. 
All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of violations. 
Coordinating Center: Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for 
review. Subsequently, the Participating Institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines. DF/HCC will 
forward all violation reports to CTEP via an internal DF/HCC process, as applicable. 
 
3.9 Safety Assessments and Toxicity Monitoring 
The study teams at all participating institutions are responsible for protecting the safety, 
rights and well-being of study participants. Recording and reporting of adverse events that 
occur during the course of a study help ensure the continuing safety of study participants. 
All participants receiving investigational agents and/or other protocol mandated therapy will 
be evaluated for safety. The safety parameters include all laboratory tests and hematological 
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abnormalities, physical examination findings, and spontaneous reports of adverse events 
reported by participants. All toxicities encountered during the study will be evaluated 
according to the NCI criteria specified in the protocol. Life-threatening toxicities must be 
reported immediately to the DF/HCC Sponsor via the Coordinating Center. 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.9.1 
Guidelines for Reporting Serious Adverse Events 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in protocol section 7. 
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the Coordinating 
Center following the DFCI IRB Adverse Event Reporting Policy. 
The Coordinating Center will maintain documentation of all Participating Institution Adverse 
Event reports and be responsible for communicating to all participating investigators, any 
observations reportable under the DFCI IRB Reporting Requirements. Participating 
Institutions will review and submit to their IRB according to their institutional policies and 
procedures 
 
3.9.2 
Guidelines for Processing IND Safety Reports 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety 
Reports are distributed to the Participating Institutions. Participating Institutions will 
review/submit to their IRB according to their institutional policies and procedures. 
 
3.10 
Data Management 
DF/HCC CTRIO develops case report forms (CRF/eCRFs), for use with the protocol. These 
forms are designed to collect data for each study. DF/HCC CTRIO provides a web based 
training for all eCRF users. 
 
3.10.1 
Data Forms Review 
Data submissions are monitored for timeliness and completeness of submission. If study 
forms are received with missing or questionable data, the submitting institution will receive 
a written or electronic query from the DF/HCC Office of Data Quality, Coordinating Center, 
or designee. 
Responses to all queries should be completed and submitted within 14 calendar days. 
Responses may be returned on the written query or on an amended paper case report form, 
or in the case of electronic queries, within the electronic data capture (eDC) system. In the 
case of a written query for data submitted on a paper case report form, the query must be 
attached to the specific data being re-submitted in response. 
If study forms are not submitted on schedule, the Participating Institution will periodically 
receive a Missing Form Report from the Coordinating Center noting the missing forms. 
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Protocol Version Date: November 4, 2019
 
 
 
4. 
REQUISITIONING INVESTIGATIONAL DRUG 
The ordering of investigational agent is specified in the protocol section 8. 
Participating Institutions should order their own agent regardless of the supplier. (i.e., 
pharmaceutical company.) 
If the agent is commercially available, check with the local Director of Pharmacy and/or the 
Research Pharmacy to ensure that the agent is in stock. If the agent is not stocked, ensure 
that the agent can be ordered once the protocol is approved by the local IRB. 
If the agent is investigational, ensure that the pharmacy will be able to receive and store the 
agent according to state and federal requirements. The local IRB should be kept informed of 
who will supply the agent (i.e., pharmaceutical company) so that any regulatory 
responsibilities can be met in a timely fashion. 
5. 
MONITORING: QUALITY CONTROL 
The quality control process for a clinical trial requires verification of protocol compliance 
and data accuracy. The Coordinating Center, with the aid of the DF/HCC Office of Data 
Quality, provides quality control oversight for the protocol. 
 
5.1 Ongoing Monitoring of Protocol Compliance 
The Participating Institutions may be required to submit participant source documents to the 
Coordinating Center for monitoring. Participating Institution may also be subject to on-site 
monitoring conducted by the Coordinating Center. 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data 
quality, and participant safety. Monitoring practices may include but are not limited to source 
data verification, and review and analysis of eligibility requirements, informed consent 
procedures, adverse events and all associated documentation, review of study drug 
administration/treatment, regulatory files, protocol departures reporting, pharmacy records, 
response assessments, and data management. 
Site visits will generally occur once a year for sites that are actively enrolling participants 
and have participants in treatment. Additional monitoring activities may occur if incidences 
of non-compliance are discovered or at the request of the DF/HCC Sponsor. Virtual 
monitoring (source documents are sent to DFCI for review) may be performed in lieu of a 
site visit if the study staff and PI determine that virtual monitoring is appropriate for the site. 
The decision to perform virtual monitoring in lieu of a site visit will be based upon the site’s 
enrollment, study compliance history, history collaborating with DFCI on other multi-center 
studies, and number of participants in active treatment. 
Monitoring will occur before the clinical phase of the protocol begins and will continue 
during protocol performance through study completion. 
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Teleconferences between DFCI and the participating sites will be conducted on 
approximately a monthly basis. Meeting minutes for teleconferences will be issued to all 
participating sites. Site initiation visits will be conducted via teleconference. Ongoing 
training will also be conducted via teleconference as needed. The Coordinating Center, Dana 
Farber Cancer Institute will be available to all participating sites for resolving questions, 
concerns and facilitating compliance. 
 
5.2 Monitoring Reports 
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. The 
DF/HCC Sponsor may increase the monitoring activities at Participating Institutions that are 
unable to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations. 
 
5.3 Accrual Monitoring 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual 
requirements for each participating institution. Accrual will be monitored for each 
participating institution by the DF/HCC Sponsor or designee. Sites that are not meeting their 
accrual expectations may be subject to termination. 
 
6. 
AUDITING: QUALITY ASSURANCE 
Auditing is a method of Quality Assurance and involves the systematic and independent 
examination of all trial related activities and documents. Audits determine if evaluated 
activities were appropriately conducted and whether data was generated, recorded and 
analyzed, and accurately reported per the protocol, applicable Standard Operating Procedures 
(SOPs), and the Code of Federal Regulations (CFR). 
 
6.1 
DF/HCC Internal Audits 
All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality 
(ODQ). Typically, approximately 3-4 participants would be audited at the site over a 2 day 
period. If violations which impact participant safety or the integrity of the study are found, 
more participant records may be audited. 
6.2 Audit Notifications 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which involve this 
protocol. All institutions will forward a copy of final audit and/or re-audit reports and 
corrective action plans (if applicable) to the Coordinating Center, within 12 weeks after the 
audit date. 
 
6.3 Audit Reports 
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The DF/HCC Sponsor will review all final audit reports and corrective action plans, if 
applicable. The Coordinating Center, must forward any reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan to 
the DFCI IRB as applicable. 
 
6.4 Participating Institution Performance 
The DF/HCC Sponsor and DFCI IRB is charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol. 
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely and accurate data, adherence to protocol requirements, and compliance with state and 
federal regulations, may be recommended for a six-month probation period. Such institutions 
must respond with a corrective action plan and must demonstrate during the probation period 
that deficiencies have been corrected, as evidenced by the improved performance measures. 
Participating Institutions that fail to demonstrate significant improvement will be considered 
by the DF/HCC Sponsor for revocation of participation. A DF/HCC Sponsor and/or the DFCI 
IRB may terminate a site’s participation if it is determined that a site is not fulfilling its 
responsibilities as described above. 
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DRS-P 
 
 
20.  APPENDIX D: FKSI-19 
 
Today’s Date:   
 
Participant Name:   
 
Participant Study ID:   
 
Cycle Number:   
  
 
 
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark one number per line to indicate your response as it applies to the last 7 days. 
 
 
 
 
 
GP1 
GP4 
C2 
HI7 
B1 
BRM3 
 
 
BP1 
L2 
HI12 
RCC2 
C6 
GF5 
DRS-E 
GE6 
 
TSE 
GP2 
 
C5 
GP5 
FWB 
GF1 
 
GF3 
GF7 
 
 
 
 
 
 
 
 
DRS-P = Disease-related symptoms subscale – Physical 
DRS-E = Disease-related symptoms subscale – Emotional 
TSE = Treatment side effects subscale 
FWB = Function and well-being subscale 
Not at 
all 
A little 
bit 
Some- 
what 
Quite a 
bit 
Very 
much 
I have a lack of energy ................................. 
0 
1 
2 
3 
4 
I have pain .................................................... 
0 
1 
2 
3 
4 
I am losing weight ........................................ 
0 
1 
2 
3 
4 
I feel fatigued .............................................. 
0 
1 
2 
3 
4 
I have been short of breath ............... 
0 
1 
2 
3 
4 
I am bothered by fevers (episodes of high 
body temperature) ........................................ 
0 
1 
2 
3 
4 
I have bone pain ........................................... 
0 
1 
2 
3 
4 
I have been coughing ................................... 
0 
1 
2 
3 
4 
I feel weak all over ....................................... 
0 
1 
2 
3 
4 
I have blood in my urine .............................. 
0 
1 
2 
3 
4 
I have a good appetite .................................. 
0 
1 
2 
3 
4 
I am sleeping well ........................................ 
0 
1 
2 
3 
4 
I worry that my condition will get worse...... 
0 
1 
2 
3 
4 
I have nausea ................................................ 
0 
1 
2 
3 
4 
I have diarrhea .............................................. 
0 
1 
2 
3 
4 
I am bothered by side effects of treatment... 
0 
1 
2 
3 
4 
I am able to work (include work at home).... 
0 
1 
2 
3 
4 
I am able to enjoy life ................................... 
0 
1 
2 
3 
4 
I am content with the quality of my life 
right now ...................................................... 
0 
1 
2 
3 
4 
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Protocol Version Date: November 4, 2019
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NCCN/FACT Kidney Symptom Index-19 (FKSI-19) 
Scoring Guidelines (Version 4) 
 
 
Instructions:* 
1. 
Record answers in "item response" column. If missing, mark with an X 
2. 
Perform reversals as indicated, and sum individual items to obtain a score. 
3. 
Multiply the sum of the item scores by the number of items in the subscale, then divide by the number of items answered. 
This produces the symptom index score. 
4. 
As with all FACIT questionnaires, a high score is good. Therefore, a score of “0” is a severely symptomatic patient and the 
highest possible score is an asymptomatic patient. 
*For guidelines on handling missing data and scoring options, please refer to the administration and scoring guidelines online at 
www.facit.org. 
 
 
Scale 
 
FKSI-19 
Total 
 
Score range: 0-76 
 
 
 
 
 
 
 
 
 
 
 
 
Sum individual item scores:    
 
Multiply by 19:   
 
Divide by number of items answered: 
  
=  FKSI-19 score 
Item Code 
Reverse item 
Item response 
Item Score 
GP1 
4 
- 
  
 
=  
 
GP4 
4 
- 
  
 
=  
 
C2 
4 
- 
  
 
=  
 
HI7 
4 
- 
  
 
=  
 
B1 
4 
- 
  
 
=  
 
BRM3 
4 
- 
  
 
=  
 
BP1 
4 
- 
  
 
=  
 
L2 
4 
- 
  
 
=  
 
HI12 
4 
- 
  
 
=  
 
RCC2 
4 
- 
  
 
=  
 
C6 
0 
+ 
  
 
=  
 
GF5 
0 
+ 
  
 
=  
 
GE6 
4 
- 
  
 
=  
 
GP2 
4 
- 
  
 
=  
 
C5 
4 
- 
  
 
=  
 
GP5 
4 
- 
  
 
=  
 
GF1 
0 
+ 
  
 
=  
 
GF3 
0 
+ 
  
 
=  
 
GF7 
0 
+ 
  
 
=  
 
Dana Farber
IRB NUMBER: 15-592
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NCI Protocol #: N/A 
DF/HCC Protocol #: 15-592 
Protocol Version Date: November 4, 2019
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21.APPENDIX E: BRIEF FATIGUE INVENTORY 
 
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IRB NUMBER: 15-592
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SAFETY REPORTING FAX COVER SHEET 
 
Genentech Supported Research 
 
 
 
 
 
 
Genentech Study Number 
Principal Investigator 
Site Name 
Reporter name 
Reporter Telephone # 
Reporter Fax # 
 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
 
 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
 
 
SAE or Safety Reporting questions, contact Genentech Safety:
 
 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET 
 
 
 
 
Version 1 31-May-2012 
Dana Farber
IRB NUMBER: 15-592
IRB APPROVAL DATE: 04/17/2020