A Randomized, Phase II/III Study of Pegylated Liposomal Doxorubicin and CTEP-Supplied Atezolizumab Versus Pegylated Liposomal Doxorubicin, CTEP-Supplied Bevacizumab and CTEP-Supplied Atezolizumab Versus Pegylated Liposomal Doxorubicin and CTEP-Supplied Bevacizumab in Platinum Resistant Ovarian Cancer
Phase: PHASE2
Conditions: Fallopian Tube High Grade Serous Adenocarcinoma, Ovarian High Grade Serous Adenocarcinoma, Ovarian Seromucinous Carcinoma, Primary Peritoneal High Grade Serous Adenocarcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Fallopian Tube Clear Cell Adenocarcinoma, Recurrent Fallopian Tube Endometrioid Adenocarcinoma, Recurrent Fallopian Tube Undifferentiated Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Ovarian Clear Cell Adenocarcinoma, Recurrent Ovarian Endometrioid Adenocarcinoma, Recurrent Ovarian Undifferentiated Carcinoma, Recurrent Platinum-Resistant Fallopian Tube Carcinoma, Recurrent Platinum-Resistant Ovarian Carcinoma, Recurrent Platinum-Resistant Primary Peritoneal Carcinoma, Recurrent Primary Peritoneal Carcinoma, Recurrent Primary Peritoneal Clear Cell Adenocarcinoma, Recurrent Primary Peritoneal Endometrioid Adenocarcinoma, Recurrent Primary Peritoneal Undifferentiated Carcinoma
Sponsor: National Cancer Institute (NCI)

NRG-GY009 
NCI Version Date: October 13, 2022 
i 
SUMMARY OF CHANGES 
For Protocol Amendment #13 to: NRG-GY009 
NCI Protocol #: NRG-GY009 
Local Protocol #: NRG-GY009 
NCI Version Date: 10/13/2022 
This amendment is in response to
notice regarding atezolizumab drug information updates. 
# 
Section 
Comments 
1. 
Title Pages 
•
NCI Version Date is now 10/13/2021.
•
Data Manager contact info has been updated.
2. 
9.1 
Updated drug information received from CTEP on Atezolizumab has been included 
throughout section 9.1 
3. 
10.4.1 
Biospecimen table has been updated. 
4. 
Appendix V 
Link to biospecimen ordering kits has been updated to https://kits.bpc-
apps.nchri.org/ 
5. 
ICDs 
Updated Version Date Only. 
Use of this document is governed by the terms of use on the first page of this document.

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NRG ONCOLOGY  
NRG-GY009 
(ClinicalTrials.gov NCT #02839707) 
A RANDOMIZED, PHASE II/III STUDY OF PEGYLATED LIPOSOMAL DOXORUBICIN 
AND CTEP-SUPPLIED ATEZOLIZUMAB 
 VERSUS PEGYLATED 
LIPOSOMAL DOXORUBICIN, CTEP-SUPPLIED BEVACIZUMAB AND CTEP-SUPPLIED 
ATEZOLIZUMAB VERSUS PEGYLATED LIPOSOMAL DOXORUBICIN AND CTEP-
SUPPLIED BEVACIZUMAB IN PLATINUM RESISTANT OVARIAN CANCER (29-JUN-2020) 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by the 
National Cancer Institute (NCI).  
Lead Organization: NRG / NRG Oncology 
The Safety Lead-in portion of the study is limited to NRG Oncology Safety Lead-in participants 
 
 
 
 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center; 1600 JFK Blvd; Suite 1020 
Philadelphia, PA 19103 
Study Team 
Study 
(06/29/2017) 
Study
 
 M.D. 
, M.D. 
Memorial Sloan Kettering Cancer Center 
Memorial Sloan Kettering Cancer Center 
300 East 66th Street 
300 East 66th Street 
New York, NY 10065 
New York, NY 10065 
/ FAX: 
 
/FAX: 
 
  
 
 
 
Patient Reported Outcomes
 
Statistician (06/29/2017) (03/19/2018) 
 PhD 
 Ph.D. 
University of California, Irvine 
NRG Oncology Biostatistical Office-Buffalo 
100 Theory, Suite 110 
Elm and Carlton Streets 
Irvine, CA  92697 
Buffalo, NY 14263 
/FAX:  
 
/FAX: 
 
  
 
 
 
Participating Organizations  
ALLIANCE / Alliance for Clinical Trials in Oncology 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
SWOG / SWOG 
Use of this document is governed by the terms of use on the first page of this document.

NRG-GY009 
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Research Nurse 
Translational Scientist (10/16/2017) 
 RN 
, PhD, MPH 
Memorial Sloan Kettering Cancer Center 
NRG BB-Columbus 
300 East 66th Street 
Biopathology Center 
New York, NY 10065 
Nationwide Children’s Hospital 
/FAX: 
 
700 Children’s Drive 
Columbus, OH 43205 
 
 
Data Manager (13-OCT-2022) 
 
Translational Research
(10/16/2017) (10/22/2018) 
Elm and Carlton Streets. 
, M.D., Ph.D. 
Buffalo, NY 14263 
Memorial Sloan Kettering Cancer Center 
/FAX: 
 
300 E. 66th Street 
   
New York, NY 10065 
 
/FAX: 
 
Disease Site 
(10/16/2017) 
(03/19/2018) (10/22/2018) 
  
 M.D. 
Protocol Coordinator 
Memorial Sloan Kettering Cancer Center 
, M.S. (30-OCT-2020) 
Department of Medicine 
NRG Oncology 
1275 York Avenue 
Four Penn Ctr, 1600 JFK Blvd, Ste 1020 
New York, NY 10065 
Philadelphia, PA 19103 
 
/FAX: 
 
 
 
NRG Oncology Contact Information (02/20/2019) 
Data Management 
For questions concerning data 
submission 
 
NRG Oncology Statistics and Data Management Center 
Elm and Carlton Streets. 
Buffalo, NY 14263 
716-845-5702/FAX:716-845-8393 
   
The following NCTN Group Study
has been added to this trial: (13-OCT-2022) 
SWOG:
 M.D., University of Mississippi
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Protocol Development 
For questions concerning protocol 
and informed consent versions and 
amendments 
Protocol Coordinator  
, M.S.(30-OCT-2020) 
NRG Oncology-Philadelphia East 
Four Penn Center, 1600 JFK Blvd., Ste 1020 
Philadelphia, PA 19103 
267-295-9476 
  
Biospecimen Bank 
For questions concerning 
biospecimen collection and 
translational research 
NRG BB-Columbus 
Biopathology Center, Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
866-464-2262/FAX: 614-722-2897 
Email: bpcbank@nationwidechildrens.org 
Gynecologic Oncology 
Committee 
 M.D. 
Memorial Sloan Kettering Cancer Center 
Department of Medicine 
1275 York Avenue 
New York, NY 10065 
646-888-4217 
 
Protocol Agents (29-JUN-2020) 
NCI-Supplied Agent(s): 
Atezolizumab (NSC 783608) 
Bevacizumab (NSC 704865) 
Commercial Agent:  
Pegylated liposomal doxorubicin (PLD) (NSC 712227) 
IND #:  
 
IND Sponsor:  DCTD, NCI  
 
Participating Sites 
U.S. 
 Canada 
 Approved International Member Sites 
Document History 
Amendment 13 
October 13, 2022 
Amendment 12  
May 17, 2021 
Amendment 11 
February 24, 2021 
Amendment 10 
January 08, 2021 
Amendment 9 
October 30, 2020 
Amendment 8 
June 29, 2020 
Amendment 7 
02/20/2019 
Amendment 6 
10/22/2018 
Amendment 5 
09/13/2018 
Amendment 4 
03/19/2018 
Amendment 3 
08/21/2017 
Amendment 2 
08/03/2017 
Amendment 1 
06/01/2017 
Activation 
04/17/2017 
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CONTACT INFORMATION (29-JUN-2020) 
 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation 
must be submitted to the CTSU 
via the Regulatory Submission 
Portal. 
 
Regulatory Submission Portal 
(Sign in at www.ctsu.org, and 
select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-2878 
to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions by phone or 
email : 1-888-823-5923, or 
ctsucontact@westat.com. 
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave.  Please see the 
data submission section of the 
protocol for further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded from the 
protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  Access to the 
CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and 
Access Management (CTEP-IAM) registration system and requires log in with a CTEP-IAM username and 
password. 
 
Permission to view and download this protocol and its supporting documents is restricted and is based on 
person and site roster assignment housed in the CTSU RSS.   
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data submission) 
Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
  
 
 
This protocol was designed and developed by NRG Oncology. It is intended to be 
used only in conjunction with IRB approval for study entry.  No other use or 
reproduction is authorized by NRG Oncology nor does NRG Oncology assume any 
responsibility for unauthorized use of this protocol. 
Use of this document is governed by the terms of use on the first page of this document.

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TABLE OF CONTENTS 
NRG-GY009 SCHEMA (10/22/2018) ........................................................................... - 8 - 
1. 
OBJECTIVES ................................................................................................................. - 9 - 
1.1 
Primary Objectives.............................................................................................. - 9 - 
1.2 
Secondary Objectives.......................................................................................... - 9 - 
1.3 
Translational Science Objectives ........................................................................ - 9 - 
2. 
BACKGROUND .......................................................................................................... - 10 - 
2.1 
Background on Atezolizumab (06/29/2017) ..................................................... - 11 - 
2.2 
Rationale for the use of Atezolizumab in Ovarian Cancer ............................... - 14 - 
2.3 
Rationale for the combination of PLD and Atezolizumab................................ - 16 - 
2.4 
Rationale for the combination of Bevacizumab and Atezolizumab ................. - 17 - 
2.5 
Rationale for the combination of PLD, Bevacizumab and Atezolizumab ........ - 18 - 
2.6 
Translational Science Background ................................................................... - 18 - 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA ............ - 21 - 
3.1 
Patient Selection Guidelines ............................................................................. - 21 - 
3.2 
Eligibility Criteria (06/29/2017) ....................................................................... - 21 - 
3.3 
Ineligibility Criteria (06/29/2017)..................................................................... - 22 - 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..... - 26 - 
4.1 
PRE-TREATMENT ASSESSMENTS (10/22/2018) ....................................... - 26 - 
4.2 
ASSESSMENTS DURING TREATMENT (29-JUN-2020) ........................... - 27 - 
4.3 
ASSESSMENTS IN FOLLOW UP .................................................................. - 28 - 
5. 
TREATMENT PLAN/REGIMEN DESCRIPTION (10/22/2018) ............................... - 29 - 
5.1 
Treatment Plan .................................................................................................. - 29 - 
5.2 
Radiation Therapy ............................................................................................. - 33 - 
5.3 
Device ............................................................................................................... - 33 - 
5.4 
Imaging (for imaging-focused study) ............................................................... - 33 - 
5.5 
Integral Assay/Biomarker ................................................................................. - 33 - 
5.6 
Intervention Not Otherwise Categorized .......................................................... - 33 - 
5.7 
Quality of Life Component ............................................................................... - 33 - 
5.8 
General Concomitant Medication and Supportive Care Guidelines ................. - 33 - 
5.9 
Duration of Therapy .......................................................................................... - 34 - 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT ................................................ - 35 - 
6.1 
PLD Dose Modification Guidelines.................................................................. - 35 - 
6.2 
Bevacizumab Dose Modification and Toxicity Management Guidelines ........ - 37 - 
6.3 
Atezolizumab Dose Modification and Toxicity Management Guidelines ....... - 42 - 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS ............................................ - 57 - 
7.1  
Protocol Agents (03/19/2018) (29-JUN-2020) ................................................. - 57 - 
7.2 
Adverse Events and Serious Adverse Events ................................................... - 57 - 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for Study 
Agents ............................................................................................................... - 57 - 
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7.4 
Adverse Events for Commercial Study Agents ................................................ - 67 - 
7.5 
Adverse Event Characteristics (06/29/2017) (03/19/2018) .............................. - 67 - 
7.6 
Expedited Reporting of Adverse Events ........................................................... - 67 - 
8. 
REGISTRATION AND STUDY ENTRY PROCEDURES (03/19/2018) (29-JUN-2020)- 71 - 
8.1 
CTEP Registration Procedures (03/19/2018).................................................... - 71 - 
8.2 
CTSU Registration Procedures (03/19/2018) ................................................... - 73 - 
8.3 
Patient Enrollment (03/19/2018)....................................................................... - 75 - 
8.4 
Agent Ordering and Agent Accountability (03/19/2018) (29-JUN-2020) ....... - 76 - 
9. 
 DRUG INFORMATION ............................................................................................. - 77 - 
9.1 
Atezolizumab, NSC # 783608, 
 (06/29/2017) ............................ - 77 - 
9.2 
Bevacizumab (rhuMAb VEGF, Avastin®) (NSC #704865) (29-JUN-2020) ... - 78 - 
9.3 
Pegylated Liposomal Doxorubicin (NSC #620212, 712227) ........................... - 79 - 
10. 
Pathology/BIOSPECIMEN (10/22/2018) ..................................................................... - 80 - 
10.1 
Central Pathology Review Guidelines .............................................................. - 80 - 
10.2 
Biospecimen Selection for Integral Marker Testing ......................................... - 80 - 
10.3 
Biospecimen Selection for Integrated Marker Testing ..................................... - 80 - 
10.4 
Biospecimen Submission Tables ...................................................................... - 82 - 
10.5 
Exploratory Biomarker Laboratory Testing ...................................................... - 83 - 
11. 
SPECIAL studies (Non-Tissue) .................................................................................... - 84 - 
11.1 
Quality of Life................................................................................................... - 84 - 
12. 
ASSESSMENT OF EFFECT ....................................................................................... - 89 - 
12.1 
Antitumor Effect – Solid Tumors ..................................................................... - 89 - 
13. 
DATA AND RECORDS .............................................................................................. - 96 - 
13.1 
Data Management/Collection (29-JUN-2020) .................................................. - 96 - 
13.2 
NRG Data Management Forms ........................................................................ - 98 - 
13.3 
Summary of Data Submission .......................................................................... - 98 - 
13.4 
Global Reporting/Monitoring ........................................................................... - 98 - 
14. 
STATISTICAL CONSIDERATIONS.......................................................................... - 98 - 
14.1 
Study Design ..................................................................................................... - 98 - 
14.2 
Study Endpoints .............................................................................................. - 100 - 
14.3 
Primary Objectives Study Design ................................................................... - 101 - 
14.4 
Study Monitoring of Primary Objectives ........................................................ - 105 - 
14.5 
Accrual/Study Duration Considerations ......................................................... - 106 - 
14.6 
Secondary or Exploratory Endpoints (including correlative science aims) .... - 107 - 
14.7 
Interim Analysis for All Other Endpoints (Goals) .......................................... - 112 - 
15. 
REFERENCES ........................................................................................................... - 114 - 
APPENDIX I – FIGO OVARIAN CANCER STAGING 2014 ............................................. - 116 - 
APPENDIX II – PERFORMANCE STATUS CRITERIA .................................................... - 118 - 
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APPENDIX III- NYHA CLASSIFICATION ........................................................................ - 119 - 
APPENDIX IV – GENERAL THERAPY GUIDELINES (29-JUN-2020) ........................... - 120 - 
APPENDIX V – TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES (10/16/2017) 
(02/20/2019) ................................................................................................................ - 121 - 
APPENDIX VI – COLLABORATIVE AGREEMENT ........................................................ - 128 - 
APPENDIX VII - LETTER TO PATHOLOGISTS (10/16/2017) ......................................... - 130 - 
APPENDIX VIII - EXAMPLES ON HOW TO ASSESS TUMOR RESPONSES (10/16/2017)- 131 - 
APPENDIX IX:  DIAGNOSTIC IMAGE COLLECTION SUMMARY (03/19/2018) (29-jun-2020) - 
135 - 
APPENDIX X – PARTICIPATING INSTITUTIONS FOR SAFETY LEAD-INS (10/22/2018)- 136 - 
 
 
 
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1. 
OBJECTIVES 
1.1 
Primary Objectives 
1.1.1 Safety Lead-in:  Estimate the probability of a dose limiting toxicity (DLT) following cycle 1 
of experimental regimens (PLD and atezolizumab and PLD/bevacizumab and atezolizumab).   
1.1.2 Phase II Study: Estimate and compare the hazard of first progression or death (PFS) of each 
experimental regimen relative to the reference regimen, PLD and bevacizumab.  
1.1.3 Phase III Study: Estimate and compare the hazard of death and the hazard of first 
progression or death (PFS) of the experimental regimen relative to the reference regimen.  
(24-FEB-2021) 
 
1.2 
Secondary Objectives 
1.2.1 Phase II Study: Secondary efficacy endpoint: Estimate and compare the probabilities of 
response (ORR, either partial or complete response) defined by RECIST v1.1 criteria on each 
study regimen. (24-FEB-2021) 
Safety endpoint: Estimate the frequency and severity of adverse events as classified and 
graded with Common Terminology Criteria for Adverse Events (CTCAE) in those patients 
who initiate their randomly assigned study treatment. (03/19/2018) 
1.2.2 Phase III Study: Secondary efficacy endpoints: Estimate and compare ORR in each 
treatment group. 
Safety endpoints: Estimate the frequency and severity of adverse events in those patients who 
initiate their randomly assigned study treatment. 
Patient Reported outcomes (PRO):  Estimate and compare mean patient reported outcome 
scores (PROs) as measured by NFOSI-18 Disease-related symptoms (DRS). 
Exploratory endpoints:  Estimate and compare the treatment groups on the basis of the 
PROs: Treatment Side Effects (TSE), Function/well-being (FWB), Fatigue (FACIT-Fatigue 
subscale-) and Abdominal Discomfort (FACT/GOG-AD subscale). (10/16/2017) 
 
1.3 
Translational Science Objectives 
1.3.1 To determine whether biomarker levels in pre-treatment tissue, and pre- or on-treatment 
peripheral blood, and stool specimens are associated with ORR, PFS and/or OS. 
 
Integrated Biomarker 
Estimate pre-treatment PD-L1 expression on tumor cells measured by quantitative 
immunohistochemistry (IHC), and determine whether it is associated with the duration of PFS 
or overall survival.  
 
 
Exploratory Biomarkers (10/16/2017) 
Note: Exploratory biomarker testing of banked specimens will not occur until an amendment 
to this treatment protocol (or separate correlative science protocol) is reviewed and approved 
in accordance with National Clinical Trials Network (NCTN) policies. 
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(1) Analysis of T cell receptor (TCR) repertoires by deep sequencing of peripheral blood 
samples; 
(2) Tumor “immunogenicity” as determined by the neo-antigen landscape and 
characterization of the tumor microenvironment using next-generation sequencing, 
including but not limited to whole exome sequencing and/or RNA sequencing; and 
 
(3) Microbiome analysis via stool sampling. 
1.3.2 To determine whether changes in quantitative biomarker parameters after the first 6 and 12 
weeks of therapy predict ORR, PFS and/or OS.    
 
2. 
BACKGROUND 
 
Prior genomic analyses of ovarian cancer have revealed far fewer somatic mutations than in 
cancers related to chronic mutagenic exposures such as lung (tobacco) and malignant 
melanoma (UV), with approximately 60 per exome in ovarian cancer compared to >400 per 
exome in melanoma and lung cancer (http://www.ncbi.nlm.nih.gov/pubmed/23945592,  
http://www.ncbi.nlm.nih.gov/pubmed/21720365). The Cancer Genome Atlas (TCGA) for 
ovarian cancer, reporting approximately 61 somatic mutations per tumor, was performed on 
chemotherapy naïve, primary tumor specimens 
(http://www.ncbi.nlm.nih.gov/pubmed/21720365). Ovarian cancers treated with DNA 
damaging chemotherapies (e.g., platinums, doxorubicin) may have more somatic mutations 
and therefore more neoantigens than untreated cancers.  Overall though, ovarian cancers have 
a substantially lower median mutational burden than other checkpoint blockade sensitive 
malignancies, yet a subset of patients still benefit clinically in early studies of PD-L1/PD-1 
blockade therapies (see Table 1 below).  
 
Tumor infiltrating lymphocytes (TILs) in both cancer stroma and within cancer epithelium 
have been shown to be associated with improved clinical outcomes in advanced ovarian 
cancer (http://www.ncbi.nlm.nih.gov/pubmed/16344461, 
http://www.ncbi.nlm.nih.gov/pubmed/12529460), further indicating the potential importance 
of immune targeting in this disease. 
 
To increase the proportion of benefiting patients, ovarian cancer must be made “visible” to the 
immune system, which may require targeting of disease specific immune targets and/or target 
enhancement through judicious combinations 
(http://www.ncbi.nlm.nih.gov/pubmed/26205340).  Strategies to improve activity of PD-
L1/PD-1 blockade include immune combinations (e.g., CTLA4/ipilimumab), chemotherapy 
combinations and targeted therapy combinations (e.g., anti-angiogenic agents, DNA repair). 
 
NRG-GY003, is a randomized phase II trial of nivolumab vs nivolumab + ipilimumab.  This 
trial has completed the second stage accrual and is in follow-up.  This trial will provide 
preliminary proof of principle concerning the anti-PD-1/CTLA4 combination. (03/19/2018) 
 
An industry sponsored phase III trial study is under way evaluating the PD-L1 targeting agent 
avelumab alone or with PLD, versus PLD alone (NCT02580058).  This trial will provide 
proof of principle concerning the PLD/anti-PD-L1 combination, although will not allow for a 
concurrent comparator arm for the current concept. 
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Preclinical and early phase clinical trial data provide the rationale for the combination of the 
anti-PD-L1 agent atezolizumab with pegylated liposomal doxorubicin (PLD) and 
bevacizumab. 
 
2.1 
Background on Atezolizumab (06/29/2017) 
Atezolizumab (MPDL3280A) 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 (Investigator’s Brochure, 2016).  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, thus eliminating detectable Fc-effector 
function and associated antibody-mediated clearance of activated effector T cells.  
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 and B7-1 (also known as CD80), both of which function as inhibitory receptors expressed 
on T cells. 
 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients and is 
being investigated as a potential therapy in a wide variety of malignancies.  Atezolizumab is 
being studied as a single agent in the advanced cancer and adjuvant therapy settings, as well 
as in combination with chemotherapy, targeted therapy, and cancer immunotherapy. 
 
Atezolizumab is approved in the United States for the treatment of locally advanced or 
metastatic urothelial carcinoma and as well as metastatic non-small cell lung carcinoma. 
Atezolizumab is being investigated as a potential therapy against additional solid tumors and 
hematologic malignancies in humans. 
 
Mechanism of Action 
PD-L1 expression is prevalent in many human tumors (e.g., lung, bladder, ovarian, melanoma, 
colon carcinoma), and its overexpression has been associated with poor prognosis in patients 
with several cancers (Thompson et al., 2006; Hamanashi et al., 2007; Okazaki and Honjo 
2007; Hino et al., 2010).  PD-L1 binds to two known inhibitory receptors expressed on 
activated T cells (PD-1 and B7.1), and receptor expression is sustained in states of chronic 
stimulation such as chronic infection or cancer (Blank et al., 2005; Keir et al., 2008).  
Ligation of PD-L1 with PD-1 or B7.1 inhibits T-cell proliferation, cytokine production, and 
cytolytic activity, leading to the functional inactivation or inhibition of T cells.  Aberrant 
expression of PD-L1 on tumor cells has been reported to impede anti-tumor immunity, 
resulting in immune evasion (Blank and Mackensen, 2007).  Therefore, interruption of the 
PD-L1/PD-1 and PD-L1/B7.1 pathway represents an attractive strategy to reinvigorate tumor-
specific T-cell immunity. Blockade of PD-L1 or PD-1 with monoclonal antibodies has been 
reported to result in strong and often rapid antitumor effects in several mouse tumor models 
(Iwai et al., 2002; Strome et al., 2003).  These data suggest that tumor-specific T cells may be 
present in the tumor microenvironment in an inactive or inhibited state, and blockade of the 
PD-L1/PD-1 pathway can reinvigorate tumor-specific T-cell responses. 
 
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Collectively, these data establish the PD-L1/PD-1 pathway as a promising new therapeutic 
target in patients with advanced tumors.  Immune-related adverse events (AEs) reported from 
the two recent studies were consistent with the role of the PD-L1/PD-1 pathway in regulating 
peripheral tolerance. 
 
Summary of Nonclinical Experience 
The safety, pharmacokinetics (PK), and toxicokinetics of atezolizumab were investigated in 
mice and cynomolgus monkeys to support intravenous (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, PK, and toxicokinetics 
of atezolizumab.  
 
Overall, the nonclinical PK and toxicokinetics observed for atezolizumab supported entry into 
clinical studies, including providing adequate safety factors for the proposed phase 1 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. 
 
Summary of Clinical Experience 
 
A summary of clinical data from company-sponsored atezolizumab trials is presented below.  
Details of all ongoing studies can be found in the Atezolizumab Investigator’s Brochure. 
 
Clinical PK and Immunogenicity 
On the basis of available preliminary PK data (0.03−20 mg/kg), atezolizumab shows linear 
PK at doses ≥1 mg/kg (Investigator’s Brochure, 2016).  Based on an analysis of exposure, 
safety, and efficacy date, the following factors had no clinically relevant effect: age (21−89 
years), body weight, gender, positive ATA status, albumin levels, tumor burden, region or 
ethnicity, renal impairment, mild hepatic impairment, level of PD-L1 expression, or ECOG 
status.  No formal PK drug-drug interaction studies have been conducted with atezolizumab, 
and the interaction potential is unknown.  Further details can be found in the current 
Investigator’s Brochure.   
The development of anti-therapeutic antibodies (ATAs) has been observed in patients in all 
dose cohorts and was associated with changes in PK for some patients in the lower dose 
cohorts (0.3, 1, and 3 mg/kg) (Investigator’s Brochure, 2016).  Patients dosed at >10 mg/kg 
maintained Cmin values well above the target serum concentration of 6 mcg/mL despite the 
detection of ATAs.  Accordingly, the development of detectable ATAs does not appear to 
have a clinically significant impact on PK for doses above 10 mg/kg.  To date, no relationship 
between the development of measurable ATAs and safety or efficacy has been observed. 
 
Clinical Safety Summary 
As of May 10, 2016, atezolizumab has been administered (alone or in combination with other 
agents) to approximately 6053 patients with solid tumor and hematologic malignancies 
(Investigator’s Brochure, 2016).The first-in-human monotherapy study PCD4989g (in patients 
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with locally advanced or metastatic solid tumors or hematologic malignancies) provides the 
majority of monotherapy safety data, with 629 safety-evaluable patients as of the data 
extraction date.  Currently, no maximum tolerated dose (MTD), no dose-limiting toxicities 
(DLTs), and no clear dose-related trends in the incidence of AEs have been determined. 
Fatigue, decreased appetite, nausea, diarrhea, constipation, and cough were commonly 
reported AEs in single and combination therapy (Investigator’s Brochure, 2016).  AE profiles 
are similar across tumor types studied, including non-small cell lung cancer (NSCLC), renal 
cell carcinoma (RCC), triple-negative breast cancer (TNBC), and urothelial carcinoma (UC), 
and are consistent with the mechanism of action of atezolizumab.  The overall immune-
mediated AEs reported were considered moderate in severity, and the majority of patients 
were able to continue on atezolizumab therapy. 
 
As of the data extraction date of December 15, 2015, there were 629 safety-evaluable patients 
from the first-in-human phase 1a study PCD4989g (Investigator’s Brochure, 2016).  The 
median age was 61 years.  Of the 629 patients, 619 patients (98.4%) reported at least one AE 
of any grade or attribution to atezolizumab, and 316 patients (50.2%) experienced at least one 
grade 3 or 4 AE of any attribution.  A total of 444 patients (70.6%) reported at least one 
treatment-related AE, and 86 patients (13.7%) experienced at least one treatment-related grade 
3 or 4 AE.  The most frequently observed AEs of any grade and attribution (occurring 
in ≥10% of treated patients) include fatigue, decreased appetite, nausea, pyrexia, constipation, 
cough, dyspnea, diarrhea, anemia, vomiting, asthenia, back pain, headache, arthralgia, 
pruritus, rash, abdominal pain, insomnia, peripheral edema, and dizziness. 
 
Serious AEs (SAEs) have been reported in 261 patients (41.5%) in study PCD4989g 
(Investigator’s Brochure, 2016).  Reported SAEs were consistent with the underlying disease.  
Treatment-related SAEs (57 patients [9.1%]) included pyrexia, dyspnea, pneumonitis, 
malaise, fatigue, hypoxia, colitis, and bone pain.  Pooled single-agent safety data from 1978 
patients with UC, NSCLC, and other indications (including trial PCD4989g) indicate that the 
most frequent (>1% of patients) serious adverse drug reactions (regardless of grade) include 
dyspnea (3.0%), back pain (1.2%), and abdominal pain (1.1%).  A list of AEs considered 
“expected” for atezolizumab is presented in the Atezolizumab Investigator’s Brochure. 
 
Immune-Related Adverse Events 
 
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 
(Investigator’s Brochure, 2016).  To date, immune-related adverse events associated with 
atezolizumab include hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, Guillain-Barré syndrome, 
myasthenic syndrome/myasthenia gravis, and meningoencephalitis.   
 
For further details, see the most recent Atezolizumab Investigator’s Brochure. 
Clinical Efficacy Summary 
 
Patients with multiple tumor types were included in study PCD4989g, with the largest cohorts 
consisting of patients with NSCLC, RCC, and UC (Investigator’s Brochure, 2016).  Objective 
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responses with atezolizumab monotherapy were observed in a broad range of malignancies, 
including NSCLC, RCC, melanoma, UC, colorectal cancer, head and neck cancer, gastric 
cancer, breast cancer, and sarcoma.  Both the preliminary and more mature efficacy data 
available suggest that treatment with atezolizumab as a single agent or in combination with 
other therapeutic agents results in anti-tumor activity across a range of tumor types and 
hematologic malignancies (UC, NSCLC, RCC, TNBC, melanoma, CRC, and NHL) and 
across lines of therapy.  Clinical benefit was observed in terms of objective responses, 
durability of responses, and overall survival (OS).  Improved efficacy of atezolizumab was 
observed in the unselected patient population, as well as in patients with higher PD-L1 
expression on TCs or ICs (e.g., NSCLC) or on ICs only (e.g., mUC, RCC). 
 
2.2 
Rationale for the use of Atezolizumab in Ovarian Cancer  
Checkpoint blockade agents that target CTLA-4, PD-1 and PD-L1 are in widespread use, 
either for FDA-approved indications or in clinical trials.  Atezolizumab, an anti PD-L1 
monoclonal, has exhibited tolerability and preliminary signs of efficacy in solid tumors and 
bladder cancers (http://www.ncbi.nlm.nih.gov/pubmed/25428504, 
http://www.ncbi.nlm.nih.gov/pubmed/25428503).  PD-1 and PD-L1-targeting agents 
manufactured by other companies have shown preliminary signs of safety and efficacy in 
ovarian cancer.  Programmed cell death one ligand one (PD-L1), the cognate ligand for PD-1, 
is expressed in a subset of ovarian cancers and is associated with poor prognosis 
(http://www.ncbi.nlm.nih.gov/pubmed/17360651).  In that study, using an antibody generated 
by the authors, 88.6% of the 70 tumors tested were scored as having PD-L1 expression >0, 
with 68.6% scored as 2-3. 
 
Promising single agent activity has been seen for anti-PD-1 and anti-PD-L1 agents tested in 
patients with ovarian cancer (Table 1).  The anti-PD-L1 agent avelumab was well-tolerated 
and showed an overall response rate of 10.7%, and a disease control rate (DCR) of 54.7%, in a 
Phase 1b study that included 75 patients with ovarian cancer (Disis et al, J Clin Oncol 33, 
2015 Abstract 5509).  In a more heavily pretreated, PD-L1 positive ovarian cancer population, 
the anti-PD-1 agent pembrolizumab showed an ORR of 11.5% and a DCR of 34.6% 
(KEYNOTE-028, Varga et al, J Clin Oncol 33, 2015 Abstract 5510).  In addition, the anti-PD-
1 agent, nivolumab, showed an ORR of 15% and DCR of 45% in a 20 patient phase I study 
(http://www.ncbi.nlm.nih.gov/pubmed/26351349).  A single agent, phase II study of 
ipilimumab in recurrent ovarian cancer has completed accrual and is in follow-up 
(NCT01611558). 
 
Table 1 
Study 
N 
RR 
Disease Control 
Rate 
Prior Treatment 
Nivolumab  
Cohort 1:  1 mg/kg 
Cohort 2:  3 mg/kg 
IV q 2 weeks 
 
10 
10 
 
1 (PR)/10 (10%) 
2 (CR)/10 (20%) 
(1 Clear Cell)  
 
Overall RR (both 
cohorts) = 15% 
 
5/10 (50%) 
4/10 (40%)  
 
> 2 priors; 
platinum 
resistant 
Avelumab  
 
75 
 
8 (PR)/75 (10.7%) 
 
41/75 (54.7%)  
 
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Phase Ib expansion 
cohort 
10 mg/kg q 2 weeks  
(2/2 Clear Cell)  
No limit on priors (median 
4, range 1-11); platinum 
resistant  
Pembrolizumab  
Phase Ib expansion 
cohort 
10 mg/kg q 2 weeks 
 
26 
 
3 (1 CR, 2 PR)/26 
(11.5%)  
 
9/26 (34.6%)  
 
No limit on priors (>80% > 
4 priors); PD-L1 IHC 
positive* 
Ipilimumab 
10 mg/kg IV q3 weeks x 
4 –> q12 weeks 
Results pending 
< 4 priors  
* Positivity defined archival as membranous PD-L1 expression in ≥1% of cells in tumor nests 
or positive bands in stroma on archived or new biopsies.  Assessed at a central laboratory 
using a prototype assay and 22C3 antibody clone (Merck).  Overall 49/96 (51%) of screened 
patients tested positive. 
 
Rationale for the combination of Bevacizumab and PLD 
Bevacizumab is a recombinant, humanized antibody targeting VEGF that has modest single 
agent activity in ovarian cancer in phase II trials, as shown in Table 2 (BV = bevacizumab; 
http://www.ncbi.nlm.nih.gov/pubmed/18024863; 
http://www.ncbi.nlm.nih.gov/pubmed/18024865; GOG186G, ASCO 2014).   
 
Table 2 
Study 
N 
Treatment 
RR 
(%) 
PFS at 6 
months (%) 
Prior Treatment 
GOG 170D  
62 
BV 15 mg/kg IV q 3 wk  
21 
40 
1-2 priors; 58% 
platinum resistant  
Cannistra et al  
44 
BV 15 mg/kg IV q 3 wk  
16 
28 
1-3 priors; platinum-
refractory or resistant 
AND progression 
on/within 3 months of 
topotecan or PLD  
GOG186G 
75 
BV 10 mg/kg IV q 2 wk 
9 
40 
1-3 priors; 68% 
platinum resistant 
 
The AURELIA study demonstrated that combining bevacizumab with chemotherapy in 
platinum resistant ovarian cancer significantly improved progression free survival (the 
primary endpoint) as well as objective response rate and the patient reported outcome end 
point of abdominal/GI symptoms (results of each arm shown in Table 3), providing the basis 
for the FDA approval (http://www.ncbi.nlm.nih.gov/pubmed/24637997).  PLD with 
bevacizumab therefore represents a standard of care backbone on which to improve.   
 
Table 3 
Agent 
Median PFS 
Chemo Alone 
(months) 
Median PFS 
Chemo + Bev 
(months) 
HR 
Median OS 
Chemo Alone 
(months) 
Median OS 
Chemo + Bev 
(months) 
HR 
Paclitaxel 
3.9 
10.4 
0.46  
(0.30-0.71) 
13.2 
22.4 
0.65 
(0.42-1.02) 
PLD 
3.5 
5.4 
0.57 
(0.39-0.83) 
14.1 
13.7 
0.91 
(0.62-1.36) 
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Topotecan 
2.1 
5.8 
0.32 
(0.21-0.49) 
13.3 
13.8 
1.09 
(0.72-1.67) 
 
2.3 
Rationale for the combination of PLD and Atezolizumab (24-FEB-2021) 
From a molecular perspective, in addition to being a mutagenic cytotoxic, doxorubicin is 
known to exert its anti-tumor effects in part through interferon signaling 
(http://www.ncbi.nlm.nih.gov/pubmed/25344738).  Atezolizumab leads to an increase in 
activated proliferating CD8+ T cells and a trend to increased circulating interferon gamma 
(http://www.ncbi.nlm.nih.gov/pubmed/25428504), suggesting a potentially complementary 
mechanism.  With the exception of fatigue, the side effect profiles of these medications are 
non-overlapping.  
 
Three examples from NSCLC provide evidence that PD-1 and PD-L1-blocking agents can be 
used safely with chemotherapy.  37 chemotherapy-naive patients with NSCLC were treated 
with atezolizumab 15mg/kg every 3 weeks in combination with carboplatin and paclitaxel, 
carboplatin and nab-paclitaxel or carboplatin and pemetrexed (Liu SV et al, 2015).  The most 
common AEs of any grade were fatigue, nausea, constipation and diarrhea, and were similar 
across arms.  The grade 3 AEs occurring in ≥5% of patients were neutropenia, anemia, 
thrombocytopenia and increased ALT/AST.  All but the increased transaminases could be 
attributed primarily to the chemotherapy component of the combinations.  35/37 patients 
experienced disease stability or better, but this study design precludes conclusions about 
efficacy. 
 
In another study, patients with chemotherapy-naïve NSCLC were treated with 4 cycles of 
pembrolizumab (2 or 10mg/kg) plus carboplatin (AUC 6) and paclitaxel (200mg/m2) every 3 
weeks followed by pembrolizumab maintenance, or the same dosing of pembrolizumab with 
carboplatin (AUC 5) and pemetrexed (500mg/m2) followed by pembrolizumab plus 
pemetrexed maintenance (Papadimitrakopoulou V et al, 2015).  Grade 3-4 toxicities were rare, 
and including 1-3 cases across cohorts of increased ALT, increased AST, anemia, atrial 
fibrillation, colitis, diarrhea, rash, fatigue, hypertension, hyponatremia, infectious pleural 
effusion, and in the carboplatin + paclitaxel cohort, leucopenia, neutropenia, decreased white 
blood cell count and febrile neutropenia.  As in the study above, the disease control rate was 
high, but conclusions about efficacy are limited given the study design. 
 
A similar study was conducted with nivolumab (platinum-based doublet paired with 
gemcitabine, pemetrexed or paclitaxel, all with nivolumab followed by nivolumab 
maintenance (Antonia SJ et al, 2014).  Grade 3-4 AE were again rare: of 56 patients, 1-3 
across arms experienced fatigue, nausea, anorexia, anemia, rash or diarrhea.  
 
Arm 1 (PLD and atezolizumab) was permanently closed to accrual with amendment 11 as the 
planned interim analysis for this regimen crossed the futility boundary for early termination, 
which was based on overall survival compared to standard of care PLD and bevacizumab 
(Arm 3). The overall survival for patients in Arm 1 (PLD/atezolizumab) was not definitively 
worse than the standard of Arm 3 (PLD and bevacizumab) and there were no notable 
additional risks.  
 
 
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2.4 
Rationale for the combination of Bevacizumab and Atezolizumab 
Preclinical data illustrate the immunosuppressive effects of VEGF, which are reversed by 
VEGF blockade.  VEGF is thought to induce myeloid derive suppressor cells (MDSC), which 
suppress the anti-tumor T-cell and dendritic cell response 
(http://www.ncbi.nlm.nih.gov/pubmed/22437938). VEGF blockade may increase T cell 
trafficking to tumors, increase anti-tumor populations of T cells (CD8+ and CD4+ central 
memory) and decrease pro-tumor immune populations (myeloid-derived suppressor cells and 
regulatory T cells) (http://www.ncbi.nlm.nih.gov/pubmed/18566400, 
http://www.ncbi.nlm.nih.gov/pubmed/24018532, 
http://www.ncbi.nlm.nih.gov/pubmed/17606729, 
http://www.ncbi.nlm.nih.gov/pubmed/20631075). 
In addition, anti-VEGF therapies may reduce suppressive cytokines, tumor-infiltrating T 
regulatory cells and MDSC (http://www.ncbi.nlm.nih.gov/pubmed/19888452). 
 
Several clinical studies have illustrated the potential advantage of adding anti-angiogenic 
agents to checkpoint blockade therapy. A Phase II study of bevacizumab with the anti-CTLA-
4 agent ipilimumab in melanoma showed a DCR of 67.4% and median survival of 25.1 
months, which was substantially better than historical controls.  Furthermore, on-treatment 
biopsies exhibited inflammation and lymphocyte infiltration 
(http://www.ncbi.nlm.nih.gov/pubmed/24838938).  In a Phase Ib study of 12 patients with 
renal cell carcinoma treated with bevacizumab and atezolizumab, 40% had an objective 
response, which appeared to occur independent of PD-L1 IHC staining (Figure 1, McDermott 
et al, ESMO 2014, Abstract 809O; Sznol et al, JClin Oncol 33, 2015 Abstract 410).  A phase 
III trial is in progress (A phase III, open label, randomized study of atezolizumab [anti-PD-L1 
antibody] in combination with bevacizumab versus sunitinib in patients with untreated 
advanced renal cell carcinoma).  Renal cell carcinomas (RCC), like ovarian cancers, do not 
harbor a high mutational burdens (thought to underlie the efficacy of checkpoint blockade 
agents in melanoma and lung cancers), and are treated with bevacizumab as a standard of 
care.  A Phase III study is also under way of atezolizumab in combination with carboplatin 
and paclitaxel with or without bevacizumab in stage IV non-squamous NSCLC 
(NCT02366143). 
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The combination of atezolizumab and bevacizumab has already provided an excellent safety 
signal.  In Study GP28328, the grade 3-5 AE rate was 1/35 patients (2.9%).  The one >= grade 
3 event was neutropenia.    
 
2.5 
Rationale for the combination of PLD, Bevacizumab and Atezolizumab 
Based on the safety of single agent atezolizumab alone, atezolizumab plus bevacizumab, and 
atezolizumab plus chemotherapy; the preliminary evidence for PD-1 and PD-L1-targeting 
agents in ovarian cancer; the non-overlapping toxicities of these three agents; the scientific 
rationale for combining PLD and/or bevacizumab with atezolizumab and the need to improve 
outcomes in patients with platinum-resistant ovarian cancers, we propose a three-arm trial 
consisting of PLD and bevacizumab (reference arm); the addition of atezolizumab to PLD 
(Experimental Regimen 1); or the addition of atezolizumab to PLD and bevacizumab 
(Experimental Regimen 2) in a Phase II/III study.   
 
2.6 
Translational Science Background 
Note: Exploratory biomarker testing of banked specimens will not occur until an amendment 
to this treatment protocol (or separate correlative science protocol) is reviewed and approved 
in accordance with National Clinical Trials Network (NCTN) policies. 
 
2.6.1 PD-L1 Expression (Integrated Biomarker) (30-OCT-2020) 
PD-L1 expression will be evaluated as an integrated biomarker in this study. PD-L1, also 
known as B7-H1, is an inhibitory ligand expressed in multiple cancer types including ovarian. 
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In addition to being inherently upregulated in some cancer types, more commonly, PD-L1 
expression is upregulated in response to tumor-infiltrating lymphocytes and thus serves as a 
mechanism of adaptive immune resistance to T cell infiltration (Taube et al., 2014).  
Expression of PD-L1 on tumor cells and tumor-infiltrating immune cells has been shown to be 
associated with response to immune checkpoint blocking antibodies targeting PD-1 or PD-L1 
in several cancer types (reviewed in https://www.ncbi.nlm.nih.gov/pubmed/24714771). PD-
L1 expression in tumor infiltrating immune cells (IC) in particular has been shown to be the 
strongest predictor of response. Powles et al. published a phase I study investigating the anti-
PD-L1 antibody atezolizumab for the treatment of metastatic urothelial bladder cancer 
(Powles et al., 2014). This study showed that atezolizumab had noteworthy activity in 
metastatic UBC with rapid responses occurring at the first response assessment (6 weeks) and 
nearly all were ongoing at the data cutoff (Powles et al., 2014). PD-L1 expression is scored in 
tumor infiltrating immune cells (as percentage of tumor area: IC3≥10%, IC2≥5% and <10%, 
IC1≥1% and <5%, and IC0<1%). 
 
VENTANA PD-L1 (SP142), is an FDA-approved complimentary diagnostic IHC assay to 
ascertain tumor PD-L1 status for patients with metastatic urothelial cancer and triple negative 
breast cancer (TNBC) considering treatment with atezolizumab, with IC1 staining (PD-L1 
positivity ≥1%) as a cutoff.  
  
The association of PD-L1 expression with response to PD-L1 blockade in ovarian cancer has 
not been established. We hypothesize that the tumor microenvironment of the ovarian cancer 
patients exhibiting higher levels of PD-L1 expression in tumor-infiltrating immune cells is 
more amenable to immunotherapy with immune checkpoint blockade. As such we 
hypothesize that patients with higher levels of PD-L1 will exhibit evidence of stronger anti-
tumor immune response and improved PFS and OS in the NRG-GY009 trial.  
 
SP142 assay was previously used to evaluate PD-L1 expression in ovarian cancer (Webb 
et.al., 2016). In the cohort of 490 ovarian cancer cases analyzed by tissue microarray, PD-L1 
IC1 positivity (defined as ≥1%) was observed in 57.4% of high-grade serous cases, 24% of 
endometrioid cases, and 16% of clear cell cases. Internal data provided by Genentech 
demonstrates IC1 staining in approximately 60% of patients and IC2 staining (>5%) in 
approximately 20% of patients with ovarian cancer. Based on the study above, we assume that 
approximately 50% of patients in our population will be PD-L1 positive (defined as ≥1%).  In 
this trial, archival pre-treatment formalin-fixed, paraffin-embedded (FFPE) tumor tissue will 
be evaluated by immunohistochemistry (IHC) for expression of PD-L1 on tumor and immune 
cells using the PD-L1 antibody clone SP142. The association of PD-L1 expression and 
clinical outcome, specifically PFS and OS, will be investigated. Details of PD-L1 testing are 
available in (section 10.3).  
 
2.6.2 T Cell Receptor (TCR) Repertoires (Exploratory Biomarker) 
The analysis of overall changes in TCR repertoires during therapy may help to determine 
whether certain dominant T cell clones emerge or persist in response to therapy. Cha and 
colleagues reported that maintenance of specific T cell clonotypes in blood of patients with 
advanced melanoma treated with ipilimumab was associated with improved survival 
(https://www.ncbi.nlm.nih.gov/pubmed/24871131). More recently, a study out of Memorial 
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Sloan Kettering Cancer Center (MSKCC) demonstrated that the baseline peripheral blood 
mononuclear cell TCR clonality and expansion of tumor-specific TCR in the peripheral blood 
3 weeks after initiating treatment were found to correlate with response to atezolizumab in 
bladder cancer (Funt et al, ASCO 2016). TCR repertoire studies were performed in tumors at 
MSKCC in the setting of a clinical trial in patients with early stage breast cancer treated with 
neoadjuvant cryoablation of breast lesion and ipilimumab, where combination therapy 
demonstrated most significant increase in intra-tumoral T cell clone (Page DB, Diab A, Yuan J, 
et al., 2014) In this trial DNA will be used for TCR repertoire analysis and deep sequencing of 
intratumoral and peripheral blood mononuclear cell TCR CDR3 regions (Adaptive 
Biotechnologies). Peripheral blood DNA will be collected at baseline (prior to initiation of 
treatment) and at 4 weeks after initiation of therapy in patients participating in the Phase II 
portion of the study. 
 
2.6.3 Neoantigen Landscape and Characterization of the Tumor Microenvironment (Exploratory 
Biomarker) (06/29/2017) (10/16/2017) 
A recent study by the group at Memorial Sloan Kettering Cancer Center (MSKCC) used next-
generation whole exome sequencing (NGS) to characterize the neoantigen landscapes in 
tumors from patients with malignant melanoma and lung cancers 
(https://www.ncbi.nlm.nih.gov/pubmed/25409260, 
https://www.ncbi.nlm.nih.gov/pubmed/25765070). In addition, it is known that the tumor 
microenvironment plays a key role in mediating response as well as immune escape to cancer 
immunotherapy.  To determine whether specific tumor genetic determinants, including 
predicted mutation burden, as well as immune-modulatory elements or other molecular 
characteristics of the tumor microenvironment influence the response to either treatment, 
DNA isolated from archived tumor samples will be processed for NGS and/or RT-PCR to 
assess for specific driver mutations, for potential neoantigens, and for potential gene 
expression signatures. 
 
2.6.4 Microbiome Analysis (Exploratory Biomarker) (10/16/2017) 
As a site of substantial immune activity, the gut (small and large intestines) represents an 
organ system of known importance to systemic inflammatory conditions 
(https://www.ncbi.nlm.nih.gov/pubmed/20620945, 
https://www.ncbi.nlm.nih.gov/pubmed/26102221).  Recent studies have demonstrated a role 
for stool microbiota in influencing response to checkpoint blockade therapy in preclinical 
models, with a small, retrospective data in human samples to corroborate its importance 
(https://www.ncbi.nlm.nih.gov/pubmed/26541610, 
https://www.ncbi.nlm.nih.gov/pubmed/26541606).  Manipulation of the gut microbiome by 
fecal transplant for the treatment of Clostridium difficile is safe and effective 
(https://www.ncbi.nlm.nih.gov/pubmed/23323867).  The importance of the gut microbiome to 
checkpoint blockade outcomes has not yet been studied in a prospective setting.  To determine 
whether the diversity or particular bacterial subtypes in the stool microbiome are associated 
with clinical benefit from checkpoint blockade therapy, DNA will be isolated from stool 
samples prior to cycles 1 and 2, using samples from patients participating in the Phase II 
portion of the study. DNA will undergo 16S Pyrosequencing, organism identification and 
analyses for prevalence and population shifts using techniques described in the 
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aforementioned publications (https://www.ncbi.nlm.nih.gov/pubmed/20620945, 
https://www.ncbi.nlm.nih.gov/pubmed/26102221). (02/20/2019) 
 
2.6.5   Additional translational studies may be performed from banked tissues or blood. (10/16/2017) 
 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 
 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Biostatistical/Data 
Management Center-Pittsburgh Office: 412-624-2666.  
 
3.1 
Patient Selection Guidelines 
Although the guidelines provided below are not inclusion/exclusion criteria, investigators 
should consider these factors when selecting patients for this trial. Investigators also should 
consider all other relevant factors (medical and non-medical), as well as the risks and benefits 
of the study therapy, when deciding if a patient is an appropriate candidate for this trial. 
3.1.1 Patients must have the psychological ability and general health that permits completion of the 
study requirements and required follow up. 
3.1.2 Administration of study drugs (pegylated liposomal doxorubicin, bevacizumab, atezolizumab) 
may have an adverse effect on pregnancy and poses a risk to the human fetus, including 
embryo-lethality.  Women of child-bearing potential (WOCBP) must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, 
for the duration of study participation, and for 5 months (150 days) after the last dose of study 
agent.  Should a woman become pregnant or suspect she is pregnant while she is participating 
in this study, she should inform her treating physician immediately. (06/29/2017) 
3.1.3 Submission of tumor tissue is required for all patients. Investigators should check with their 
site Pathology Department regarding release of biospecimens before approaching patients 
about participation in the trial. 
 
3.2 
Eligibility Criteria (06/29/2017) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
3.2.1 High grade ovarian cancer, including high grade serous; clear cell; endometrioid, grade 3; and 
others (adenocarcinoma, NOS; mixed epithelial carcinoma; undifferentiated carcinoma).  
NOTE:  Low grade serous, mucinous and carcinosarcoma histologies are excluded due to 
their different underlying genomic features and/or clinical behavior.  Ovarian cancer = 
ovarian, fallopian tube or primary peritoneal cancer.  Required data element:  submission of 
pathology report.  
3.2.2 Recurrent, platinum resistant ovarian cancer (defined as progression within < 6 months from 
completion of platinum based therapy.  The date should be calculated from the last 
administered dose of platinum therapy). 
3.2.3 1-2 prior regimens (including primary therapy).  Hormonal therapies (e.g., tamoxifen, 
aromatase inhibitors) will not count toward the prior regimen limit. PARP inhibitors given in 
the maintenance setting post response to platinum-based therapy will not count as a separate 
regimen from the preceding platinum-based therapy. (30-OCT-2020). 
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3.2.4 Measurable disease (defined by RECIST v 1.1) or evaluable disease (defined as solid and/or 
cystic abnormalities on radiographic imaging that do not meet RECIST 1.1 definitions for 
target lesions OR ascites and/or pleural effusion that has been pathologically demonstrated to 
be disease related in the setting of CA125 ≥ 2xULN). 
3.2.5 Age ≥ 18 
3.2.6 The trial is open to females only 
 
3.2.7 Performance Status 0, 1 or 2 (see Appendix II)   
3.2.8 Adequate hematologic function within 14 days prior to registration defined as follows: 
• ANC ≥ 1,500/mcl 
• Platelets ≥ 100,000/mcl 
• Hgb ≥ 8 g/dl 
3.2.9 Adequate renal function within 14 days prior to registration defined as follows: 
• Creatinine ≤ 1.5 x institutional upper limit of normal (ULN) 
• Urine protein creatinine (UPC) ratio must be < 1.0.  If UPC ratio > 1, collection of 24-
hour urine measurement of urine protein is recommended (24-hour urine protein level 
must be < 1000 mg for patient enrollment). If UPC ratio cannot be calculated because the 
urine protein is below the lower limit of detection of the assay this will not exclude the 
patient. (10/22/2018) (30-OCT-2020). 
 
UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion – a UPC 
ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm.  UPC ratio is calculated 
using one of the following formulas: 
1. [urine protein]/[urine creatinine] – if both protein and creatinine are reported in mg/dL 
2. [(urine protein) x0.088]/[urine creatinine] – if urine creatinine is reported in mmol/L 
(03/19/2018) 
3.2.10 Adequate hepatic function within 14 days prior to registration defined as follows: 
• Total Bilirubin ≤ 1.5 x ULN (patients with known Gilbert disease who have serum 
bilirubin level ≤ 3 x ULN may be enrolled) 
• AST/ALT ≤ 3 x ULN (AST and/or ALT ≤ 5 x ULN for patients with liver involvement) 
3.2.11 INR and aPTT ≤ 1.5 x ULN (or on stable dose of therapeutic anticoagulation, such as low-
molecular-weight heparin, warfarin or rivaroxaban) (10/16/2017) 
3.2.12 TSH within normal limits (Euthyroid patients on thyroid replacement therapy allowed 
provided TSH < ULN.)  (02/20/2019) 
3.2.13 The patient or legally authorized representative must provide study-specific informed consent 
prior to study entry and, for patients treated in the U.S., authorization permitting release of 
personal health information. 
 
3.3 
Ineligibility Criteria (06/29/2017) 
Patients with any of the following conditions are NOT eligible for this study. 
3.3.1 Patients with prior allogeneic bone marrow transplantation or prior solid organ 
transplantation. 
3.3.2 Patients who have had systemic anticancer therapy (e.g., chemotherapy, targeted therapy 
including PARP inhibitors or bevacizumab) within 3 weeks prior to entering the study. (30-
OCT-2020). 
3.3.3 Patients who have had hormonal therapy (e.g., tamoxifen, aromatase inhibitor) within 1 week 
prior to entering the study. 
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3.3.4 Patients with prior treatment with anti-PD-1, anti-PD-L1 or anti-CTLA-4 therapeutic antibody 
or other similar agents. (10/16/2017) 
3.3.5 Patients with prior treatment with bevacizumab (or any other anti vascular therapy, e.g., 
cediranib) for platinum resistant recurrence.  (Note:  Prior bevacizumab in initial therapy 
and/or platinum sensitive recurrent setting is allowed.) (10/16/2017) 
3.3.6 Patients with prior treatment with PLD. 
3.3.7 Prior radiotherapy to the abdomen or pelvis. 
3.3.8 Patients who have not recovered from adverse events to < grade 1 (other than alopecia) due to 
agents administered more than 3 weeks earlier. (10/16/2017) 
However, the following therapies are allowed: 
• Hormone replacement therapy or oral contraceptives 
• Herbal therapy >1 week prior to Cycle 1, Day 1 (herbal therapy intended as anticancer 
therapy must be discontinued at least 1 week prior to Cycle 1, Day 1) 
• Palliative radiotherapy for bone metastases >2 weeks prior to Cycle 1, Day 1 
3.3.9 Treatment with any other investigational agent within 4 weeks prior to Cycle 1, Day 1. 
3.3.10 Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
[IFN]-alpha or interleukin [IL]-2) within 6 weeks prior to Cycle 1, Day 1. 
3.3.11 Treatment with systemic immunosuppressive medications (including, but not limited to, 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 
necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1. 
• Patients who have received acute, low dose, systemic immunosuppressant medications 
(e.g., a one-time dose of dexamethasone for nausea or steroids as CT scan contrast 
premedication) may be enrolled. 
• The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for 
patients with orthostatic hypotension or adrenocortical insufficiency is allowed. 
3.3.12 Patients taking bisphosphonate therapy for symptomatic hypercalcemia within the past 28 
days.  Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) 
is allowed. 
3.3.13 Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS 
metastases are excluded, with the following exceptions:   
• Patients with asymptomatic untreated CNS disease may be enrolled, provided all of 
the following criteria are met: 
o Evaluable or measurable disease outside the CNS 
o No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 
mm of the optic apparatus (optic nerves and chiasm) 
o No history of intracranial hemorrhage or spinal cord hemorrhage 
o No ongoing requirement for dexamethasone for CNS disease; patients on a 
stable dose of anticonvulsants are permitted. 
o No neurosurgical resection or brain biopsy within 28 days prior to Cycle 1, 
Day 1 
• Patients with asymptomatic treated CNS metastases may be enrolled, provided all the 
criteria listed above are met as well as the following: 
o Radiographic demonstration of improvement upon the completion of CNS 
directed therapy and no evidence of interim progression between the 
completion of CNS directed therapy and the screening radiographic study 
o No stereotactic radiation or whole brain radiation within 28 days prior to Cycle 
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1, Day 1 
o Screening CNS radiographic study ≥ 4 weeks from completion of radiotherapy 
and ≥ 2 weeks from discontinuation of corticosteroids 
3.3.14 Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human 
antibodies. 
3.3.15 History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins. 
3.3.16 Patients requiring treatment with a RANKL inhibitor (e.g., denosumab) who cannot 
discontinue it before treatment with atezolizumab. 
3.3.17 Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; 
cirrhosis; fatty liver; and inherited liver disease.  
• Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis 
B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core 
antigen] antibody test) are eligible. 
• 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction (PCR) is negative for HCV RNA. 
3.3.18 History or risk of autoimmune disease, including but not limited to systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis 
associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, 
Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or 
glomerulonephritis. (02/20/2019) 
• Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid 
replacement hormone are eligible. 
• Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen or Type 2 
diabetes mellitus are eligible. 
• Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are 
permitted provided that they meet the following conditions: 
 
Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular 
manifestations 
 
Rash must cover less than 10% of body surface area (BSA) 
 
Disease is well controlled at baseline and only requiring low potency topical steroids 
(e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, 
desonide 0.05%, alclometasone dipropionate 0.05%) 
 
No acute exacerbations of underlying condition within the last 12 months (not 
requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors; high potency or oral steroids) 
3.3.19 History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing 
pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence 
of active pneumonitis on screening chest computed tomography (CT) scan.  History of 
radiation pneumonitis in the radiation field (fibrosis) is permitted. 
3.3.20 Patients with active tuberculosis (TB) are excluded. 
3.3.21 Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited 
to hospitalization for complications of infection, bacteremia, or severe pneumonia. 
3.3.22 Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1. 
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3.3.23 Received oral or intravenous (IV) antibiotics within 2 weeks prior to Cycle 1, Day 1.  Patients 
receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic 
obstructive pulmonary disease) are eligible. 
3.3.24 Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need for a 
major surgical procedure during the course of the study. 
3.3.25 Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or 
anticipation that such a live, attenuated vaccine will be required during the study and up to 5 
months after the last dose of atezolizumab. (06/29/2017)  
• 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.  
3.3.26 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
3.3.27 HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 
months are eligible for this trial. (08-JAN-2021) 
3.3.28 Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a 
minimum of 3 years, with the exception of those with a negligible risk of metastases or death, 
such as carcinoma in situ of the breast or cervix. 
3.3.29 Severe, active co-morbidity defined as follows: 
• Current (within 28 days of Cycle 1, Day 1) signs and/or symptoms of bowel obstruction 
• Patients who require parental hydration and/or nutrition 
• Patients who require drainage gastrostomy tube 
• Evidence of bleeding diathesis or clinically significant coagulopathy 
• Serious, non-healing or dehiscing wound, active ulcer or untreated bone fracture 
• History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month of 
study enrollment 
3.3.30 Significant cardiovascular or cerebrovascular disease including: 
• Uncontrolled hypertension (SBP >150 and/or DBP >90) (29-JUN-2020) 
• History of myocardial infarction within 6 months 
• Unstable angina 
• New York Heart Association functional classification II, III or IV (See Appendix III) 
• Baseline ejection fraction ≤ 50% as assessed by echocardiogram or MUGA 
• Cerebral vascular accident (CVA) or transient ischemic attack (TIA) within 6 months 
• Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or peripheral 
arterial thrombosis) within 6 months 
3.3.31 History of abdominal/pelvic or tracheoesophageal fistula or gastrointestinal perforation and/or 
abdominal/pelvic abscess within 6 months prior to initiation of treatment. (02/20/2019) 
3.3.32   Pregnant or lactating patients. 
 
 
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4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
4.1 
PRE-TREATMENT ASSESSMENTS (10/22/2018) 
Assessments 
Prior to 
Registration 
 (calendar 
days) 
Prior to Treatment 
(calendar days) 
(Cycle 1, Day 1) 
History and Physical 
≤ 14 days 
≤ 14 days 
Concomitant Medications 
≤ 14 days 
≤ 14 days 
Vital Signs 
≤ 14 days 
≤ 14 days 
Performance Status 
≤ 14 days 
≤ 14 days 
Toxicity Assessment 
≤ 14 days 
≤ 14 days 
CBC/Differential/Platelets 
≤ 14 days 
≤ 14 days 
Chemistries (BUN, Creatinine, Sodium, Potassium, 
Chloride, CO2, Calcium, Glucose, Bilirubin, Protein, 
Albumin, Alkaline Phosphatase, AST, ALT) 
≤ 14 days 
≤ 14 days 
TSH 
≤ 14 days 
≤ 14 days 
Hepatitis B Surface Antigen 
≤ 28 days 
≤ 28 days 
Hepatitis B Core Antibody 
≤ 28 days 
≤ 28 days 
Hepatitis C Antibody 
≤ 28 days 
≤ 28 days 
UPCR 
≤ 14 days 
≤ 14 days 
INR and aPTT§ (06/29/2017) 
≤ 28 days 
≤ 28 days 
Pregnancy Test (if childbearing potential exists) 
≤ 14 days 
≤ 24 hours 
ECG 
≤ 28 days 
≤ 28 days 
ECHO or MUGA† 
≤ 28 days 
≤ 28 days 
CA-125 (10/16/2017) 
≤ 28 days 
≤ 28 days 
Radiographic Tumor Measurement* 
≤ 28 days 
≤ 28 days 
Patient Reported Outcomes (PRO)+ 
 
Baseline – prior to any 
premedication or 
treatment administration 
 
§ See Sec 3.2.11.(10/16/2017) 
† The same method should be used for each patient throughout the study. 
*Radiographic tumor measurements should be obtained via imaging of the chest, abdomen and 
pelvis to establish the location and extent of disease. See RECIST 1.1 for allowable imaging 
modalities used to assess disease at baseline (and subsequent assessments). Contrast CT is the 
preferred modality. Images from radiographic studies should be uploaded for future independent 
radiologic review via TRIAD Digital Image Submission as detailed in Appendix IX. (03/19/2018) 
+All PRO questionnaires should be completed before any study specific procedures are 
performed and before the patient sees the physician. 
 
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4.2 
ASSESSMENTS DURING TREATMENT (29-JUN-2020) 
Assessments 
Prior to Each 
Cycle, Day 1 
(after Cycle 1, 
Day 1) 
Prior to Every Odd 
Cycle (i.e., Cycle 3, 
Day 1; Cycle 5, Day 
1; etc.) 
Timed 
(Treatment 
Cycle 
Independent) 
History and Physical 
 ≤ 1 day 
 
 
Concomitant Medications* 
 ≤ 1 day 
 
 
Corticosteroid Use (to manage adverse 
events) 
 ≤ 1 day 
 
 
Secondary Immunosuppressive Agent 
Use (e.g., infliximab) 
 ≤ 1 day 
 
 
Vital Signs 
 ≤ 1 day 
 
 
Performance Status 
 ≤ 1 day 
 
 
Toxicity Assessment 
 ≤ 1 day 
 
 
CBC/Differential/Platelets 
≤ 3 days 
 
 
Chemistries (BUN, Creatinine, 
Sodium, Potassium, Chloride, CO2, 
Calcium, Glucose, Bilirubin, Protein, 
Albumin, Alkaline Phosphatase, AST, 
ALT) 
≤ 3 days 
 
 
TSH 
≤ 7 days 
 
 
UPCR 
 
≤ 7 days 
 
ECHO or MUGA 
 
1 ≤ 7 days 
(10/22/2018) 
 
CA125 
X 
 
 
Radiographic Tumor Measurement 
 
 
X2 
Patient Reported Outcomes (PRO) 
 
 
X3 
* Due to their immunosuppressive effect, administration of systemic steroids (e.g., 
dexamethasone) as an antiemetic and/or preparative regimen for hypersensitivity reactions 
should be avoided if other means of treatment are available and medically appropriate. 
 
1 
Necessary when the cumulative dose of PLD exceeds 550 mg/m2. Repeat echocardiogram or 
MUGA scan every other cycle or according to institutional standards. Please include any prior 
anthracycline therapy when determining the cumulative lifetime dose of anthracyclines. The 
same method should be used for each patient throughout the study. (02/20/2019) 
 
2 
Every 8 weeks (+/- 7 days) from cycle 1, day 1 (regardless of delays and/or changes in treatment 
schedule) for the first 12 months; then every 12 weeks (+/- 7 days) thereafter. Radiographic tumor 
measurements are obtained until disease progression is confirmed; at the investigator’s discretion, 
they can be repeated any other time if clinically indicated based on symptoms or physical signs 
suggestive of new or progressive disease. A tool is provided to calculate dates of re-imaging. 
Utilize same imaging modality of abdomen, pelvis and chest (see footnote under Pre-Treatment 
Assessments) as for pre-cycle 1 baseline assessment. Images from radiographic studies should be 
uploaded for future independent radiologic review via TRIAD Digital Image Submission as 
detailed in Appendix IX.  An excel tool is available on the CTSU website to calculate dates of re-
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imaging.  Chest imaging is also indicated to monitor for evidence of immune pneumonitis. See 
below for guidance concerning continuation of treatment in cases of radiologic progression at the 
first 8 week (+/- 7 days) CT. (03/19/2018) 
The protocol specifies continuation of treatment in cases of radiologic progression at the 
first 8 week (+/- 7 days) CT if all of the following criteria are satisfied: 
• No decrease in performance status 
• No requirement for immediate alternative treatment or urgent palliative treatment 
• Progression limited to an increase of 40% in the sum of diameters of target lesions 
(including the addition of up to 4 new lesions to the sum) 
• No more than 4 new lesions included in the sum 
 
For patients who continue treatment in the case of radiologic progression at the first 8 week 
(+/- 7 days) CT: 
• At any subsequent CT scan patients who have stable disease as compared to the 8 week 
(+/- 7 days) CT scan will be allowed to continue on study treatment. 
• Patients who continue treatment in the case of radiologic progression at the first 8 week 
(+/- 7 days) CT, and later experience a PR or CR (as compared to baseline CT) will be 
recorded as delayed responses by the Statistics and Data Management Center. 
 
For patients who continue treatment in the case of radiologic progression at the first 8 week 
(+/- 7 days) CT, must have repeat CT in 4 weeks (+/- 7days) to rule out further progression. 
3 
Patient Reported Outcomes (PRO) assessments will be performed every 8 weeks during the first 
year (which coincides with radiographic tumor assessment and treatment cycles 3, 5, 7, 9, 11, and 
13, if on schedule), and every 12 weeks during the second year, unless the patient withdraws from 
study participation. PRO assessments should continue post-progression.  All questionnaires 
should be completed before any study specific procedures are performed and before the patient 
sees the physician. (10/16/2017) 
 
4.3 
ASSESSMENTS IN FOLLOW UP 
Assessments 
Timed 
Vital Status 
1 
Toxicity Assessment 
2 
Radiographic tumor measurement 
3 
Patient reported outcomes (PRO) 
4 
1 Every 3 months for 2 years and then every 6 months for 3 years. Follow-up Forms are 
collected for the 5-year follow-up period or until study termination. The Follow-up 
assessments should include the collection of information regarding non-protocol therapy. 
(29-JUN-2020) 
2 Patients who discontinue treatment for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. For reporting of delayed toxicity, see 
Section 7. 
3 In the case that protocol directed therapy is discontinued for reasons other than disease 
progression, follow radiographic tumor measurement schedule as defined under 
Assessments During Treatment (until disease progression documented by RECIST 1.1 or 
until patient initiates a subsequent cancer therapy). 
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4  Patient Reported Outcomes (PRO) assessments will be performed every 8 weeks during the 
first year (which coincides with radiographic tumor assessment and treatment cycles 3, 5, 
7, 9, 11, and 13, if on schedule), and every 12 weeks for the second year, unless the patient 
withdraws from study participation. PRO assessments should continue post-progression. 
All questionnaires should be completed before any study specific procedures are performed 
and before the patient sees the physician. (10/16/2017) 
 
5. 
TREATMENT PLAN/REGIMEN DESCRIPTION (10/22/2018) 
Safety Lead-In for ARM1 (Experimental Regimen 1) will accrue first.  
Assignment to treatment arm will then be randomized (1:1:1). 
 
(Note: The SLI was completed as of May 2, 2018.)  
 
TREATMENT SHOULD BEGIN WITHIN 14 DAYS OF REGISTRATION in order to avoid 
having to repeat pre-treatment assessments as outlined in Section 4.1. 
 
5.1 
Treatment Plan (24-FEB-2021) 
 
ARM 1 (Experimental Regimen 1) (Closed to accrual as of February 09, 2021) 
 
PLD 40 mg/m2 IV Day 1 
Atezolizumab 800 mg IV Days 1 and 15 
 
Note: NRG-GY009 was temporarily closed to accrual on February 09, 2021. Arm 1 is 
permanently closed to accrual as of Protocol Amendment 11. Patients randomized to Arm 1 
may continue on the assigned therapy per protocol (or PLD alone) if the treating physician, 
after discussing with the patient, determines that the patient would benefit from the treatment. 
Monitoring, assessments, and data collection are to proceed per protocol. Patients choosing to 
discontinue study therapy should continue to be followed per protocol.  
 
ARM 2 (Experimental Regimen 2) 
 
PLD 40 mg/m2 IV Day 1 
 
Bevacizumab 10 mg/kg IV Days 1 and 15 
Atezolizumab 800 mg IV Days 1 and 15 
 
ARM 3 
 
PLD 40 mg/m2 IV Day 1 
 
Bevacizumab 10 mg/kg IV Days 1 and 15 
 
ONE CYCLE = 4 weeks 
 
5.1.1 Administration of Pegylated Liposomal Doxorubicin (PLD) 
PLD will be administered in a manner consistent with the current labeled dosing regimen.  
PLD is administered as an intravenous infusion on Day 1 of a 28-day cycle at an initial rate of 
1 mg/min to minimize the risk of infusion reactions. If no infusion-related adverse reactions 
are observed, the rate of infusion can be increased to complete administration of the drug over 
one hour (60 min). 
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Do not use with in-line filters. Rapid flushing of the infusion line should be avoided. Do not 
administer as a bolus injection or undiluted solution. 
 
Acute infusion-related reactions have occurred in up to 10% of patients treated with PLD. 
Serious and sometimes life-threatening or fatal allergic/anaphylaxis-like infusion reactions 
have been reported. Medications to treat such reactions, as well as emergency equipment, 
should be available for immediate use.  
 
The recommended total cumulative dosage of PLD is 550 mg/m2. Therefore, once this 
cumulative dose of PLD is reached (with no dose reductions, this would be approximately 13 
cycles of therapy), patients will—at the Investigator’s discretion—either continue with PLD + 
other assigned study drugs (ARM1:  atezolizumab; ARM2:  bevacizumab/atezolizumab; 
ARM3:  bevacizumab) or discontinue PLD and continue other assigned study drugs (ARM1:  
atezolizumab; ARM2:  bevacizumab/atezolizumab; ARM3:  bevacizumab).  Note that patients 
who continue to receive PLD beyond a cumulative dose of 550 mg/m2 must undergo 
echocardiogram or MUGA scan every 2 cycles or in accordance with institutional standards to 
monitor for cardiac toxicity. Patients will discontinue treatment should their resting left 
ventricular ejection fraction (LVEF) demonstrate an absolute decrease of > 10% below the 
institutional lower limit of normal or should they develop Grade 3 (or greater) left ventricular 
systolic dysfunction (symptomatic due to drop in ejection fraction responsive to intervention). 
 
Due to their immunosuppressive effect, administration of systemic steroids (e.g., 
dexamethasone) as an antiemetic and/or preparative regimen for hypersensitivity 
reactions should be avoided if other means of treatment are available and medically 
appropriate. 
 
Preparative antihistamine use is allowed (e.g., diphenhydramine 25 mg IV) prior to FIRST 
dose (and subsequent doses if hypersensitivity reaction is seen with a previous dose). 
 
5.1.2 Administration of Bevacizumab 
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 (e.g., 
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 adverse event, 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 
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90±15 minutes.  Similarly, if a subject experiences an infusion associated adverse event with 
the 30-minute infusion, all subsequent doses should be given over 60±10 minutes. 
 
Due to their immunosuppressive effect, administration of systemic steroids (e.g., 
dexamethasone) as an antiemetic and/or preparative regimen for hypersensitivity 
reactions should be avoided if other means of treatment are available and medically 
appropriate. 
5.1.3 Administration of Atezolizumab (06/29/2017) (10/22/2018) 
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. 
 
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, if clinically indicated, vital signs (heart 
rate, respiratory rate, blood pressure, and temperature) should be recorded during the infusion 
at 15, 30, 45, 60 minutes (±5 minutes for all timepoints) and at 30 minutes (± 10) after the 
infusion.  For subsequent infusions, if the patient experienced an infusion-related reaction 
with the previous infusion or if clinically indicated, vital signs should be recorded during the 
infusion and at 30 minutes (± 10) after the infusion.   Patients will be informed about the 
possibility of delayed post-infusion symptoms and instructed to contact their study physician 
if they develop such symptoms. 
 
Premedication is not permitted for the first dose of atezolizumab (Preparative antihistamine 
use is allowed (e.g., diphenhydramine 25 mg IV) prior to FIRST dose of PLD (and subsequent 
doses if hypersensitivity reaction is seen with a previous dose; see section 5.1.1). (10/16/2017) 
Premedication with antihistamines or antipyretics/analgesics (e.g., acetaminophen) may be 
administered for subsequent infusions at the discretion of the treating physician.  The 
management of Infusion Related Reactions will be according to severity as follows: 
 
• In the event that a patient experiences a Grade 1 Infusion Related Reaction during 
Cycle 1, 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 Grade 2 Infusion Related Reaction, 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 Infusion Related Reaction.  For subsequent infusions, 
administer oral premedication with antihistamine and anti-pyretic and monitor closely 
for Infusion Related Reactions. 
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• For Grade 3 or 4 Infusion Related Reactions, the infusion should be stopped 
immediately, and aggressive resuscitation and supportive measures should be initiated 
(e.g., oral or IV antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen).  Atezolizumab should be permanently discontinued.  
Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event; retreatment requires 
consultation with, and consent of, the trial Principal Investigator (PI). 
 
For anaphylaxis precautions, use the following procedure: 
 
Equipment Needed 
 
• Tourniquet 
• Oxygen 
• Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice  
• Antihistamines 
• Corticosteroids 
• Intravenous infusion solutions, tubing, catheters, and tape 
 
Procedures 
 
In the event of a suspected anaphylactic reaction during atezolizumab infusion, the following 
procedures should be performed: 
 
1. Stop the study drug infusion. 
2. Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
drug.  Do not obstruct arterial flow in the limb. 
3. Maintain an adequate airway. 
4. Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge. 
5. Continue to observe the patient and document observation. 
 
5.1.4 Sequencing and Timing of Drug Administration 
PLD will be administered on Day 1.  Atezolizumab will be administered on Days 1 and15.  
Bevacizumab with be administered on Days 1 and 15. 
 
On days where more than one study drug is to be administered, the order of administration 
should be as follows: 
1. PLD 
2. Bevacizumab 
3. Atezolizumab 
 
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If patient requires discontinuation of a study drug(s) (for reason other than protocol defined 
progression), the patient should continue other assigned study drug(s), if clinically 
appropriate, until protocol defined progression. 
 
5.2 
Radiation Therapy 
 
Not Applicable 
 
5.3 
Device  
 
Not Applicable. 
 
5.4 
Imaging (for imaging-focused study) 
 
Not Applicable. 
 
5.5 
Integral Assay/Biomarker  
 
Not applicable. 
 
5.6 
Intervention Not Otherwise Categorized 
 
Not Applicable. 
 
5.7 
Quality of Life Component 
See Section 11.1 
 
5.8 
General Concomitant Medication and Supportive Care Guidelines 
5.8.1 Concomitant Medications (06/29/2017) 
Concomitant therapy includes any prescription medications or over the counter preparations 
used by a patient between the 7 days preceding the screening evaluation and the treatment 
discontinuation visit. 
 
Patients who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or cimetidine 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 (e.g., 
supplemental oxygen and β2-adrenergic agonists). 
 
Systemic corticosteroids and TNFα inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab but may be administered at the 
discretion of the treating physician.  If feasible, alternatives to corticosteroids should be 
considered.  Premedication may be administered for Cycles ≥2 at the discretion of the 
treating physician.  The use of inhaled corticosteroids and mineralocorticoids (e.g., 
fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is 
allowed. Megestrol administered as appetite stimulant is acceptable while the patient is 
enrolled in the study. 
 
Patients who use oral contraceptives, hormone-replacement therapy, prophylactic or 
therapeutic anticoagulation therapy (such as low-molecular-weight heparin or warfarin at a 
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stable dose level), or other allowed maintenance therapy (See Section 3.3) should continue 
their use.   
 
Females of reproductive potential should use highly effective means of contraception during 
study treatment and for 5 months following completion of study treatment. 
 
5.8.2 Prohibited Therapies (06/29/2017) 
Any concomitant therapy intended for the treatment of 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 (except for maintenance therapies outlined in Section 3.3). 
It is strongly recommended that:  
• Traditional herbal medicines 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. 
• The use of a RANKL inhibitor (denosumab) should be discontinued during the study; 
this agent could potentially alter the activity and the safety of atezolizumab. 
 
Prophylactic use of granulocyte colony-stimulating factors (e.g., granulocyte 
colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, and/or 
pegfilgrastim) is prohibited for patients with solid malignancies. (10/16/2017) 
 
Patients are not allowed to receive immunostimulatory agents, including, but not limited to, 
IFN-α, IFN-γ, 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 be receiving 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-TNFα agents may attenuate potential beneficial immunologic effects of treatment 
with atezolizumab but may be administered at the discretion of the treating physician.  If 
feasible, alternatives to these agents should be considered. Inhaled corticosteroids are 
permitted. 
 
In addition, all patients (including those who discontinue the study early) should not receive 
other immunostimulatory agents for 10 weeks after the last dose of atezolizumab. 
 
5.9 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), 
 
Patient decides to withdraw consent for participation in the study, or 
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 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
6. TREATMENT MODIFICATIONS/MANAGEMENT 
 
6.1 
PLD Dose Modification Guidelines 
 
Refer to the PLD label for current commendations regarding dose delays and 
reductions.   
 
 
Once the dose of PLD has been reduced due to drug-related toxicity, it should not be 
increased at a later time. If more than 2 dose reductions are required due to PLD-
related toxicity, consult the study chair to determine if PLD should be discontinued. 
 
PLD Dose Reduction (30-OCT-2020) 
Dose reduction  
Dose  
1st 
30mg/m2 
2nd 
22.5mg/m2  
3rd  
Consult the study chair to determine if PLD should be discontinued 
 
 
In the event of a delay in PLD dosing due to drug-related toxicity, doses of atezolizumab 
and/or bevacizumab should also be delayed.  
6.1.1 Modifications for Hematologic Toxicity 
The prophylactic use of growth factors is not recommended in this study. Investigators may 
follow their institutional guidelines/standard practices for use of growth factors for supportive 
care (e.g., NCCN guideline for management of patients with febrile neutropenia). 
PLD Dose Modification Guidelines for Hematological Toxicity* 
Toxicity 
Grade 
ANC 
Platelets 
Modification 
1 
1,500–1,900 
75,000–150,000 
Resume treatment with no dose 
reduction 
2 
 
1,000–< 1,500 
50,000–< 75,000 
Wait until ANC ≥ 1,500 and platelets 
≥ 75,000;  
redose with no dose reduction 
3 
500 –999 
25,000–< 50,000 
Wait until ANC ≥ 1,500 and platelets 
≥ 75,000;  
redose with no dose reduction 
4 
< 500 
< 25,000 
Wait until ANC ≥ 1,500 and platelets 
≥ 75,000;  
redose at 25% dose reduction 
*Modification should be guided by the more severe toxicity, if both ANC and platelets are 
affected. 
 
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6.1.2 
Modifications for Hand-Foot Syndrome (02/20/2019) 
 
PLD Dose Modification Guidelines for Hand-Foot Syndrome (HFS) 
Palmar-Plantar Erythrodysesthesia Syndrome (PPE) 
Toxicity Grade 
Dose Adjustment 
1:  
Minimal skin changes or 
dermatitis (e.g., erythema, 
edema, or hyperkeratosis) 
without pain  
 
Redose unless patient has experienced previous ≥ Grade 3 
(PPE) 
If so, delay up to 2 weeks and decrease dose by 25%. Return 
to original dose interval. 
 
2:  
Skin changes (e.g., peeling, 
blisters, bleeding, fissures, 
edema, or hyperkeratosis) 
with pain; limiting 
instrumental ADL  
 
Delay dosing up to 2 weeks or until resolved to Grade 0-1.  
If after 2 weeks there is no resolution, PLD should be 
discontinued. If resolved to Grade 0–1 within 2 weeks, and 
there are no prior ≥Grade 3 PPE, continue treatment at 
previous dose and return to original dose interval. If patient 
experienced previous ≥Grade 3 toxicity, continue treatment 
with a 25% dose reduction and return to original dose interval. 
3:  
Severe skin changes (e.g., 
peeling, blisters, bleeding, 
fissures, edema, or 
hyperkeratosis) with pain; 
limiting self care ADL  
 
Delay dosing up to 2 weeks or until resolved to Grade 0–1. 
Decrease dose by 25% and return to original dose interval. If 
after 2 weeks there is no improvement to Grade 0–1, PLD 
should be discontinued.  
 
 
6.1.3 Modifications for Stomatitis 
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PLD Dose Modification Guidelines for Stomatitis /Oral Mucositis (30-OCT-2020) 
Toxicity Grade  
Dose Adjustment  
1: painless ulcers,  
erythema, or mild  
soreness 
Redose unless patient has experienced previous Grade 3 or 4 
toxicity.  
If so, delay up to 2 weeks and decrease dose by 25%.  
Return to original dose interval.  
2: painful erythema, 
edema, or ulcers, 
but can eat 
Delay dosing up to 2 weeks or until resolved to Grade 0-1.  
If after 2 weeks there is no resolution, PLD should be 
discontinued.  
–If resolved to Grade 0–1 within 2 weeks and there was no prior 
Grade 3–4 stomatitis, continue treatment at previous dose and 
return to original dose interval. If patient experienced previous 
Grade 3–4 toxicity, continue treatment with a 25% dose reduction 
and return to original dose interval. 
3: painful erythema, 
edema, or ulcers, 
and cannot eat 
Delay dosing up to 2 weeks or until resolved to Grade 0–1. 
Decrease dose by 25% and return to original dose interval. If after 
2 weeks there is no resolution, PLD should be discontinued. 
4:  requires 
parenteral or  
enteral support 
Delay dosing up to 2 weeks or until resolved to Grade 0–1.  
Decrease dose by 25% and return to PLD original dose interval. If 
after 2 weeks there is no resolution, PLD should be discontinued. 
 
6.1.4    Modifications for Hepatic Toxicity 
PLD Dose Modification Guidelines for Impaired Hepatic Function 
Limited clinical experience exists in treating patients with hepatic impairment with PLD. 
Based on experience with doxorubicin HCl, it is recommended that the PLD dosage be 
reduced if the bilirubin is elevated as follows:  
Serum bilirubin 1.2 to 3.0 mg/dL: give ½ normal dose 
Serum bilirubin > 3 mg/dL: give ¼ normal dose 
6.2 
Bevacizumab Dose Modification and Toxicity Management Guidelines 
There will be no dose reduction for bevacizumab in this study.  Patients may temporarily 
suspend study treatment for up to 84 days (12 weeks) beyond the scheduled date of delayed 
infusion if study drug-related toxicity requiring dose suspension is experienced.  If 
bevacizumab is held because of AEs for >84 days beyond the scheduled date of infusion, the 
patient will be discontinued from bevacizumab. 
 
Bevacizumab dose will not be reduced for reasons other than a >10% 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 (or RPLS) and 
hypersensitivity/allergic reactions in addition to any other serious bevacizumab-related 
toxicity (grade 3 or 4).  
 
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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 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 (permanently discontinue) 
• 
GI perforation (permanently discontinue) 
• 
Major surgery or wound healing complications (hold temporarily or permanently 
discontinue, decision requires discussion with Study Chair) 
• 
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, decision requires 
discussion with Study Chair) 
• 
Hypersensitivity/allergic reactions related to bevacizumab (permanently discontinue) 
• 
PRES (or RPLS) (permanently discontinue) 
 
Posterior Reversible Encephalopathy Syndrome (PRES/RPLS) 
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. 
 
Gastrointestinal Perforation and Fistula 
Bevacizumab has been associated with serious cases of GI perforation 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 
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established. However, caution should be exercised when treating patients with intra-
abdominal inflammatory process with bevacizumab. 
 
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 mCRC 
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. 
 
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 mCRC and BC. 
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. 
 
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 
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controlled with antihypertensive therapy, or if the patient develops hypertensive crisis or 
hypertensive encephalopathy. 
 
Congestive Heart Failure (CHF)   
Events consistent with CHF were reported in clinical trials. The findings ranged from 
asymptomatic declines in left ventricular ejection fraction (LVEF) 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. 
 
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 urinalysis as directed by protocol (see section 3.2.9). (24-
FEB-2021) 
 
Bevacizumab Treatment Management for Proteinuria (03/19/2018) (02/20/2019) 
NCI 
CTCAE  Urinalysis 
Treatment Action 
Grade 1 
urinary protein < 1.0 
g/24 hrs 
No bevacizumab dose modification 
Grade 2 
urinary protein 1.0-3.4 
g/24 hrs 
No bevacizumab dose modification 
Grade 3 
urinary protein ≥3.5 
g/24 hrs 
Suspend bevacizumab.  
Resume bevacizumab when proteinuria is < 3.5 g/24 
hrs. 
Nephrotic syndrome  
Permanently discontinue bevacizumab 
 
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 
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thromboembolism and age greater than 65 years have a higher risk. Caution should be taken 
when treating these patients with bevacizumab.  
 
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 for at least 2 
weeks prior to restarting study drug treatment. Patients on warfarin should have an INR 
between 2.0 and 3.0 assessed in two consecutive measurements 1-4 days apart. 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) venous 
thrombosis/embolism. 
 
Hemorrhage (10/16/2017) 
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 
hemoptysis (defined as ≥ 2.5 mL bright red blood per episode). The safety of re-initiating 
bevacizumab in patients previously experiencing grade ≥ 2 hemoptysis 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 reversal with Protamin or vitamin K and infusion of 
vitamin K dependent factors should be considered dependent on the severity of the bleeding. 
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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. 
 
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 Avastin® Investigator’ 
Brochure. 
 
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 Avastin® Investigator’ Brochure. 
 
6.3 
Atezolizumab Dose Modification and Toxicity Management Guidelines 
 
6.3.1 General AE Management and Dose Modification Guidelines (06/29/2017) 
 
There will be no dose reduction for atezolizumab in this study.  
 
Patients may temporarily suspend study treatment for up to 84 days (12 weeks) beyond the 
scheduled date of delayed infusion if study drug-related toxicity requiring dose suspension is 
experienced.  If atezolizumab is held because of AEs for >84 days beyond the scheduled date 
of infusion, the patient will be discontinued from atezolizumab and will be followed for safety 
and efficacy as specified in this protocol.  If the AE resolves within 84 days and the patient is 
receiving corticosteroid therapy for the event, atezolizumab may be held for longer than 84 
days (up to 4 weeks) in order to allow tapering of the steroid dose to ≤10 mg oral prednisone 
or equivalent. 
 
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 study PI in 
consultation with CTEP. 
 
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Atezolizumab must be permanently discontinued if the patient experiences any of the 
following events, regardless of benefit: 
 
• Grade 4 pneumonitis 
• AST or ALT >5×ULN or total bilirubin >3×ULN  
• Grade 4 diarrhea or colitis 
• Grade 4 hypophysitis 
• Any grade myasthenic syndrome/myasthenia gravis, Guillain-Barré or 
meningoencephalitis 
• Grade 4 ocular inflammatory toxicity 
• Grade 4 pancreatitis or any grade of recurrent pancreatitis 
• Grade 4 rash 
• Any grade myocarditis 
 
Treatment may, under limited and compelling circumstances, be resumed in patients who 
have recovered from the following events, but only after consultation with the trial Principal 
Investigator: 
• Grade 3 pneumonitis 
• Grade 3 ocular inflammatory toxicity 
• Grade 3 or 4 infusion-related reactions 
 
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 immune-related adverse events (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 (Di Giacomo et al., 2010).  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, or other immunosuppressive agents.  The 
investigator should consider the benefit-risk balance prior to further administration of 
atezolizumab. (03/19/3018) 
 
For detailed information regarding management of adverse events associated with 
atezolizumab, please refer to the most current version of the Atezolizumab Investigator’s 
Brochure and the FDA product label. 
 
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. 
 
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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. 
 
Systemic Immune Activation (06/29/2017) 
 
Systemic immune activation is a rare condition characterized by an excessive immune 
response. Given the mechanism of action of atezolizumab, systemic immune activation is 
considered a potential risk when given in combination with other immunomodulating agents.  
Systemic immune activation should be included in the differential diagnosis for patients who, 
in the absence of an alternative etiology, develop a sepsis-like syndrome after administration 
of atezolizumab, and the initial evaluation should include the following: 
• CBC with peripheral smear 
• PT, PTT, fibrinogen, and D-dimer 
• Ferritin 
• Triglycerides 
• AST, ALT, and total bilirubin 
• LDH 
• Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
 
If systemic immune activation is still suspected after the initial evaluation, contact the 
Principal Investigator for additional recommendations. 
 
6.3.2 Management of Specific AEs (06/29/2017) (10/22/2018)  
 
Management of certain AEs of concern, including immune-related pneumonitis, hepatitis, 
colitis, endocrinopathies, pancreatitis, neuropathies, nenigoencephalitis, and potential ocular 
toxicities are presented in the Atezolizumab Investigator’s Brochure.  See Section 5.1.3 and 
the AE Management and Dose Interruption Guidelines for Specific Toxicities table below 
for guidelines for the management of Infusion Related Reactions and Anaphylaxis. 
 
For recommendations to hold atezolizumab and begin corticosteroid treatment, use the 
following guidance for tapering the corticosteroid and resuming atezolizumab therapy after 
resolution of the event: 
 
• Corticosteroids must be tapered over ≥1 month to ≤10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. If clinically indicated, a shorter 
course of steroid taper may be appropriate following discussion with the study chair.  
(02/20/2019) 
• Atezolizumab may be held for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to ≤10 mg/day oral prednisone or equivalent. 
 
Pulmonary Events 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for pulmonary 
signs and symptoms throughout the study  
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All pulmonary events should be thoroughly evaluated for other commonly reported etiologies 
such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, 
heart failure, chronic obstructive pulmonary disease, or pulmonary hypertension.  
Management guidelines for pulmonary events are provided in the AE Management and Dose 
Interruption Guidelines for Specific Toxicities table below.  
  
Endocrine Disorders  
Patients experiencing one or more unexplained AEs possibly indicative of endocrine 
dysfunction (including fatigue, myalgias, impotence, mental status changes, or constipation) 
should be investigated for the presence of thyroid, pituitary, or adrenal endocrinopathies.  The 
patient should be referred to an endocrinologist if an endocrinopathy is suspected.  
Thyroid-stimulating hormone (TSH) and free T3 and T4 levels should be measured to 
determine whether thyroid abnormalities are present.  TSH, prolactin, and a morning cortisol 
level will help to differentiate primary adrenal insufficiency from primary pituitary 
insufficiency. 
 
Dose management guidelines for hyperthyroidism, hypothyroidism, symptomatic adrenal 
insufficiency, and hyperglycemia are described in the  AE Management and Dose 
Interruption Guidelines for Specific Toxicities table below. 
 
Meningoencephalitis 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab.  Immune-related meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered 
or depressed level of consciousness.  Encephalopathy from metabolic or electrolyte 
imbalances needs to be distinguished from potential meningoencephalitis resulting from 
infection (bacterial, viral, or fungal) or progression of malignancy, or secondary to a 
paraneoplastic process.   
 
All patients being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema.  If 
deemed safe by the treating physician, a lumbar puncture should be performed and a 
neurologist should be consulted. 
 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in the AE Management and 
Dose Interruption Guidelines for Specific Toxicities table below. 
 
 
 
Neurologic disorders 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
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neuropathy.  Diagnostic work-up is essential for an accurate characterization to differentiate 
between alternative etiologies.  Management guidelines for neurologic disorders are provided 
in the table below. 
 
For recommendations to hold atezolizumab and begin corticosteroid treatment, use the 
following guidance for tapering the corticosteroid and resuming atezolizumab therapy after 
resolution of the event: 
• Corticosteroids must be tapered over ≥1 month to ≤10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. If clinically indicated, a shorter course 
of steroid taper may be appropriate following discussion with the study chair.  
• Atezolizumab may be held for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to ≤10 mg/day oral prednisone or equivalent. 
 
AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ Duration 
Management 
Abdominal pain 
Acute abdominal pain 
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.  See the guidelines for “Amylase 
and/or lipase increase” and “Immune-related 
pancreatitis” elsewhere in this table, as needed. 
 
Right upper-quadrant abdominal pain and/or 
unexplained nausea or vomiting should be 
evaluated for potential hepatotoxicity (see the 
“Hepatotoxicity” guideline elsewhere in this 
table). 
Adrenal 
insufficiency 
Grade 2+ 
(symptomatic) 
Hold atezolizumab. 
 
Refer patient to endocrinologist. 
 
Perform appropriate imaging. 
 
Initiate treatment with 1−2 mg/kg/day 
intravenous methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 
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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ Duration 
Management 
If event resolves to grade 1 or better and patient 
is stable on replacement therapy (if required) 
within 12 weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to grade 1 or better or patient is 
not stable on replacement therapy within 12 
weeks. 
Amylase and/or 
lipase increased 
Grade 1 
Continue atezolizumab. 
 
Monitor amylase and lipase prior to dosing. 
Grade 2 
Continue atezolizumab. 
 
Monitor amylase and lipase weekly. 
 
For prolonged elevation (e.g., >3 weeks), 
consider treatment with 10 mg/day oral 
prednisone or equivalent. 
Grade 3 or 4 
Hold atezolizumab. 
 
Consider referral to gastrointestinal (GI) 
specialist. (10/16/2017) 
 
Monitor amylase and lipase weekly. (10/16/2017) 
 
If no improvement, consider treatment with 
1−2 mg/kg/day oral prednisone or equivalent. 
 
If event resolves to grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to grade 1 or better within 12 
weeks. 
 
For recurrent events, permanently discontinue 
atezolizumab. c 
Dermatologic 
toxicity/rash 
(e.g., 
Grade 1 
Continue atezolizumab. 
 
Consider topical steroids and/or other 
symptomatic therapy (e.g., antihistamines). 
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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ Duration 
Management 
maculopapular or 
purpura) 
Grade 2 
Continue atezolizumab.  Consider dermatologist 
referral. 
 
Administer topical corticosteroids. 
 
Consider higher potency topical corticosteroids if 
event does not improve. 
Grade 3 
Hold atezolizumab.   
 
Refer patient to dermatologist.  Administer oral 
prednisone 10 mg or equivalent.  If the event 
does not improve within 48−72 hours, increase 
dose to 1–2 mg/kg/day or equivalent. 
Restart atezolizumab if event resolves to grade 1 
or better within 12 weeks. 
 
Permanently discontinue atezolizumab if event 
does not resolve to grade 1 or better within 12 
weeks. 
Grade 4 
Permanently discontinue atezolizumab.  Patient 
may not resume treatment, regardless of benefit.  
Otherwise, manage as above. 
Persistent and/or 
severe rash or pruritus, 
any grade 
A dermatologist should evaluate the event.  A 
biopsy should be performed unless 
contraindicated. Please refer to Section 6.3.2 
regarding duration of steroids. (02/20/2019) 
Diarrhea or 
colitis 
Any grade 
Patients should be advised to inform the 
investigator if any diarrhea occurs, even if it is 
mild. 
 
All events of diarrhea or colitis should be 
thoroughly evaluated for other more common 
etiologies.  For events of significant duration or 
magnitude or associated with signs of systemic 
inflammation or acute-phase reactants 
(e.g., increased CRP, platelet count, or 
bandemia):  Perform sigmoidoscopy (or 
colonoscopy, if appropriate) with colonic biopsy, 
with three to five specimens for standard paraffin 
block to check for inflammation and lymphocytic 
infiltrates to confirm colitis diagnosis. 
Grade 1 
Continue atezolizumab. 
 
Initiate symptomatic treatment. 
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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ Duration 
Management 
 
Endoscopy is recommended if symptoms persist 
for >7 days. 
 
Monitor closely. 
Grade 2 
Hold atezolizumab. 
 
Initiate symptomatic treatment. 
 
Patient referral to GI specialist is recommended. 
 
For recurrent events or events that persist >5 
days, initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent.  
 
If event resolves to grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to grade 1 or better within 12 
weeks.  Resumption of atezolizumab may be 
considered, after consultation with the trial PI, in 
patients who are deriving benefit and have fully 
recovered from the immune-related event. 
Grade 3 
Hold atezolizumab. 
 
Refer patient to GI specialist for evaluation and 
confirmatory biopsy. 
 
Initiate treatment with 1−2 mg/kg/day 
intravenous methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 
If event resolves to grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to Grade 1 or better within 12 
weeks.  Resumption of atezolizumab may be 
considered, after consultation with the trial PI, in 
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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ Duration 
Management 
patients who are deriving benefit and have fully 
recovered from the immune-related event. 
Grade 4  
Permanently discontinue atezolizumab. Patient 
may not resume treatment, regardless of benefit. 
 
Refer patient to GI specialist for evaluation and 
confirmation biopsy. 
 
Initiate treatment with 1−2 mg/kg/day 
intravenous methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 
Permanently discontinue atezolizumab.  Patient 
may not resume treatment, regardless of benefit.  
Otherwise, manage as above. (02/20/2019) 
Hepatotoxicity  
Right upper-quadrant 
abdominal pain and/or 
unexplained nausea or 
vomiting 
Risk of immune-mediated hepatitis.  LFTs should 
be performed immediately, and LFTs should be 
reviewed before administration of the next dose 
of study drug.  For patients with elevated LFTs, 
concurrent medication, viral hepatitis, and toxic 
or neoplastic etiologies should be considered and 
addressed, as appropriate. 
 
Symptoms of abdominal pain associated with 
elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the 
administration of atezolizumab.  The differential 
diagnosis of acute abdominal pain should also 
include pancreatitis, as described below. 
Grade 1 hepatic event 
Continue atezolizumab. 
 
Monitor LFTs until values resolve to within 
normal limits. 
Grade 2 hepatic event, 
≤5 days 
Continue atezolizumab. 
 
Monitor LFTs more frequently until values 
resolve to baseline values. 
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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ Duration 
Management 
Grade 2 hepatic event, 
>5 days 
Hold atezolizumab. 
 
Initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
 
If event resolves to grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to Grade 1 or better within 12 
weeks. 
Grade 3 or 4 hepatic 
event 
Permanently discontinue atezolizumab. 
 
Consider patient referral to GI specialist for 
evaluation and liver biopsy to establish etiology 
of hepatic injury.  
 
Initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 
If event resolves to grade 1 or better, taper 
corticosteroids over ≥1 month. 
Hyperglycemia 
Grade 1 or 2 
Continue atezolizumab. 
 
Initiate treatment with insulin if needed. 
 
Monitor for glucose control. 
Grade 3 or 4 
Hold atezolizumab. 
 
Initiate treatment with insulin. 
 
Monitor for glucose control. 
 
Resume atezolizumab when symptoms resolve 
and glucose levels are stable. 
Hyperthyroidism 
(02/20/2019) 
Grade 1/2 
(asymptomatic) 
TSH ≥ 0.1 mU/L and < 0.5 mU/L: 
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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ Duration 
Management 
Continue atezolizumab.  Monitor TSH every 4 
weeks. 
 
TSH < 0.1 mU/L: 
Follow guidelines for symptomatic 
hyperthyroidism. 
Grade 2+ 
(symptomatic) 
Hold atezolizumab. 
 
Initiate treatment with anti-thyroid drug such as 
methimazole or carbimazole as needed. 
 
Consider patient referral to endocrinologist. 
 
Resume atezolizumab when symptoms are 
controlled and thyroid function is improving. 
 
Permanently discontinue atezolizumab for 
life-threatening immune-related hyperthyroidism. 
Hypothyroidism 
(02/20/2019) 
Grade 1/2 
(asymptomatic) 
Continue atezolizumab.   
 
Start thyroid-replacement hormone.   
 
Monitor TSH weekly until improving then 
resume per assessment schedule 4.2. (08-JAN-
2021) 
Grades 2+ 
(symptomatic) 
Hold atezolizumab.   
 
Start thyroid-replacement hormone.  Consider 
referral to an endocrinologist.  
 
Monitor TSH weekly until improving then 
resume per assessment schedule 4.2. (24-FEB-
2021) 
 
Restart atezolizumab when symptoms are 
controlled and thyroid function is improving.  
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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ Duration 
Management 
Meningo-
encephalitis, 
immune-related 
 
(signs and 
symptoms in 
absence of an 
identified 
alternate 
etiology) 
 
All grades 
Permanently discontinue atezolizumab. Patient 
may not resume treatment, regardless of benefit. 
 
Refer patient to neurologist. 
 
Initiate treatment with 1−2 mg/kg/day IV 
methylprednisolone or equivalent and convert to 
1−2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
 
If event resolves to grade 1 or better, taper 
corticosteroids over ≥1 month. 
 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
Myasthenia 
gravis and 
Guillain-Barré 
syndrome 
All grades 
Permanently discontinue atezolizumab. Patient 
may not resume treatment, regardless of benefit. 
 
Refer patient to neurologist. 
 
Initiate treatment as per institutional guidelines. 
 
Consider initiation of 1−2 mg/kg/day oral or IV 
prednisone or equivalent. 
Myocarditis 
All grades 
Permanently discontinue atezolizumab.  Patient 
may not resume treatment, regardless of benefit. 
Refer patient to cardiologist. (24-FEB-2021) 
Neuropathy, 
immune-related 
 
(sensory and/or 
motor) 
Grade 1 
Continue atezolizumab. 
 
Evaluate for alternative etiologies. 
Grade 2 
Hold atezolizumab. 
 
Evaluate for alternative etiologies. 
 
Initiate treatment as per institutional guidelines. 
 
Resume atezolizumab if event resolves to grade 1 
or better within 12 weeks. 
 
Permanently discontinue atezolizumab if event 
does not resolve to grade 1 or better within 12 
weeks. 
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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ Duration 
Management 
Grade 3 or 4 
Permanently discontinue atezolizumab. 
 
Initiate treatment as per institutional guidelines. 
Ocular event 
(e.g., uveitis, 
retinal events) 
Grade 1 
Continue atezolizumab. 
 
Patient referral to ophthalmologist is strongly 
recommended. 
 
Initiate treatment with topical corticosteroid eye 
drops and topical immunosuppressive therapy. 
 
If symptoms persist, treat as a grade 2 event. 
Grade 2 
Withhold atezolizumab. 
 
Patient referral to ophthalmologist is strongly 
recommended. 
 
Initiate treatment with topical corticosteroid eye 
drops and topical immunosuppressive therapy. 
 
If event resolves to grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to grade 1 or better within 
12 weeks. 
Grade 3 or 4 
Permanently discontinue atezolizumab.   
 
Refer patient to ophthalmologist. 
 
Initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
 
If event resolves to grade 1 or better, taper 
corticosteroids over ≥1 month. For grade 3 AEs, 
patient may only resume treatment after 
consultation with the trial PI; for grade 4, patient 
cannot resume treatment, regardless of benefit. 
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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ Duration 
Management 
Pancreatitis, 
immune related 
(10/16/2017) 
 
See Amylase 
and/or lipase 
increased section 
above 
Grade 2 (with 
radiographic findings) 
or 3 (10/16/2017) 
Hold atezolizumab. 
 
Refer patient to GI specialist. 
 
Initiate treatment with 1−2 mg/kg/day 
intravenous methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 
If event resolves to grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to grade 1 or better within 
12 weeks.  Patient may only resume treatment 
after consultation with the trial PI. 
 
For recurrent events, permanently discontinue 
atezolizumab.  Patient may not resume treatment, 
regardless of benefit. 
Grade 4 
Permanently discontinue atezolizumab. Patient 
may not resume treatment, regardless of benefit. 
 
Refer patient to GI specialist. 
 
Initiate treatment with 1−2 mg/kg/day 
intravenous methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 
If event resolves to grade 1 or better, taper 
corticosteroids over ≥1 month. 
Pulmonary 
toxicity 
All pulmonary events 
Evaluate thoroughly for other commonly reported 
etiologies such as pneumonia/infection, 
lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive 
pulmonary disease (COPD), or pulmonary 
hypertension. 
Grade 1 
Continue atezolizumab and monitor closely.   
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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ Duration 
Management 
 
Re-evaluate on serial imaging. 
 
Consider patient referral to a pulmonary 
specialist. 
 
For recurrent pneumonitis, treat as a grade 3 or 4 
event. 
Grade 2 
Hold atezolizumab.   
 
Refer patient to pulmonary and infectious disease 
specialists and consider bronchoscopy or 
bronchoscopic alveolar lavage (BAL). 
 
Initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
 
If event resolves to grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to grade 1 or better within 
12 weeks. 
 
For recurrent events, treat as a Grade 3 or 4 
event. 
Grade 3 or 4 
Permanently discontinue atezolizumab. 
 
Bronchoscopy or BAL is recommended. 
 
Initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 
If event resolves to grade 1 or better, taper 
corticosteroids over ≥1 month.  For grade 3 AEs, 
patient may only resume treatment after 
consultation with the trial PI; for grade 4, patient 
cannot resume treatment, regardless of benefit. 
 
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7. 
ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1  
Protocol Agents (03/19/2018) (29-JUN-2020) 
Investigational Agents 
The investigational agents administered in NRG-GY009 are atezolizumab and bevacizumab, 
which are being made available under an IND sponsored by DCTD, NCI.   
Commercial Agents 
The commercial agent in NRG-GY009 is pegylated liposomal doxorubicin.   
For all patients, determination of whether an adverse event meets expedited reporting criteria, 
see the reporting table in Section 7.6.2.1 of the protocol. 
 
7.2 
Adverse Events and Serious Adverse Events 
7.2.1 This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 until March 31, 2018 (CTCAE version 5.0 will be utilized for AE reporting 
beginning April 1, 2018) for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs 
reporting of adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0. (03/19/2018) 
7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related.  Therefore, an AE can be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not considered related to the 
medicinal (investigational) product (attribution of unrelated, unlikely, possible, probable, or 
definite). (International Conference on Harmonisation [ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited manner. 
 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for Study Agents 
7.3.1 Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Bevacizumab (rhuMAb VEGF, NSC 704865) (09/13/2018) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events 
by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf for further 
clarification. Frequency is provided based on 3540 patients. Below is the CAEPR for bevacizumab 
(rhuMAb VEGF). 
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5Gastrointestinal hemorrhage may include: Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, 
Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Oral 
hemorrhage, Rectal hemorrhage, and other sites under the GASTROINTESTINAL DISORDERS SOC. 
 
6Gastrointestinal obstruction may include: Colonic obstruction, Duodenal obstruction, Esophageal obstruction, Ileal 
obstruction, Jejunal obstruction, Rectal obstruction, Small intestinal obstruction, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 
7Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric 
perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation. 
 
8Gastrointestinal ulcer may include: Duodenal ulcer, Esophageal ulcer, Gastric ulcer, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 
9Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
10Anastomotic leak may include Gastric anastomotic leak; Gastrointestinal anastomotic leak; Large intestinal anastomotic 
leak; Rectal anastomotic leak; Small intestinal anastomotic leak; Urostomy leak; Vaginal anastomotic leak. 
 
11There have been reports of non-mandibular osteonecrosis (avascular necrosis) in patients under the age of 18 treated 
with bevacizumab. 
 
12Metaphyseal dysplasia was observed in young patients who still have active epiphyseal growth plates. 
 
13Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients in association with bevacizumab 
treatment, the majority of whom had received prior or concomitant treatment with i.v. bisphosphonates. 
 
14Increased rate of peripheral sensory neuropathy has been observed in trials combining bevacizumab and chemotherapy 
compared to chemotherapy alone.  
 
15Ovarian failure, defined as amenorrhea lasting 3 or more months with follicle-stimulating hormone (FSH) elevation 
(≥30 mIU/mL), was increased in patients receiving adjuvant bevacizumab plus mFOLFOX compared to mFOLFOX alone 
(34% vs. 2%).  After discontinuation of bevacizumab, resumption of menses and an FSH level <30 mIU/mL was 
demonstrated in 22% (7/32) of these women.  Long term effects of bevacizumab exposure on fertility are unknown. 
 
16Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, heart attack, and stroke. 
 
 
Adverse events reported on bevacizumab (rhuMAb VEGF) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that bevacizumab (rhuMAb VEGF) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Disseminated intravascular 
coagulation; Hemolysis; Thrombotic thrombocytopenic purpura 
CARDIAC DISORDERS - Atrioventricular block complete; Atrioventricular block first degree; Cardiac arrest; 
Myocarditis; Pericardial effusion; Restrictive cardiomyopathy; Right ventricular dysfunction 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (tympanic membrane perforation); 
Hearing impaired; Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; Eye disorders - Other (blindness); 
Eye disorders - Other (conjunctival hemorrhage); Eye disorders - Other (corneal epithelial defect); Eye disorders - Other 
(ischemic CRVO); Eye disorders - Other (macular pucker); Eye disorders - Other (transient increased IOP > or =30 mm 
Hg); Eye pain; Floaters; Keratitis; Optic nerve disorder; Photophobia; Retinal detachment; Retinal tear; Retinopathy; 
Vitreous hemorrhage; Watering eyes 
GASTROINTESTINAL DISORDERS - Ascites; Cheilitis; Colonic stenosis; Dry mouth; Dysphagia; Enterocolitis; 
Esophageal pain; Esophageal stenosis; Flatulence; Gastrointestinal disorders - Other (peritonitis); Oral pain; Pancreatitis; 
Proctitis; Rectal mucositis; Rectal stenosis; Typhlitis 
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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema face; Edema limbs; 
Edema trunk; Facial pain; Fever; Flu like symptoms; Gait disturbance; Injection site reaction; Localized edema; Multi-
organ failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder necrosis; Gallbladder obstruction; Hepatic failure; 
Hepatic necrosis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Bruising; Burn; Dermatitis 
radiation; Fracture 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood antidiuretic hormone abnormal; CD4 
lymphocytes decreased; CPK increased; Carbon monoxide diffusing capacity decreased; Electrocardiogram QT corrected 
interval prolonged; Forced expiratory volume decreased; GGT increased; INR increased; Lipase increased; Lymphocyte 
count decreased; Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; Hypermagnesemia; 
Hypernatremia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hypomagnesemia; 
Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone pain; Chest wall 
pain; Fibrosis deep connective tissue; Head soft tissue necrosis; Joint effusion; Muscle weakness lower limb; Muscle 
weakness upper limb; Musculoskeletal and connective tissue disorder - Other (polymyalgia rheumatica); Neck pain; 
Osteonecrosis; Pain in extremity; Pelvic soft tissue necrosis; Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Arachnoiditis; Ataxia; Central nervous system necrosis; Cerebrospinal fluid 
leakage; Cognitive disturbance; Depressed level of consciousness; Dysesthesia; Dysgeusia; Dysphasia; Encephalopathy; 
Extrapyramidal disorder; Facial nerve disorder; Hydrocephalus; Leukoencephalopathy; Memory impairment; Myasthenia 
gravis; Nervous system disorders - Other (increased intracranial pressure); Paresthesia; Peripheral motor neuropathy; 
Pyramidal tract syndrome; Seizure; Somnolence; Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Libido decreased; Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; Cystitis noninfective; Dysuria; Renal 
and urinary disorders - Other (ureterolithiasis); Renal hemorrhage; Urinary frequency; Urinary incontinence; Urinary 
retention; Urinary tract obstruction; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Erectile dysfunction; Irregular menstruation; 
Pelvic pain; Vaginal discharge 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Atelectasis; Hypoxia; Nasal congestion; Pulmonary fibrosis; Respiratory failure; Respiratory, thoracic and mediastinal 
disorders - Other (dry nares); Respiratory, thoracic and mediastinal disorders - Other (pulmonary infarction) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis; Nail loss; Pain of skin; 
Photosensitivity; Purpura; Rash acneiform; Skin and subcutaneous tissue disorders - Other (diabetic foot ulcer); Skin and 
subcutaneous tissue disorders - Other (skin breakdown/ decubitus ulcer); Skin hyperpigmentation; Skin induration; Skin 
ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Lymphocele; Phlebitis; Vasculitis 
 
Note: Bevacizumab (rhuMAb VEGF) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously associated with 
either agent. 
 
 
 
 
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1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Atezolizumab, being a member of a class of agents involved in the inhibition of “immune checkpoints,” may 
result in severe and possibly fatal immune-mediated adverse events probably due to T-cell activation and 
proliferation. Immune-mediated adverse reactions have been reported in patients receiving atezolizumab. 
Adverse events potentially related to atezolizumab may be manifestations of immune-mediated adverse events. 
In clinical trials, most immune-mediated adverse reactions were reversible and managed with interruptions of 
atezolizumab, administration of corticosteroids and supportive care. 
 
3Infusion reactions, including high-grade hypersensitivity reactions, anaphylaxis, and cytokine release 
syndrome, which have been observed following administration of atezolizumab, may manifest as fever, chills, 
shakes, itching, rash, hypertension or hypotension, or difficulty breathing during and immediately after 
administration of atezolizumab. 
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on atezolizumab (MPDL3280A) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that atezolizumab (MPDL3280A) caused 
the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Febrile neutropenia 
CARDIAC DISORDERS - Cardiac arrest; Ventricular tachycardia 
GASTROINTESTINAL DISORDERS - Constipation; Dry mouth; Ileus 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Malaise; Multi-
organ failure 
HEPATOBILIARY DISORDERS - Portal vein thrombosis 
INVESTIGATIONS - Lymphocyte count decreased; Neutrophil count decreased; Weight loss; White blood cell 
decreased 
METABOLISM AND NUTRITION DISORDERS - Hypophosphatemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Muscle cramp: Pain in 
extremity 
NERVOUS SYSTEM DISORDERS - Headache 
PSYCHIATRIC DISORDERS - Confusion; Insomnia; Suicide attempt 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Pulmonary hypertension; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin2; Hyperhidrosis 
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event 
 
 
Note: Atezolizumab (MPDL3280A) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
 
 
 
 
 
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7.4 
Adverse Events for Commercial Study Agents  
Refer to the package insert for detailed pharmacologic and safety information 
7.5 
Adverse Event Characteristics (06/29/2017) (03/19/2018) 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will 
be utilized until March 31, 2018 for AE reporting. CTCAE version 5.0 will be utilized for AE 
reporting beginning April 1, 2018. All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be downloaded from 
the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. (03/06/2018) 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Sections 7.3.1 and 7.3.2) should be reported through CTEP-AERS only if 
the grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in section 
7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.6 
Expedited Reporting of Adverse Events 
All serious adverse events that meet expedited reporting criteria defined in the reporting table 
below will be reported via the CTEP Adverse Event Reporting System, CTEP-AERS, 
accessed via the CTEP web site,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to NRG and satisfies NRG 
requirements for expedited adverse event reporting. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to CTEP for this study by telephone at 301-897-7497 and to NRG Regulatory 
Affairs by phone at 215-854-0770. An electronic report must be submitted immediately 
upon re-establishment of the Internet connection. 
 
7.6.1 Expedited Reporting Methods 
• Per CTEP NCI Guidelines for Adverse Events Reporting Requirements, a CTEP-AERS 
24-hour notification must be submitted within 24 hours of learning of the adverse event. 
Each CTEP-AERS 24-hour notification must be followed by a complete report within 3 
days.  
• Supporting source documentation is requested by the IND sponsor for this study 
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(CTEP/DCTD) and NRG as needed to complete adverse event review.  When submitting 
supporting source documentation, include the protocol number, patient ID number, and 
CTEP-AERS ticket number on each page, and fax supporting documentation to CTEP at 
301-230-0159 and NRG Regulatory Affairs at 215-854-0716. 
• A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not recommended” 
must still be reported to fulfill NRG safety reporting obligations. Sites must bypass the 
“NOT recommended” assessment; the CTEP-AERS allows submission of all reports 
regardless of the results of the assessment.  
 
 
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Additional Protocol-Specific Instructions or Exceptions to Expedited Reporting 
Requirements 
 
Adverse Events of Special Interest in Bevacizumab (24-FEB-2021) 
 
The following AEs are considered of special interest in patients receiving bevacizumab and 
must be reported expeditiously through CTEP-AERS, irrespective of regulatory seriousness 
criteria:  
• Hypertension ≥ grade 3 
• Proteinuria ≥ grade 3 
• GI perforation, abscesses and fistulae (any grade) 
• Wound healing complications ≥ grade 3 
• Haemorrhage ≥ grade 3 (any grade CNS bleeding; > grade 2 haemoptysis) 
• Arterial thromboembolic events (any grade) 
• Venous thromboembolic events ≥ grade 3 
• Posterior reversible encephalopathy syndrome (PRES - any grade) 
• CHF ≥ grade 3 
• Non-GI fistula or abscess ≥ grade 2 
 
Adverse Events of Special Interest in Atezolizumab Studies (06/29/2017) (24-FEB-2021) 
 
The following AEs are considered of special interest in patients receiving atezolizumab and 
must be reported expeditiously through CTEP-AERS, irrespective of regulatory seriousness 
criteria:  
• Pneumonitis 
• Colitis 
• Endocrinopathies:  diabetes mellitus, pancreatitis, hyperthyroidism, hypophysitis, and 
adrenal insufficiency 
• Hepatitis including AST or ALT >10 × ULN  
• Systemic lupus erythematosus 
• Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
• Events suggestive of hypersensitivity, cytokine release, influenza-like illness, systemic 
inflammatory response syndrome, systemic immune activation, or infusion-related 
reactions 
• Nephritis 
• Ocular toxicities (e.g., uveitis, retinitis) 
• 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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7.6.3 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board (IRB) 
or Research Ethics Board (REB) responsible for oversight of the patient according to 
institutional policy. 
 
7.6.4 Pregnancy (24-FEB-2021) 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included 
within the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient from the time of consent to 5 
months after the last dose of study drug must be reported and then followed for outcome.  
Newborn infants should be followed until 30 days old.  Please see the “NCI Guidelines for 
Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP 
INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse effects.htm) for 
more details on how to report pregnancy and its outcome to CTEP.  
 
7.6.5 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur during or subsequent to treatment with 
an agent under an NCI IND/IDE be reported via CTEP-AERS. In addition, secondary 
malignancies following radiation therapy must be reported via CTEP-AERS. Three options 
are available to describe the event: 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
8. 
REGISTRATION AND STUDY ENTRY PROCEDURES (03/19/2018) (29-JUN-2020) 
8.1 
CTEP Registration Procedures (03/19/2018) 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their 
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8.2 
CTSU Registration Procedures (03/19/2018) 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval:   
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI Central 
Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI 
CIRB review to activate new studies at the site after March 1, 2019. Local IRB review will 
continue to be accepted for studies that are not reviewed by the CIRB, or if the study was 
previously open at the site under the local IRB. International sites should continue to submit 
Research Ethics Board (REB) approval to the CTSU Regulatory Office following country-
specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRBManager to indicate their intent to open the study 
locally. The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU 
Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by email or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB 
approval record to be completed: 
• Holds an active CTEP status; 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) 
and on at least one participating roster; 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCE profile; and 
• Holds the appropriate CTEP registration type for the protocol. 
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number; 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• Compliance with all protocol-specific requirements (PSRs). 
 
 
 
 
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Downloading Site Registration Documents:   
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment. To participate, the 
institution and its associated investigators and staff must be associated with the LPO or a 
Protocol Organization (PO) on the protocol.  One way to search for a protocol is listed below.  
 Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password; 
 Click on Protocols tab in the upper left of the screen 
o 
Enter the protocol number in the search field at the top of the protocol tree; or 
o 
Click on the By Lead Organization folder to expand, then select NRG Oncology, 
and protocol number NRG-GY009. 
 Click on Documents, select Site Registration, and download and complete the forms 
provided. (Note: For sites under the CIRB, IRB data will load automatically to the 
CTSU.)   
 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website.  
 
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission  
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
 
Checking Site’s Registration Status: 
 
Site registration status may be verified on the CTSU members’ website.   
 
• Click on Regulatory at the top of the screen; 
• Click on Site Registration; and  
• Enter the sites 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
 
Note: The status given only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
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requirements for individuals participating on the protocol or the enrolling investigator’s status 
with NCI or their affiliated networks. 
 
8.3 
Patient Enrollment (03/19/2018) 
For the Phase I portion, the SDMC-Buffalo Office web-based patient reservation system will 
be used, in which slots for particular patients are reserved.  Reservations are not transferrable 
to other patients, and if the patient is not enrolled within the required timeframe, the 
reservation is cancelled and the slot is then made available to other patients and sites.  If all 
slots are reserved, patients can be added to a waiting list.    
 
The URL for the Phase I reservation system can be found at 
https://nrg42.nrgoncology.org/phaseireservations. (10/16/2017) 
 
8.3.1 Patient Enrollment  
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with 
the LPOs registration/randomization systems or the Theradex Interactive Web Response 
System (IWRS) for retrieval of patient registration/randomization assignment. OPEN will 
populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave.  
Requirements for OPEN access: 
• A valid CTEP-IAM account; 
• To perform enrollments or request slot reservations: Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role of 
Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
• If a Delegation of Tasks Log (DTL) is required for the study, the registrar must hold 
the OPEN Registrar task on the DTL for the site; and 
• Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR.  If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated timeframes; and 
• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
 
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. You may print this confirmation for your records.  
 
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Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
 
8.4 
Agent Ordering and Agent Accountability (03/19/2018) (29-JUN-2020) 
8.4.1 NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual submission 
of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment Form, and 
Financial Disclosure Form (FDF).  If there are several participating investigators at one 
institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead investigator at that institution. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application. 
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account and the maintenance of an “active” account status, a “current” password, and 
active person registration status.  For questions about drug orders, transfers, returns, or 
accountability, call or email PMB any time.  Refer to the PMB’s website for specific policies 
and guidelines related to agent management. (10/22/2018) (02/20/2019) 
8.4.2 Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application.  Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account status, a 
“current” password and active person registration status.  Questions about IB access may be 
directed to the PMB IB Coordinator via email. (02/20/2019) 
8.4.3 Agent Accountability 
 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB 
using the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) 
available on the CTEP forms page. Store and maintain separate NCI Investigational Agent 
Accountability Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
8.4.4 PMB Useful Links and Contacts (02/20/2019) 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov   
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/ (10/22/2018) 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/aim/index.jsp  
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• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator: IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
 
9.  
DRUG INFORMATION  
9.1 
Atezolizumab, NSC # 783608, 
 (06/29/2017) (13-OCT-2022) 
9.1.1 Other Names: Tecentriq™, MPDL3280A 
 
Classification: monoclonal antibody 
 
M.W.: 150 KD 
 
Mode of Action: anti-PD-L1 
9.1.2 Description: 
Atezolizumab is a humanized IgG1 monoclonal antibody consisting of two heavy chains (448 
amino acids) and two light chains (214 amino acids). Atezolizumab targets human PD-L1 and 
inhibits its interaction with its receptor 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 (Butte 
et al. 2007).  
 
9.1.3 How Supplied:  
 Atezolizumab is provided by Genentech/F.Hoffmann-La Roche LTD and distributed by the 
Pharmaceutical Management Branch, CTEP, NCI.  The agent is supplied in a single-use, 20-
mL glass vial as a colorless-to-slightly-yellow, sterile, preservative-free clear liquid solution 
intended for IV administration. Each 20 mL vial contains 1200 mg of atezolizumab and is 
formulated in glacial acetic acid (16.5 mg), L-histidine (62 mg), polysorbate 20 (8 mg), and 
sucrose (821.6 mg), with a pH of 5.8.  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. 
 
Atezolizumab is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
Atezolizumab is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Appendix VI). 
 
9.1.4 Preparation:   
 
The prescribed dose of atezolizumab should be diluted in 0.9% NaCl to a concentration 
between 3.2 mg/mL and 16.8 mg/mL and infused with or without a low-protein binding 0.2 or 
0.22 micrometer in-line filter. The IV bag may be constructed of polyvinyl chloride (PVC), 
polyolefin (PO), or polyethylene (PE).  The prepared solution may be stored at 2°C-8°C for up 
to 24 hours or at ambient < 25°C (77°F) for 6 hours from the time of preparation.  If the dose 
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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.  These times include the storage 
and administration times for the infusion. Do not shake or freeze infusion bags containing the 
dose solution.9.1.5 
 
 
Storage:  2°C-8°C (36°F-46°F) Vial contents should not be frozen or shaken and should be 
protected from direct sunlight. 
 
If a storage temperature excursion is identified, promptly return atezolizumab to 2°C-8°C 
(36°F-46°F) and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
9.1.6 Stability:  Stability studies are ongoing. 
CAUTION:  No preservative is used in atezolizumab; therefore, the vial is intended for single 
use only. Discard any unused portion of drug remaining in a vial.  
 
9.1.7 Route of Administration: IV infusion 
 
Method of Administration:  
Atezolizumab is administered as an intravenous infusion over 60 minutes. If the first infusion 
is tolerated, all subsequent infusions may be delivered over 30 minutes. Do not administer 
atezolizumab as an intravenous push or bolus. No premedication is indicated for 
administration of Cycle 1 of atezolizumab. Patients who experience an infusion related 
reaction with Cycle 1 of atezolizumab may receive premedications with subsequent infusions. 
9.1.8 Potential Drug Interactions:  
Cytochrome P450 enzymes as well as conjugation/glucuronidation reactions are not involved 
in the metabolism of atezolizumab. No drug interaction studies for atezolizumab have been 
conducted or are planned. There are no known interactions with other medicinal products or 
other form of interactions. 
9.1.9 Patient Care Implications: 
Female patients of childbearing potential should utilize contraception and take active measures to 
avoid pregnancy while undergoing atezolizumab treatment and for at least 150 days after the last dose 
of atezolizumab.9.1.10 
 
Adverse Events:  Please see Section 7.3.2 for the Atezolizumab CAEPR. 
 
9.2 
Bevacizumab (rhuMAb VEGF, Avastin®) (NSC #704865) (29-JUN-2020) 
 
 
9.2.1 Classification: Recombinant humanized monoclonal antibody 
9.2.2 Molecular Weight: Approximate molecular weight is 149,000 daltons 
9.2.3 Mode of Action: Bevacizumab blocks the binding of vascular endothelial growth factor 
(VEGF) to its receptors resulting in inhibition of angiogenesis. 
9.2.4 Description: Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody 
consisting of 93% human and 7% murine amino acid sequences. The agent is composed of 
human IgG framework and murine antigen-binding complementarity-determining regions. 
9.2.5 How Supplied:  Bevacizumab is provided by Genentech and distributed by the Pharmaceutical 
Management Branch, CTEP, NCI.  Bevacizumab is supplied as a clear to slightly opalescent, 
sterile liquid for parenteral administration.  Each 400 mg (25mg/ml – 16 mL fill) glass vial 
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contains bevacizumab with phosphate, trehalose, polysorbate 20, and Sterile Water for 
Injection, USP.  
9.2.6 Preparation: Vials contain no preservatives and are intended for single use only. The 
calculated dose should be diluted in 0.9% sodium chloride for injection to a final 
concentration of bevacizumab between 1.4 and 16.5 mg/ml. 
9.2.7 Storage: Upon receipt, refrigerate bevacizumab (2°to 8°C). Keep vial in the outer carton due 
to light sensitivity. Do not freeze. Do not shake. 
 
 
If a storage temperature excursion is identified, promptly return bevacizumab to 2º-8ºC (36ºF-
46ºF) and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
9.2.8 Stability: Please see the product label for expiration information. The sterile single use vials 
contain no antibacterial preservatives.  Discard vials 8 hours after initial entry. 
 
 
Once diluted in 0.9% sodium chloride, the product should be used immediately. If not used 
immediately, in-use storage times are the responsibility of the user and should not be longer 
than 24 hours at 2ºC-8ºC. 
9.2.9 Route of Administration:  Intravenous 
9.2.10 Method of Administration: Administer the initial dose over a minimum of 90 minutes.  If no 
adverse reactions occur, administer the second dose over a minimum of 60 minutes. If no 
adverse reactions occur after the second dose, administer subsequent doses over a minimum 
of 30 minutes. If infusion-related adverse reactions occur, all subsequent infusions should be 
administered over the shortest period that was well tolerated.  
9.2.11 Adverse Events:  Please see Section 7.3.1 for the Bevacizumab CAEPR. 
 
9.3 
Pegylated Liposomal Doxorubicin (NSC #620212, 712227) 
Sites must refer to the package insert for detailed pharmacologic and safety information. 
9.3.1 Formulation:  Please see the doxorubicin HCl liposome package insert.  
9.3.2 Storage: Refrigerate unopened vials of PLD at 2°–8°C (36°–46°F). Avoid freezing. Prolonged 
freezing may adversely affect liposomal drug products; however, short-term freezing (less 
than 1 month) does not appear to have a deleterious effect on PLD. 
9.3.3 Preparation: PLD doses must be diluted in 5% Dextrose Injection, USP prior to administration 
in accordance with the package insert and/or institutional procedures. . Aseptic technique 
must be strictly observed since no preservative or bacteriostatic agent is present in PLD. 
Diluted PLD should be refrigerated at 2°C–8°C (36°F–46°F) and administered within 24 
hours. 
 
Do not mix with other drugs. 
 
Do not use with any diluent other than 5% Dextrose Injection.  
 
Do not use any bacteriostatic agent, such as benzyl alcohol. 
  
PLD is not a clear solution but a translucent, red liposomal dispersion.  
 
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Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration, whenever solution and container permit. Do not use if a precipitate or 
foreign matter is present.  
9.3.4 Procedure for Proper Handling and Disposal: Caution should be exercised in the handling and 
preparation of PLD.  
 
The use of gloves is required.  
 
If PLD comes into contact with skin or mucosa, immediately wash thoroughly with soap and 
water.  
 
PLD should be considered an irritant and precautions should be taken to avoid extravasation. 
With intravenous administration of PLD, extravasation may occur with or without an 
accompanying stinging or burning sensation, even if blood returns well on aspiration of the 
infusion needle. If any signs or symptoms of extravasation have occurred, the infusion should 
be immediately terminated and restarted in another vein.  
PLD must not be given by the intramuscular or subcutaneous route.  
 
PLD should be handled and disposed of in a manner consistent with other anticancer drugs.  
9.3.5 Adverse Effects:  Consult the PLD package insert for the most current and complete 
information. 
9.3.6 Drug Ordering:  Commercially Available. Consult the American Hospital Formulary Service 
Drug Information guide, Facts and Comparisons, or the package insert for additional 
information. 
 
10. 
PATHOLOGY/BIOSPECIMEN (10/22/2018)   
10.1 
Central Pathology Review Guidelines 
Not Applicable.   
10.2 
Biospecimen Selection for Integral Marker Testing 
 
Not applicable. 
10.3 
Biospecimen Selection for Integrated Marker Testing  
10.3.1  Marker to be Tested (30-OCT-2020)  
 
PD-L1 expression will be evaluated as an integrated biomarker in this study. PD-L1, also 
known as B7-H1, is an inhibitory ligand expressed in multiple cancer types including ovarian. 
In addition to being inherently upregulated in some cancer types, more commonly, PD-L1 
expression is upregulated in response to tumor-infiltrating lymphocytes and thus serves as a 
mechanism of adaptive immune resistance to T cell infiltration (Taube et al., 2014).  
Expression of PD-L1 on tumor cells and tumor-infiltrating immune cells has been shown to be 
associated with response to immune checkpoint blocking antibodies targeting PD-1 or PD-L1 
in several cancer types (reviewed in https://www.ncbi.nlm.nih.gov/pubmed/24714771). PD-
L1 expression in tumor infiltrating immune cells (IC) in particular has been shown to be the 
strongest predictor of response. Powles et al. published a phase I study investigating the anti-
PD-L1 antibody atezolizumab for the treatment of metastatic urothelial bladder cancer 
(Powles et al., 2014). This study showed that atezolizumab had noteworthy activity in 
metastatic UBC with rapid responses occurring at the first response assessment (6 weeks) and 
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nearly all were ongoing at the data cutoff (Powles et al.,  2014). PD-L1 expression is scored in 
tumor infiltrating immune cells (as percentage of tumor area: IC3≥10%, IC2≥5% and <10%, 
IC1≥1% and <5%, and IC0<1%). 
 
VENTANA PD-L1 (SP142), is an FDA-approved complimentary diagnostic IHC assay to 
ascertain tumor PD-L1 status for patients with metastatic urothelial cancer and triple negative 
breast cancer (TNBC) considering treatment with atezolizumab, with IC1 staining (PD-L1 
positivity ≥1%) as a cutoff.  
  
The association of PD-L1 expression with response to PD-L1 blockade in ovarian cancer has 
not been established. We hypothesize that the tumor microenvironment of the ovarian cancer 
patients exhibiting higher levels of PD-L1 expression in tumor-infiltrating immune cells is 
more amenable to immunotherapy with immune checkpoint blockade. As such we 
hypothesize that patients with higher levels of PD-L1 will exhibit evidence of stronger anti-
tumor immune response and improved PFS and OS in the NRG-GY009 trial.  
 
SP142 assay was previously used to evaluate PD-L1 expression in ovarian cancer (Webb et 
al., 2016). In the cohort of 490 ovarian cancer cases analyzed by tissue microarray, PD-L1 
IC1 positivity (defined as ≥1%) was observed in 57.4% of high-grade serous cases, 24% of 
endometrioid cases, and 16% of clear cell cases. Internal data provided by Genentech 
demonstrates IC1 staining in approximately 60% of patients and IC2 staining (>5%) in 
approximately 20% of patients with ovarian cancer. Based on the study above, we assume that 
approximately 50% of patients in our population will be PD-L1 positive (defined as ≥1%).  
 
10.3.2 Testing Requirements and Reporting 
A formalin-fixed, paraffin-embedded (FFPE) primary, metastatic, recurrent, or persistent 
tumor block must be submitted for retrospective PD-L1 testing. The tumor block must 
contain at least 50% viable tumor and intact architecture. See Mandatory Biospecimen 
Submission Table (section 10.4.1) for details. 
10.3.3 Method of Testing (30-OCT-2020 ) (24-FEB-2021) 
VENTANA PD-L1 (SP142), assay is FDA approved as a complimentary diagnostic 
immunohistochemistry (IHC) assay to ascertain tumor PD-L1 status for patients with 
metastatic urothelial cancer considering treatment with atezolizumab. In ovarian cancer 
patients, SP142 detects PD-L1 on immune cells (Webb, et al, 2016). 
 
The Ventana PD-L1 (SP142) assay kit uses the OptiView DAB IHC detection kit and 
OptiView Amplification kit on a Ventana BenchMark Ultra Instrument along with the 
specified antibody. PD-L1 expression within tumor tissue will be assessed using (n=6) 4 um 
sections cut within a 60 day period from the FFPE block.. PD-L1 positive status is defined as  
≥ 1% staining of tumor-infiltrating immune cells as a percentage of tumor area using the 
SP142 Ventana assay. Exploratory PD-L1 positive status is defined as > 5% staining of 
tumor-infiltrating immune cells as a percentage of tumor area using the Ventana SP142 assay. 
The details about the assay performance characteristics are available at: 
https://www.accessdata.fda.gov/cdrh docs/pdf16/p160002s009c.pdf 
 
 
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10.3.4 Location of Testing (30-OCT-2020) 
The NRG Oncology Biospecimen Bank (NRG-BB)-Columbus will batch ship fresh cut (not 
older than 60 days) sections of FFPE tumor to a Genentech designated laboratory 
(Histogenex) upon closure of each trial phase and receipt of all tumor blocks from sites. The 
laboratory is specifically set up to perform SP142 testing and quantification and will be used 
for the assessment of all samples on the study.  
10.3.5 Biospecimen Submission for Testing 
FFPE tumor blocks must be shipped to the NRG BB-Columbus. See Mandatory Biospecimen 
Submission Table (section 10.4.1) for details. 
10.4 
Biospecimen Submission Tables 
Biospecimens listed below should not be submitted until after patient registration and 
Bank ID assignment. 
 
 
 
A detailed description of biospecimen procedures can be found in Appendix V. 
10.4.1 Mandatory Biospecimen Submissions (10/16/2017) (10/22/2018)(13-OCT-2022) 
The patient must give permission to participate in this mandatory study component. 
Participating sites are required to submit the patient’s biospecimens as outlined below. 
Biospecimen (Biospecimen Code)  
Collection Time Point 
Ship 
Biospecimens 
To 
FFPE – Submit one (listed in order of preference) 
FFPE Persistent Metastatic Tumor (FPM01)1 
Block containing at least 50% viable tumor and intact architecture2 
Prior to study treatment 
(Preferred FFPE) 
NRG Oncology 
BB-Columbus 
within 8 weeks 
of registration3 
FFPE Persistent Primary Tumor (FPP01)1 
Block containing at least 50% viable tumor and intact architecture2 
Prior to study treatment 
(Preferred FFPE; optional if 
another FFPE type is submitted) 
FFPE Recurrent Metastatic Tumor (FRM01)1 
Block containing at least 50% viable tumor and intact architecture2 
Prior to study treatment 
(Optional if another FFPE type 
is submitted) 
FFPE Recurrent Primary Tumor (FRP01)1 
Block containing at least 50% viable tumor and intact architecture2 
Prior to study treatment 
(Optional if another FFPE type 
is submitted) 
FFPE Metastatic Tumor (FM01)1 
Block containing at least 50% viable tumor and intact architecture2 
Prior to all treatment (Optional if 
another FFPE type is submitted) 
FFPE Primary Tumor (FP01)1 
Block containing at least 50% viable tumor and intact architecture2 
Prior to all treatment (Optional if 
another FFPE type is submitted) 
FFPE Metastatic Neoadjuvant Tumor (FMT01)1 
Block containing at least 50% viable tumor and intact architecture2 
After receiving neoadjuvant 
treatment, but prior to study 
treatment (Optional if another 
FFPE type is submitted) 
FFPE Primary Neoadjuvant Tumor (FPT01)1 
Block containing at least 50% viable tumor and intact architecture2 
After receiving neoadjuvant 
treatment, but prior to study 
treatment (Optional if another 
FFPE type is submitted) 
1 A copy of the corresponding pathology report must be shipped with all tissue biospecimens sent to the NRG BB-
Columbus 
2 Due to the complexity of the FFPE requirements, only blocks will be accepted. Please provide Appendix VII to your 
pathologist. 
3 NRG Oncology BB-Columbus / Protocol NRG-GY009, Nationwide Children’s Hospital, 700 Children’s Drive, 
WA1340, Columbus, OH 43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: 
BPCBank@nationwidechildrens.org 
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sequencing or alternative methodologies to characterize the neoantigen landscape and the 
tumor microenvironment. *DNA and RNA will be isolated from one tumor type (order of 
preference: persistent, recurrent, metastatic, primary). 
10.5.3 Microbiome Analysis 
Pre-cycles 1 and 2 frozen stool will be batch shipped by the NRG Oncology BB-Columbus to 
Dr.
(University of Chicago) for microbiome analysis. 
 
11. 
SPECIAL STUDIES (NON-TISSUE) 
11.1 
Quality of Life 
Although there is a relatively small body of literature examining quality of life (QoL) with 
recurrent, platinum resistant ovarian cancer, QOL may be maintained for those receiving 
further chemotherapy, particularly if they are responding to treatment (Beesley et al., 2014).  
Similarly, among a sample of recurrent, platinum resistant symptomatic patients, 40% derived 
a clinical benefit from chemotherapy, and 50% reported symptom improvement (Friedlander 
et al., 2014).   In the AURELIA trial, patients with platinum-resistant ovarian cancer were 
randomly assigned to chemotherapy alone, or with bevacizumab.  Patients who received 
bevacizumab with chemotherapy reported a significantly greater improvement in abdominal 
symptoms and QOL during active treatment (Stockler et al., 2014), supporting a role for 
bevacizumab with chemotherapy in the treatment of women with platinum-resistant ovarian 
cancer.  However, in a recent Cochrane report in which QOL data were deemed insufficient 
for meta-analyses, authors note that much more research is needed to determine the role of 
PARP inhibitors in platinum-resistant disease (Wiggans et al., 2015).  Adding to this current 
and significant area of inquiry, we are now considering the AURELIA trial regimen as the 
new standard care arm, since combining bevacizumab with chemotherapy in platinum 
resistant ovarian cancer significantly improved progression free survival (the primary 
endpoint) as well as objective response rate and the patient reported outcome end point of 
abdominal/GI symptoms and quality of life.   
 
Therefore in this study, PLD with bevacizumab will be the backbone on which to improve and 
will serve as the reference group.   Specific to patient-reported outcomes, we will examine the 
effects of the addition of atezolizumab to PLD (Experimental Regimen 1); or the addition of 
atezolizumab to PLD and bevacizumab (Experimental Regimen 2) in a Phase II/III study, 
compared to the reference group. Given the non-overlapping toxicities of these three agents, 
with the exception of fatigue, both patient-reported experiences of disease response and 
treatment side effects are of interest.   
 
In the face of recurrent, platinum resistant disease, and the absence of an OS benefit, it is 
difficult to place a value upon PFS. On the one hand, delaying cancer progression is likely to 
confer some benefit to a person’s quality of life, not only because of the psychological benefit 
of knowing one’s disease is stable, but also based upon the fact that delaying progression is 
also likely to delay the onset of life-limiting symptoms. On the other hand, treatment itself 
carries toxicities which themselves can be distressing and life-limiting. In order to fully 
appreciate the benefits and risks associated with delaying PFS, these studies require careful 
assessment of targeted quality of life domains, in particular, disease symptoms, treatment side 
effects, and patient functioning.  
 
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The patient reported outcome (PRO) plan for this trial was assembled to capture disease 
symptoms, treatment side effects, general function and well-being. Disease related symptom 
benefit is the primary and only planned PRO analysis. Evaluation of differences in side effects 
and function are also proposed, in order to estimate the extent to which symptoms and side 
effects affect function and well-being, and to plan for future study of the relative weight 
patients place upon each of these endpoints alongside clinical endpoints such as PFS. For this 
study, the following measures are proposed: 
• 
Disease-related symptoms: The NCCN/FACT-Ovarian Cancer Symptom Index-18 
(NFOSI-18; Jensen et al., 2011). Half (9 items) of the NFOSI-18 comprise the Disease-
Related Symptom-Physical (DRS-P) scale, which is the primary planned PRO endpoint 
• 
Treatment side effects: Three measures of treatment side effects will be employed: The 5-
item Treatment Side Effects (TSE) scale from the NFOSI-18; the 13-item FACIT-Fatigue 
subscale; and the four-item FACT/GOG-AD subscale. 
• 
Patient function and well-being: Two brief measures of patient function and well-being 
will be employed: The 3-item function and well-being (F/WB) scale from the NFOSI-18, and 
the 1-item worry item from the NFOSI-18. (10/16/2017) 
 
A proposed PRO assessment comprises a total of 35 questions to measure symptoms, side 
effects, function, and well-being. This is a shorter assessment than has been used in prior 
GOG trials that have consistently seen >80% follow-up assessment adherence. Patient time to 
complete averages less than 10 minutes for the entire set of questions, and this has historically 
been a very motivated and engaged group of participants. To keep the assessment brief, 
questions were selected only if they served a specific and planned purpose as described below. 
Within the Phase II trial, these same 35 items will be collected for their use rolling into the 
Phase III trial. Excluding these in Phase II would compromise the power to detect between-
arm differences in Phase III. (10/16/2017) 
 
Study Hypotheses and Instrument Selection 
 
It is anticipated that disease-related symptoms, as measured by the DRS-P of each 
experimental regimen will be significantly better/less than the reference regimen at each of the 
assessment times during the first year. This is based in part on an underlying assumption that 
the disease symptom benefit of delaying progression will be greater than any differences in 
toxicities that might exist between treatments. Therefore, it is critically important that all 
living patients be assessed, even after progression, for the full follow-up window specified in 
the protocols. If, as has been the case in many prior trials, PRO assessment stops at the time of 
progression, this will introduce a bias in the group comparison, one which typically 
disadvantages the more effective treatment (because it retains more patients, including some 
who may have progressed on the inferior treatment).  Although it is a limitation to attribute 
QoL changes identified while patients are receiving subsequent therapies after discontinuation 
of study drug, to the original treatment assignment, there is an even greater limitation imposed 
by a decision to stop assessment of these patients altogether. That greater limitation is the 
introduction of bias to any random effects longitudinal model caused by non-ignorable 
missing data over time.  We therefore propose to continue assessment of all living patients 
during the study observation period. This is consistent with recommendations that have been 
made by the NCI Symptom and Quality of Life Steering Committee, and with best QoL and 
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statistical research practices. Limitations associated with subsequent therapies can therefore 
be explored with available data. 
 
In the PRO component of this trial, the primary emphasis will be placed on symptoms of 
disease (with the understanding that some symptoms such as fatigue and nausea are caused by 
both disease and treatment), with exploratory emphases on treatment side effects and 
function/well-being.  Specifically, assessment of disease related symptoms will evaluate the 
benefit of PFS as experienced by the patient, and address the question of whether 
symptomatic progression accompanies radiographic progression.  Similarly, the patient 
experience of side effects (at least the more common or consequential ones anticipated in this 
trial, such as fatigue) will be an important exploratory indicator of the acceptability of one 
treatment relative to another. 
 
Main PRO Endpoint.  The Disease-Related Symptom-Physical (DRS-P) scale from the 
NCCN/FACT-Ovarian Cancer Symptom Index-18 (NFOSI-18), (Jensen et al., 2011), is a 9-
item scale which comprises the first 9 items of the NFOSI-18.  This scale was developed 
using a qualitative methodology with 50 advanced ovarian cancer patients and 10 expert 
clinicians.  Most of the items come from the FACT-O questionnaire (Basen-Engquist et al., 
2001), but they have been supplemented, reorganized and validated to create a set of targeted 
outcome tools for disease related symptoms, treatment side effects, general functioning and 
well-being.  Of note, after establishing that these 9 questions are the most important disease-
related symptoms to women with ovarian cancer (Jensen et al., 2011), these questions have 
been further evaluated and demonstrated through cognitive debriefing interviews with 18 
women with ovarian cancer to be understood as intended.  The targeted 9-item DRS-P 
subscale will serve as the main PRO endpoint, and is currently being utilized in GY004 and 
GY005. Disease-Related Symptoms-Physical, as measured by the DRS-P, have been selected 
as the main PRO endpoint because we expect that the treatment arm which provides a greater 
PFS benefit will be demonstrated through a delay or reduction of disease symptoms. The 
hypothesis, as stated above, is that the treatment arm with the superior PFS benefit will also 
have a superior DRS-P benefit, lending confirmation as a patient-reported symptomatic 
benefit associated with delaying disease progression. The 9-item NFOSI-18 DRS-P is the 
main PRO endpoint for the Phase II and III trials and has a specified analysis plan. 
 
Exploratory endpoints: Additional endpoints are exploratory for the Phase III studies and 
will be analyzed post-hoc.  
Treatment Side Effects (TSE).  One measure of treatment side effects will be employed:  
The 5-item Treatment Side Effects (TSE) scale from the NFOSI-18.  As the TSE scale is not 
intended to cover all, or even most, of the anticipated side effects across these two trials, we 
propose to use the single summary TSE item (“I am bothered by side effects of treatment”) as 
the unit of analysis comparing overall side effect bother of the treatment arms. There is 
precedent for this (Cella et al., 2013).  
Patient function and well-being (PF/WB). Two brief measures of patient function and well-
being will be employed: The 3-item function and well-being (F/WB) scale from the NFOSI-
18, and the 1-item worry item from the NFOSI-18.  
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FACIT-Fatigue subscale.  Recent studies of the proposed monoclonal antibody indicate that 
fatigue is the cardinal treatment side effect, therefore justifying a more detailed investigation 
of this construct. (10/16/2017) 
FACT/GOG-AD subscale: is a 4-item subscale used to measure the disease or treatment 
related abdominal discomfort. (10/16/2017) 
 
PRO Assessment Timing.  The following PRO assessments will be performed every 8 weeks 
for the first year, which corresponds to radiographic assessments, and every 12 weeks for the 
second year. PRO assessments should be conducted on all living patients, even post-
progression, for time points as scheduled in the protocol, and will be discontinued after two 
years on study.  
 
1. 
(MAIN QOL/PRO endpoint):  PRO: DRS-P (from NFOSI-18) 
2. 
(exploratory):  PRO: TSE (from NFOSI-18) 
3. 
(exploratory):  PRO: Function/Well-Being (from NFOSI-18) 
4.  
(exploratory):  PRO: FACIT-Fatigue-13 
5. 
(exploratory): PRO: FACT/GOG-AD subscale (10/16/2017) 
 
QOL Data compliance: 
 
 In GY009, similar to other trials with very advanced disease populations, the compliance 
challenge will occur because of the relatively short intervals of PFS and OS.  In the platinum-
resistant population, the median PFS is 12 weeks and the median OS is less than one year.   
Our QOL non-compliance is highest among those patients who have stopped study treatment 
for either progression or adverse events.  Importantly, these two reasons do not obviate the 
need for the research nurses and clinical research associates to continue to collect QOL data as 
scheduled.  It is frequently the case, under these scenarios, that an institutions’ research team 
assumes that if the patient is off of the clinical trial, that she is also finished with her QOL 
assessments.  These “institutional errors” can be remedied by diligent educational efforts and 
frequent reminders for follow-up, even if the patient is “off study.”  We are mindful of the fact 
that even with progressing disease, patients appreciate being asked about their health and 
well-being, and are compliant with completing the questionnaires.  This is especially true for 
the ovarian cancer patient population.  It is worth noting that in previous ovarian trials (e.g., 
24 months follow-up) we achieved close to 80% compliance.   
 
NRG will utilize the following strategies to optimize compliance: 
 
TARGET:  CLINICAL RESEARCH ASSOCIATES & NURSING  
 
Task 1.  Compliance Task Force, Chaired by Dr.
 convenes monthly via 
teleconference to assess compliance of each active protocol and initiate strategies for 
improvement.  Presentation at each semi-annual group meeting on compliance updates and 
challenges, sharing QOL results, and reinforcing the message that QOL should continue to be 
assessed after the patient progresses or is off the study treatment.   
 
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Assigned to:  Presenters will include the leadership of the data management and nursing 
committees. 
 
Task 2.  Send an initial email message, prior to study activation to all institutions’ CRA’s, 
nurses and site PI detailing the requirements, and procedures for QOL data collection, along 
with the importance of continuing timely assessments.   
 
Assigned to:  This message can be prepared by the QOL study chair together with the Data 
Management and Nursing committee leaders. 
 
Task 3.  Quarterly distribution list email message to the data management and nursing 
committees on compliance updates and challenges, reinforcing the message that QOL should 
continue to be assessed after the patient progresses or is off the study treatment.   
 
Assigned to:  Compliance reports will be prepared by the statistical office, and the email 
message will be sent by the PCOR leaders. 
 
Task 4.  Newsletters with study updates, including QOL compliance can be prepared semi-
annually for activated trials.  Sites that are doing especially well with compliance can be 
featured. 
 
Assigned to:  The QOL study Chair, the study statistician and the data management leaders 
should contribute to individual study updates.   
 
Task 5.  The IT staff is developing a forms-due calendar in Medidata/Rave to remind clinic 
staff of upcoming assessments for each patient. 
 
Assigned to:  IT Staff with oversight from the Statistical Office 
 
Task 6.  A patient form schedule is provided to the institution at the time of registration, 
indicating due dates for QOL assessments. 
 
Assigned to:  IT Staff with oversight from the Statistical Office 
 
Task 7.   A monthly forms tracking list is provided to the institutions, listing all forms due, 
including QOL, projecting 30 days in advance. 
 
Assigned to:  IT Staff with oversight from the Statistical Office 
 
Task 8.  A 14-day advance notice is sent to institutions notifying them of QOL assessments 
that will be due.  Past due notifications will be sent out 15, 30, 60 and 90 days to the data 
management CRAs with site PIs copied. 
 
Assigned to:  IT Staff with oversight from the Statistical Office 
 
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Task 9.  Delinquency reports will be generated with expectation of 80% compliance, sent to 
site PIs and CRAs.  
 
Assigned to:  IT Staff with oversight from the Statistical Office 
 
TARGET:  PATIENT ADVOCATES 
 
Task 1.  Provide advice on strategies to improve awareness of the importance of timely and 
complete QOL data (e.g., brochure, letter, message in the informed consent). 
 
Assigned to:  Disease site patient advocates. 
12. 
ASSESSMENT OF EFFECT  
12.1 
Antitumor Effect – Solid Tumors  
Response and progression will be evaluated in this study using a slightly modified version of 
the international criteria proposed by the revised Response Evaluation Criteria in Solid 
Tumors (RECIST) guideline (version 1.1).  Changes in the largest diameter (uni-dimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria.  The modification to these criteria minimizes the 
possibility that therapeutic agents that induce T cell infiltration into tumors as an early 
manifestation of anti-tumor effect could be erroneously interpreted as disease progression on 
imaging and result in premature discontinuation of a therapeutically effective agent.  
Therefore, the protocol specifies continuation of treatment in cases of radiologic 
progression at the first 8 week (+/- 7 days) CT if all of the following criteria are satisfied: 
 
• 
No decrease in performance status 
• 
No requirement for immediate alternative treatment or urgent palliative treatment 
• 
Progression limited to an increase of 40% in the sum of diameters of target lesions 
(including up to 4 new lesions added to the sum) 
• 
No more than 4 new lesions included in the sum 
 
For patients who continue treatment in the case of radiologic progression at the first 8 
week (+/- 7 days) CT: 
• 
At any subsequent CT scan patients who have stable disease as compared to the 8 
week (+/- 7 days) CT scan will be allowed to continue on study treatment. 
• 
Patients who continue treatment in the case of radiologic progression at the first 8 
week (+/- 7 days) CT, and later experience a PR or CR (as compared to baseline CT) 
will be recorded as delayed responses by the Statistics and Data Management Center. 
For patients who continue treatment in the case of radiologic progression at the first 8 
week (+/- 7 days) CT, must have repeat CT in 4 weeks (+/- 7days) to rule out further 
progression. 
 
12.1.1 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 ≥10 mm with CT scan, as ≥20 
mm by chest x-ray, or ≥10 mm with calipers by clinical exam. All tumor measurements must 
be recorded in decimal fractions of centimeters. 
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Note: Tumor lesions that are situated in a previously irradiated area will not be considered 
measurable unless progression is documented or a biopsy is obtained to confirm persistence at 
least 90 days following completion of radiation therapy. 
  
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
  
Non-measurable disease: All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are 
considered non-measurable disease. Leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pneumonitis, inflammatory breast disease, and abdominal/pelvic 
masses (identified by physical exam and not CT or MRI), are considered as non-measurable.  
Notes:  
Bone lesions: Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by CT or MRI can be considered as measurable lesions if 
the soft tissue component meets the definition of measurability described above. Blastic bone 
lesions are non-measurable. 
 
Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurability described 
above. However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions.  
 
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, and 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. 
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12.1.2 Methods for Evaluation of Measurable Disease  
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
  
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using 
calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g. for body scans), but NOT 
lung. 
  
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, subsequent 
image acquisitions should use the same type of scanner and follow the baseline imaging 
protocol as closely as possible. If possible, body scans should be performed with breath-hold 
scanning techniques. 
 
NRG Oncology will not allow PET-CT use for RECIST 1.1 response criteria.  
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation by 
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CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
 
CA-125 (Ovarian, fallopian tube and primary peritoneal cancer trials): CA125 cannot be 
used to assess response or progression in this study. If CA125 is initially above the upper 
normal limit, it must normalize for a patient to be considered in complete clinical response. 
Specific guidelines for CA-125 response (in recurrent ovarian cancer) have been published 
[JNCI 96:487-488, 2004]. In addition, the Gynecologic Cancer Intergroup has developed CA-
125 progression criteria that are to be integrated with objective tumor assessment for use only 
in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases, e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain. 
 
It is mandatory to obtain cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when measurable disease has met criteria for response or 
stable disease. This confirmation is necessary to differentiate response or stable disease versus 
progressive disease, as an effusion may be a side effect of the treatment. 
  
12.1.3 Response Criteria  
Determination of response should take into consideration all target and non-target lesions and, 
if appropriate, biomarkers. 
 
12.1.3.1  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). 
 
Note:  The protocol specifies continuation of treatment in cases of radiologic progression 
at the first 8 week (+/- 7 days) CT if all of the criteria are satisfied. 
  
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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters (i.e. the nadir) while on 
study.  
 
12.1.3.2  Evaluation of Non-Target Lesions  
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must 
be non-pathological in size (<10 mm short axis). 
  
Note: If CA-125 is initially above the upper normal limit, it must normalize for a patient to 
be considered in complete clinical response. 
  
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 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. 
  
Not evaluable (NE): When at least one non-target lesion is not evaluated at a particular 
time point. 
  
Although a clear progression of only “non-target” lesions is exceptional, the opinion of the 
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). 
  
12.1.3.3 
Evaluation of Biomarkers  
If serum CA-125 is initially above the upper normal limit, it must normalize for a patient 
to be considered in complete clinical response.  
 
Progression cannot be based upon biomarkers, including serum CA-125 and HE4 for this 
study. 
  
12.1.3.4 
Evaluation of Best Overall Response (10/22/2018) 
The best overall response is the best time point response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive disease 
the smallest sum recorded since baseline). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria in some 
circumstances. 
 
 
 
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Time Point Response for Patients with Measurable Disease at baseline (i.e., Target 
Disease) 
 
 
*See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion 
 
** In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
 
Time Point Response for Patients with only Non-Measurable Disease at 
baseline (i.e., Non-Target Disease) 
 
 
 
*See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion 
 
** ‘Non-CR/non-PD’ is preferred over ‘stable disease’ 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 
 
12.1.3.5 
Best Overall Confirmed Response (10/22/2018) 
 
 
In non-randomized trials where response is the primary endpoint, confirmation of PR and 
CR is required to ensure responses identified are not the result of measurement error.  This 
will also permit appropriate interpretation of results in the context of historical data where 
response has traditionally required confirmation in such trials. 
 
Target 
Lesions 
Non-Target 
Lesions 
Biomarker 
CA-125 
New 
Lesions* 
Time Point 
Response 
CR 
CR 
Within 
normal limits 
No 
CR 
CR 
Non-CR/Non-PD 
Any value 
No 
PR 
CR 
NE 
Any value 
No 
PR 
PR 
Non-PD or NE 
Any value 
No 
PR 
SD 
Non-PD or NE 
Any value 
No 
SD 
NE 
Non-PD 
Any value 
No 
NE 
PD 
Any 
Any value 
Yes or No 
PD 
Any 
PD** 
Any value 
Yes or No 
PD 
Any 
Any 
Any value 
Yes 
PD 
Non-Target Lesions 
Biomarker 
CA-125 
New Lesions* 
Time Point 
Response 
CR 
Within normal limits 
No 
CR 
CR 
Above normal limits 
No 
Non-CR/non-PD* 
Non-CR/non-PD 
Any value 
No 
Non-CR/non-PD* 
NE 
Any value 
No 
NE 
Unequivocal PD 
Any value 
Yes or No 
PD 
Any 
Any value 
Yes 
PD 
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However, in all other circumstances, i.e. in randomized trials (phase II or III) or studies 
where stable disease or progression are the primary endpoints, confirmation of response is 
not required since it will not add value to the interpretation of results. 
 
 
Time Point Response 
First time point 
Time Point 
Response 
Subsequent time 
point 
BEST overall confirmed 
response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR* 
CR 
SD 
SD provided minimum 
criteria for SD 
duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum 
criteria for SD 
duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum 
criteria for SD 
duration met, 
otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum 
criteria for SD 
duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum 
criteria for SD 
duration met, 
otherwise, NE 
NE 
NE 
NE 
 
 
*If a CR is truly met at first time point, then any disease seen at a subsequent time point, 
even disease meeting PR criteria relative to baseline, makes the disease PD at that point 
(since disease must have reappeared after CR).  However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact 
the patient had PR or SD, not CR at the first time point. Under these circumstances, the 
original CR should be changed to PR or SD and the best response is PR or SD. 
 
In non-randomized trials where response is part of the primary endpoint, confirmation 
of CR or PR is needed to deem either one the “best overall response.”   Responses (CR 
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and PR) require confirmation at greater than or equal to 4 weeks from initial 
documentation. 
 
For this study, the minimum criteria for SD duration is 8 weeks. 
 
Patients with a global deterioration of health status requiring discontinuation of treatment 
or die without objective evidence of disease progression at that time should be reported to 
be off study treatment due to “symptomatic deterioration.”  Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
 
12.1.4 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). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
date of study entry, including the baseline measurements. 
 
12.1.5 Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from study entry to time of 
progression or death, whichever occurs first. 
 
12.1.6 Survival 
Survival is defined as the duration of time from study entry to time of death or the date of last 
contact. 
 
13. 
DATA AND RECORDS 
13.1 
Data Management/Collection (29-JUN-2020) 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
 
Requirements to access Rave via iMedidata: 
• A valid CTEP-IAM account; and  
• Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
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o Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) 
or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-
mail from iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password and 
click on the accept link in the upper right-corner of the iMedidata page. Site staff will not be 
able to access the study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings) and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen. If an 
eLearning is required and has not yet been taken, the link to the eLearning will appear under 
the study name in iMedidata instead of the Rave EDC link; once the successful completion of 
the eLearning has been recorded, access to the study in Rave will be granted, and a Rave EDC 
link will display under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website in the Data Management section under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). Additional information on 
iMedidata/Rave is available on the CTSU members’ website in the Data Management > Rave 
section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or 
by e-mail at ctsucontact@westat.com.   
 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The 
Rave Home section displays a table providing summary counts of Total Delinquencies 
and Total Queries. DQP Queries, DQP Delinquent Forms and the DQP Reports 
modules are available to access details and reports of unanswered queries, delinquent 
forms, and timeliness reports. Review the DQP modules on a regular basis to manage 
specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the 
CTSU website. Staff that have Rave study access can access the Rave study data using 
a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries, and DQP Delinquent Forms modules. 
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Note: Some Rave protocols may not have delinquent form details or reports specified on the 
DQP. A protocol must have the Calendar functionality implemented in Rave by the Lead 
Protocol Organization for delinquent form details and reports to be available on the DQP. Site 
staff should contact the LPO Data Manager for their protocol regarding questions about Rave 
Calendaring functionality.   
 
13.2 
NRG Data Management Forms 
Refer to the CTSU member website for the table of Required Forms and Materials 
 
13.3 
Summary of Data Submission 
Adverse event data collection and reporting, which are required as part of every clinical trial, 
are done to ensure the safety of patients enrolled in the studies as well as those who will enroll 
in future studies using similar agents. Adverse events are reported in a routine manner at 
scheduled times during the trial using Medidata Rave®. Additionally, certain adverse events 
must be reported in an expedited manner for more timely monitoring of patient safety and 
care. See Section 7.5.2 for information about expedited and routine reporting.   
 
13.4 
Global Reporting/Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis, either by FTP burst of data or via the CDS web application.  
Reports are due January 31, April 30, July 31, and October 31.  Instructions for submitting 
data using the CDUS can be found on the CTEP Web site 
(http://ctep.cancer.gov/reporting/cdus.html) 
 
14. 
STATISTICAL CONSIDERATIONS 
14.1 
Study Design 
This study consists of four components which will be conducted in sequence: 
a. Stage 1 of a safety lead-in 
b. Stage 2 of a safety lead-in 
c. A randomized phase II study 
d. A randomized phase III study 
 
The first component is a 2-part safety lead-in trial in which the frequency of dose limiting 
toxicities in the experimental regimens will be evaluated.  If the DLT rate on the experimental 
regimens is deemed acceptable, then the second component, which provides a randomized 
phase II evaluation of the study regimens, will be initiated.  Specifically, the phase II 
component of this study will assess whether one or both of the experimental regimens 
increase the duration of progression-free survival adequately to warrant a phase III evaluation.  
The subjects enrolled onto earlier components of this study will be included in the analyses of 
subsequent components.  That is, the subjects enrolled into the safety lead-in will be included 
in the analysis of the phase II endpoints and subjects enrolled during the safety lead-in or the 
phase II component will be included in the analyses of the phase III objectives.  This approach 
is intended to reduce the number of patients required when compared to the strategy of 
conducting three independent, sequential trials with the same objectives. 
 
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Treatment Randomization Procedure 
Patients are electronically registered and enrolled onto the study via an electronic, web-based 
procedure. This electronic process also assigns a study treatment to each patient who is 
successfully enrolled.  The treatment allocation procedure will allot approximately 1 patient to 
each available experimental regimen for each patient allocated to PLD+Bev (reference 
regimen).  
 
The assigned treatment will be sequentially allotted from a pre-allocated list of treatments that 
have been randomly permuted within blocks.  The assigned treatment will remain concealed 
until the patient’s enrollment procedure has been successfully completed.  The same treatment 
allocation procedure will be used during the second stage of the safety lead-in, as well as the 
phase II and phase III components of this study.  While there is a specific sample size 
specified for each of these study components, the randomization process will not be 
constrained to randomize any specific number of individuals to each regimen at the end of 
each stage.  
 
14.2 
Study Endpoints 
 
 
Safety lead-in (stage 1 and 2) 
Dose limiting toxicity (DLT) following cycle 1 of experimental regimens.    
 
Definition of a Dose-Limiting Toxicity (DLT) 
For the safety lead-in components of this study a DLT is defined as: 
• Any Grade 4 immune related adverse event 
• Any >= grade 3 colitis 
• Any Grade 3 or 4 noninfectious pneumonitis (irrespective of duration) 
• Any Grade 2 noninfectious pneumonitis that does not resolve to <= grade 1 within 7 
days of the initiation of maximal supportive care 
• Liver transaminase elevation > 8 x ULN or total bilirubin > 5 x ULN 
• Any >= grade 3 non immune related adverse event except for the exclusion list below 
• Delay of initiation of cycle 2 of greater than 3 weeks due to failure to recover 
AE/failure to meet protocol directed treatment parameters for restart after management 
of AE 
• Any treatment related death 
 
A DLT does not include: 
• Grade 3 fatigue, anorexia or constipation lasting less than one week 
• Grade 3 endocrine disorders (thyroid, pituitary, and/or adrenal insufficiency) that 
is managed with or without systemic corticosteroid therapy and/or hormone 
replace therapy and the subject is asymptomatic 
• Grade 3 infusion related reaction 
• Grade 3 or 4 neutropenia (that is not associated with fever or infection) lasting <=7 
days 
• Grade 3 or 4 lymphopenia 
• Grade 3 thrombocytopenia that is not associated with clinically significant 
bleeding 
• Isolated grade 3 electrolyte abnormalities that are not associated with clinical signs 
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or symptoms and are reversed with appropriate maximal medical intervention 
• Grade 3 hypertension 
 
Phase II and Phase III Study 
Progression-Free survival (PFS), defined as time from the date of study enrollment to the 
investigator determined date of progression (see Section 12.1 for RECIST v1.1 definition of 
progression), or death due to any cause, whichever occurs first.  For individuals who are alive 
and progression free, the censored time at risk will be defined as the time from the study 
enrollment date to the date of the patient’s last radiographic disease assessment. 
 
The objective tumor response rate is defined as the proportion of patients with complete or 
partial tumor response by RECIST 1.1. (10/16/2017) 
 
Phase III Study 
Overall survival (OS), defined as the time from the date of study enrollment to the date of 
death regardless of the cause.  For those individuals, who have no death reported at the time of 
the analysis, the time at risk of death will be assessed from the date of study enrollment to the 
date that the patient was last contacted and known to be alive. 
 
14.3 
Primary Objectives Study Design 
14.3.1 Primary Hypotheses and Type 1 Error Allocation (Phase III) 
 
The null hypotheses of therapeutic efficacy for the phase III component of this study are:  
 
H1,os: The hazard of death among women in the target population treated with PLD + 
atezolizumab is equivalent to those treated with PLD + bevacizumab. 
 
H2,os: The hazard of death among women in the target population treated with PLD + 
bevacizumab + atezolizumab is equivalent to those treated with PLD + bevacizumab. 
 
H3,os: The hazard of death among women in the target population treated with PLD + 
atezolizumab is equivalent to those treated with PLD + bevacizumab + atezolizumab. 
 
H1,pfs: The hazard of first progression or death among women in the target population treated 
with PLD + atezolizumab is equivalent to those treated with PLD + bevacizumab. 
H2,pfs: The hazard of first progression or death among women in the target population treated 
with PLD + bevacizumab + atezolizumab is equivalent to those treated with PLD + 
bevacizumab. 
 
H3,pfs: The hazard of first progression or death among women in the target population treated 
with PLD + atezolizumab is equivalent to those treated with PLD + bevacizumab + 
atezolizumab. 
 
Note: Arm 1 (PLD and atezolizumab) was permanently closed to accrual with amendment 11 
as the planned interim analysis for this regimen crossed the futility boundary for early 
termination, which was based on overall survival compared to the reference regimen of PLD 
and bevacizumab (Arm 3). The hypotheses H1,os, H1,pfs, H3,os, and H3,pfs will not be open for 
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further testing since the regimen PLD + atezolizumab is deemed futile (that is, not likely to be 
declared active against the reference regimen). (24-FEB-2021) 
 
Type I error allocation (24-FEB-2021) 
The strategy for controlling the overall type I error for these six hypotheses is to allocate 
0.0124 type I error (1-sided) to H1,os, and 0.0001 (1-sided) to H1,pfs (0.0124 + 0.0001 = 
0.0125).  Likewise, 0.0124 and 0.0001 type I errors will be allocated to H2,os and H2,pfs, 
respectively, so the type 1 error allocated to all four of these hypotheses is 0.025 
(=0.0125+0.0125, 1-sided).  These type I errors will not be redistributed in the event that one 
of the experimental regimens are dropped following the phase II component of this trial.  
Moreover, the type I errors for H1,os  and H2,os include the type I errors spent for interim 
analyses (H1,pfs and H2,pfs will not be assessed at the interim analysis). Dropping the PLD + 
atezolizumab regimen after the interim analysis does not change the allocation of alpha. The 
original specifications listed above remain. 
 
If and only if both H1,os and H2,os are rejected, then the type I error allocated to these 2 
hypotheses will be “passed-on” to H3,os.  In this case the type I error allocated to this 
hypothesis will be 0.0248 (=0.0124+0.0124, 1-sided).  Likewise, if both H1,pfs and H2,pfs are 
rejected, then type I error allocated to H3,pfs will be 0.0002 (=0.0001+0.0001, sided). This 
allocation is not relevant if an arm is dropped for futility at an interim analysis. 
 
14.3.2 Power and Sample Size 
 
Safety lead-in (Stage 1 and 2) 
 
The safety lead-in will consist of 2 stages.  During the first stage, at least 8 individuals will be 
assigned (not randomly assigned) to receive the PLD + atezolizumab regimen.  The first 8 
individuals allocated to and treated with PLD + atezolizumab will form the basis of a safety 
evaluation.  If 2 or more of these individuals experience a dose-limiting toxicity (DLT) then 
enrollment will be stopped and the doses and schedule will be reconsidered.  Otherwise, the 
regimen will be considered sufficiently safe to continue onto the second stage of the safety 
lead-in.   
 
During the second stage of the safety lead-in the treatment allocation procedure will begin to 
allocate all three of the study regimens with nearly equal frequency.  The second stage of the 
safety lead-in will continue until 8 individuals are randomly allocated to and treated with PLD 
+ bevacizumab + atezolizumab.  These 8 individuals will form the sample for assessing the 
safety of the PLD + bevacizumab + atezolizumab regimen.  If two or more of these 
individuals experience a DLT, then consideration will be given to adjusting the 
doses/schedule or discontinuing the allocation of this regimen to future enrollees. 
 
If the true probability of a DLT is no larger than 0.10, then this criterion provides at least 81% 
chance of classifying the regimen as acceptable.  On the other hand, if the true probability of a 
DLT is 0.35 then this criterion provides an 83% chance of declaring the regimen as 
unacceptable.   
 
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In the event that 2 individuals experience confirmed DLTs before the target enrollment for the 
lead-in is attained, then the outcome for this stage of the study will be considered ineluctable 
and accrual to that experimental regimen will be stopped. 
 
The enrollment during the lead-in component of this trial will be limited to selected 
institutions.  The accrual rate during this period is expected to be about 5 patients per month.  
Therefore the first stage of the safety lead-in is expected to require 1.5 months following a 
brief start-up period.  If the PLD + atezolizumab regimen is deemed safe, then the second 
stage of the safety lead-in is expected to require an additional 3-4 months of enrollment. 
 
Phase II Study 
The target enrollment for the phase II component of the study is 80 additional patients 
allocated to the reference regimen and each of the experimental regimens selected following 
the safety lead-in component of this study (see target accrual table above).  That is, if both of 
the experimental regimens are selected following the safety lead-in, then there will be 
approximately 88 patients randomly allocated to the PLD + bevacizumab, PLD + 
atezolizumab and PLD + bevacizumab +atezolizumab regimens, respectively at the end of the 
phase II study including those enrolled during the stage 2 safety lead-in.  These patients will 
form the basis of the phase II futility assessment.  Once the targeted number of patients has 
been enrolled, enrollment will be suspended in order to permit the PFS data to mature for the 
post-phase II analysis. The purpose of these analyses is to restrict the number of patients 
treated with experimental regimens that exhibit insufficient evidence of activity to warrant a 
phase III evaluation at this time. 
 
The enrollment will be opened group wide for this component of the study and the expected 
annual accrual rate for this component of the study is 168 patients.  Therefore, this component 
of the study is expected to require an additional 17 months of accrual.  
 
When at least 110 patients who were randomly allocated to receive the reference regimen or 
the PLD + bevacizumab + atezolizumab have reported either progression or death, the PFS 
relative hazard for these two regimens will be estimated.  A proportional hazards (PH) model 
will be used to estimate the relative hazards, which is described below.  The PLD + 
bevacizumab + atezolizumab regimen will be considered sufficiently active to warrant phase 
III evaluation if the estimated relative hazards indicates at least a 21.7% reduction (HRPFS < 
0.783) in the estimated PFS hazard (compared to the reference regimen) at this time.  If the 
true PFS hazard for this regimen is equivalent to the reference regimen (null hypothesis is 
true), then there is a 90% chance that this regimen will be deemed insufficiently active to 
warrant a phase III evaluation, based on this criterion.  On the other hand, if this regimen truly 
reduces the PFS hazard 37.5% (HR=0.625) in the target population, then this sample size 
provides a 88% chance of declaring the PLD + bevacizumab + atezolizumab regimen 
sufficiently active to advance to the phase III component of the study.  If the PLD + 
bevacizumab + atezolizumab regimen is selected, then the PLD + atezolizumab regimen will 
also be selected for phase III evaluation.  This automatic selection of the experimental doublet 
is necessary because the triplet regimen may need to ultimately demonstrate definitive 
superiority over both the reference regimen and the experimental doublet regimen in the phase 
III study (see below) in order to be declared the overall preferred regimen.   
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On the other hand, if the PLD + bevacizumab + atezolizumab regimen is not selected, then the 
PFS hazard of PLD + atezolizumab regimen will be compared to the reference regimen.  This 
regimen will be considered sufficiently active to warrant phase III evaluation if it exhibits at 
least a 21.7% reduction (HRPFS < 0.783) in the estimated PFS hazard (compared to the 
reference regimen) at this time.  In this case, the probabilities of selecting (not selecting) this 
regimen are similar to those for the experimental triplet that are provided above. For the 
purposes of calculating these selection probabilities, the variance of the log hazard ratio is 
estimated assuming the null hypothesis is true.   
 
Proportional Hazards Model for Estimating Relative Hazards 
A proportional hazards (PH) model (Cox, 1972) will be used to estimate the relative hazards.  
All of the individuals who have been enrolled during stage 2 of the safety lead-in, the phase II 
component and the phase III components will be included in these analyses regardless of their 
eligibility status, or compliance with their assigned study treatment.  The proportional hazards 
model will not be stratified.  
 
Phase III Study (24-FEB-2021) 
 
If at least one experimental regimen is deemed sufficiently active following the phase II study, 
then 72 additional patients will be enrolled and designated to receive the reference regimen 
and a nearly equal number of individuals to each of the experimental regimens that were 
selected following the phase II component of this study in order to evaluate the phase III 
objectives (the treatment randomization procedure is describe above).  Since the expected 
annual accrual rate is 168 patients, the enrollment period for the phase III component is 
expected to require approximately 15 months if both experimental regimens are selected.  
 
Hypotheses: H1,os and H2,os 
When there are at least 128 deaths reported among those patients randomly allocated to the 
reference regimen, this study will be considered sufficiently mature for evaluating the 
hypotheses H1,os and H2,os. The type I error will be set to 0.0124 (one-tail, see Type I Error 
Allocation above) for each of these two hypotheses including the type I error spent for interim 
analyses.    If an experimental regimen truly reduces the hazard of death 37.5% (HR=0.625) 
then the expected number of deaths at this time among those randomly allocated to that 
experimental regimen is 108.  This sample size (128+108=236 deaths for each pairwise 
comparison) provides approximately 91% power for a true hazard ratio of 0.625 (80% power 
for HR=0.667).  The median duration of survival for women from the target population and 
treated with PLD+Bev is 14 months.  Assuming proportional hazards with exponential 
survival function, a HR=0.625 is comparable to increasing the median duration of survival by 
8.4 (median 14 to median=22.4) months.  All of the subjects enrolled, regardless of the 
whether they were enrolled during the safety the stage 2 lead-in, phase II or phase III 
components will be included in these final analysis. These power estimates do not account for 
the chance that a treatment is dropped for safety concerns during the safety lead-in or 
following the phase II component for exhibiting insufficient activity to warrant a phase III 
evaluation.  Based on simulation where OS and PFS times were generated using a normal 
copula with correlation 0.70 between event times, it is estimated that the power for H1,os, is 
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0.77, accounting for the chance of dropping an active treatment at the end of the phase II 
study, if the true PFS and OS hazard ratios are 0.625 (likewise for H2,os).  
 
Hypothesis: H3,os 
See section 14.3.1 regarding H3,OS 
In the event that both experimental regimens are selected following the phase II component of 
this study and both of these regimens demonstrate statistical superiority over the reference 
regimen, then the death rates of the two experimental regimens will be compared to each other 
(H3,os).  The study will be considered sufficiently mature for an evaluation of this hypothesis 
when there are 195 deaths reported among those patients who were enrolled and allocated to 
either of the experimental regimens.  The type I error for this comparison will be set to 0.0248 
(one-tail).  This sample size provides 90% power when the triplet regimen reduces the death 
rate 37.5% (HR=0.625) relative to the experimental doublet regimen (80% power for 
HR=0.667), not accounting for the possibility of dropping an active regimen following the 
phase II component or for the prerequisite for rejecting H1,os  and H2,os  It is possible for the 
data for this hypothesis to mature before the data mature for H1,os and H2,os.  In this case, H3,os 
will not be assessed until after the data for H1,os and H2,os have matured. 
 
Hypotheses H1,pfs and H2,pfs 
See section 14.3.1 regarding H1,pfs. The hypotheses H1,pfs and H2,pfs will not be assessed until 
the study has sufficiently matured to assess H1,os and H2,os.  It is anticipated that approximately 
90% of the patients enrolled onto the study will have experienced either a progression or death 
event at this time.  Therefore the expected number of events available for each pairwise 
treatment comparison of H1,pfs and H2,pfs is approximately 280.   With this number of events, 
each pairwise comparison has 90% power for a true hazard ratio of 0.55 when type I error is 
0.0001 (1-sided), not accounting for the possibility of dropping an active regimen at the end of 
the phase II component. 
 
Hypotheses H3,pfs 
See section 14.3.1 regarding H3,pfs. The hypothesis H3,pfs will not be assessed until the study is 
sufficiently mature to assess H3,os.  This hypothesis will not be assessed unless H1,pfs and H2,pfs 
have been rejected.   
 
Logrank Procedure for Final Analyses of the Phase III Objectives 
A logrank test will be used to evaluate the null hypotheses for the phase III objectives.  The 
logrank procedures will involve all of the patients who were enrolled onto the trial during 
stage 2 of the safety lead-in, phase II or phase III components.   Patients will be grouped by 
their randomly assigned treatment and included in the analysis regardless of their eligibility or 
compliance with their assigned study treatment. The logrank procedures will not be stratified.  
The individuals who were enrolled during stage 1 of the safety lead-in will not be included in 
the testing of these hypotheses, since these individuals do not have their study treatment 
randomly assigned. 
 
14.4 
Study Monitoring of Primary Objectives (24-FEB-2021) 
As described in previous sections, there are assessments of safety following stages 1 and 2 of 
the safety lead-in and an assessment of therapeutic futility following the phase II study 
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component.  Additionally, an interim analysis will be performed when at least half of the 
number of deaths (128/2=64 deaths among those allocated to the reference regimen) required 
for the final analysis has occurred.  The interim analysis will include an assessment of both 
futility and superiority for hypotheses H1,os and H2,os.   O’Brien and Fleming-like (β(t)=2-
2Φ(Zβ/2/√t; Lan et al., 1989) Type I and Type II error spending functions (non-binding) will 
be used for assessing futility and efficacy.  These functions require that the percent of 
information time be specified at the time of the interim analyses.  The percent information 
time will be calculated as the proportion of deaths reported at the time of the interim analyses 
among those allocated to the reference regimen relative to the required number for the final 
analysis.  The previously described logrank statistic will be calculated and compared to these 
boundaries.  If the logrank statistic does not exceed the futility boundary for H1,os (or H2,os) 
then consideration will be given to stop allocating the PLD + Atezolizumab (or PLD + 
bevacizumab + atezolizumab) regimen to future enrollees and concluding that it is unlikely 
that the experimental regimen extends overall survival compared to the reference regimen. 
These boundaries will restrict the treatment hazard ratio (experimental: reference) for OS to 
be less than (approximately) 0.90 at the time of the interim analysis.    
 
The interim analysis will also include estimates of the hazard ratios and the corresponding 
confidence intervals for the experimental regimen relative to the reference regimen, as well as 
Kaplan-Meier (Kaplan and Meier, 1958) estimates of the survivorship function for each 
treatment group.   
 
The results of interim analyses are reviewed by the NRG Oncology Data Monitoring 
Committee (DMC).  This DMC meets semi-annually to review the progress of all NRG 
Oncology ongoing randomized phase II or III trials.  The DMC can also schedule additional 
meetings on an as-needed basis.  The dates for the semi-annual DMC meetings are 
administratively scheduled without any knowledge of the study results.  Approximately eight 
weeks prior to its scheduled meetings, the study database is locked in order to prepare a semi-
annual study report.  This study report includes summarizes of accrual and adverse event data.  
If the prerequisite number of deaths for a scheduled interim analysis has been attained, a 
report summarizing the results of the interim analysis is also prepared and presented to the 
DMC at their upcoming meeting.  The actual decision to terminate accrual or to release study 
results includes consideration of toxicities, treatment compliance, as well as results from 
external studies. 
 
 
14.5 
Accrual/Study Duration Considerations (24-FEB-2021) 
 
During the safety lead-in, accrual will be limited to institutions that have experience running 
multi-center phase I/II studies.  The expected accrual rate during this component of the study 
is 4 patients per month.  Therefore, the first and second stages of accrual are expected to 
require about 1.5 and 4 months after a brief start-up period, respectively, to complete accrual.  
If the results are not ineluctable at the time when the accrual has completed, then a short 
interruption may be needed until the last patient enrolled is treated and evaluated.  
 
 
Enrollment during the phase II and phase III components will be opened to all eligible 
institutions.  Accrual rate is expected to be about 168 patients per year.  Therefore, the accrual 
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periods for the phase II and the phase III components are anticipated to be 17 and 15 months, 
respectively.   A 12- to 18-month post-accrual follow-up period is expected. 
 
Interim Analysis Results and Implications to the Study Accrual Target and Duration 
 
An interim analysis was conducted when 64 deaths were observed in the reference regimen 
(PLD + bevacizumab). This corresponded to ½ the information time. Tests for efficacy and 
futility were conducted on the two experimental regimens as described above. The PLD+ 
atezolizumab regimen (Arm 1) exceeded the futility boundary (i.e. was greater than ─0.435). 
The DMC recommendation for dropping the PLD+ atezolizumab regimen was accepted. The 
study will proceed as a two-arm study with equal randomization to each arm (1:1) until about 
72 phase III patients are accrued to the reference regimen (160 patients in total for the 
reference regimen). 
 
As of the study suspension, there were 124, 115, and 116 patients enrolled to Arms 1, 2, and 
3, respectively. The study needs 160 patients in Arms 2 and 3. The remaining number of 
patients needed to finish accrual is 89. The study will have completed accrual when a total of 
444 patients are enrolled. The anticipated time it will take to complete recruitment is 6.4 
months after study reactivation. 
 
The final analysis will occur when 128 deaths are seen on Arm 3 (the reference regimen) as 
stated above. Hypotheses H2,os and H2,pfs will be tested at that time in accordance with the 
original Phase III procedures. 
 
14.6 
Secondary or Exploratory Endpoints (including correlative science aims) 
14.6.1 Secondary Hypotheses and Endpoints (30-OCT-2020 ) (08-JAN-2021) 
Phase II and Phase III  
Safety endpoints: Frequency and severity of adverse events as classified and graded according 
to Common Terminology Criteria for Adverse Events (CTCAE) assessed among those 
patients who initiate their randomized study treatment. (03/19/2018) 
 
Efficacy Endpoint: The objective tumor response rate is defined as the proportion of patients 
with complete or partial tumor response by RECIST 1.1. (10/16/2017)  
The hazard ratios of treatment to reference regimen for death and progression (OS and PFS) 
will be estimated with a Cox proportional hazards model without stratification variables for 
both the phase II and III components of the trial. PFS HR will be a primary endpoint for the 
phase II study. In addition, confidence intervals and KM plots will be provided. Trial stage 
will be examined in an exploratory manner to see if there is a trial stage influence on these 
endpoints. 
In addition to the formal analyses of the integrated biomarker, we will examine through 
exploratory analyses response, PFS, and OS by PDL1 (+) status as defined with IC0, IC1/2/3, 
and IC 2/3. HR estimates with corresponding 95% CI, Chi-square tests, and odds ratio 
estimates will be reported.  
It is common to analyze survival endpoints with log-rank statistics and Cox proportional 
hazards models. For translational research endpoints, it is common to dichotomize continuous 
marker values to ease interpretation of results. However, analysis as a continuous variable is 
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done frequently with care to note influential cases. With large sample sizes, logistic regression 
often yields satisfactory results when examining tumor response. For TR endpoints obtained 
after randomization, we propose using landmark analyses when doing survival analyses as 
well looking at changes of the marker over time (simple paired t-tests for example). 
Patient Reported Outcomes:  Main endpoint is disease-related symptoms as assessed by the 
NFOSI-DRS; Exploratory PROs include measurement of treatment side effects, fatigue, 
function/well-being, and health status. 
 
14.6.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
Efficacy 
The objective tumor response rate will be tabulated by treatment group, and 95% confidence 
intervals will be presented using Wilson’s Score Method.  Treatment arms will be compared 
using a likelihood ratio chi-square test. (10/16/2017) 
 
Adverse Events 
 
The maximum grade of each adverse event (AE) by system organ class and CTC 4.0 specific 
term will be tabulated for those individuals who at least initiate study treatment.  The number 
and percent of individuals will be tabulated by the maximum grade of their AE.  No specific 
hypothesis test is pre-specified. 
 
14.6.3  Integrated Biomarker – PD-L1 (30-OCT-2020) (08-JAN-2021) (24-FEB-2021) 
 
There is interest in examining the relative impact of the experimental therapies on OS 
compared to the control regimen within the patients who express PD-L1 (that is those patients 
considered to be PD-L1 positive; PD-L1+). The definition of PD-L1 expression within 
patients is given in the following paragraph: 
 
PD-L1 testing will be performed with the FDA approved Ventana PD-L1 (SP142) assay kit 
which uses the OptiView DAB IHC detection kit and OptiView Amplification kit on a 
Ventana BenchMark Ultra Instrument along with the specified antibody. PD-L1 expression 
within tumor tissue will be assessed using (n=6) 4 um sections cut within a 60 day period 
from the FFPE block. PD-L1 positive status is defined as ≥ 1% staining of tumor-infiltrating 
immune cells as a percentage of tumor area using the SP142 Ventana assay. Exploratory PD-
L1 positive status is defined as > 5% staining of tumor-infiltrating immune cells as a 
percentage of tumor area using the Ventana SP142 assay. 
 
The study is not prospectively stratified before randomization by the patient’s PD-L1 level of 
expression, so an imbalance of the treatment regimen by PD-L1 expression is possible but 
highly improbable with the sample sizes to be seen in the phase II/III study. Therefore, the 
odds of randomization of the treatments in this subset should be very close to the wider 
sample in the entire clinical trial (e.g. randomization in a 1:1:1 fashion or 1:1 in the case that 
one treatment arm is dropped). What is unknown is the proportion of patients who are PD-
L1+ as well as the prognostic or predictive impact of PD-L1 on the hazard of death. The 
question of the proportion of patients who are PD-L1+ translates into the sample size for this 
subset analysis. The statistical power of the study for the subset analysis is directly tied to the 
total number of deaths seen within the subset, and that number is closely related to the sample 
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size. Because the sample size is largely unknown, it will be difficult to predict the power of 
the subset analysis based on this factor alone. 
 
In addition to the sample size factor lies an additional complication of the unknown 
prognostic or predictive effects of PD-L1. For example, PD-L1 may increase or decrease the 
hazard of death, so the total number of deaths within the PD-L1 + group can be proportionally 
larger or smaller than the proportion of patients who do not express PD-L1. In the simplest 
case, we can assume that PD-L1 expression has no prognostic nor predictive effect on OS. 
Suppose then, for instance, that 50% of patients express PD-L1. Since the final analysis will 
be triggered when 344 to 384 deaths are observed in the entire study (when the experimental 
regimens are active or inactive respectively), the total number of deaths observed in the subset 
would be expected to be between 172 to 192 (and 118 to 128 per treatment comparison when 
the regimens are active or not, respectively). To be clear, patients will be classified as PD-
L1(+) if they express the biomarker to a greater level. Patients who express less biomarker 
will be classified as PD-L1(-).  
 
To be assured that a subset of patients is not driving the significance of a test for treatment 
activity (in the case of a positive study), the alpha spent on the primary hypotheses will be 
forwarded to subset analyses based on whether patients are PD-L1(+) or (-). The alpha will be 
split equally on each subset only if the primary hypothesis is rejected. The significance of 
treatment effect will be examined with a log-rank test. These tests will be underpowered but 
may offer insight into differences in treatment efficacy based on this biomarker level. 
Approximately 0.0124/2 will be spent on each subset if the regimen of interest rejects the null 
hypothesis for overall survival. A similar procedure will be done with PFS where 0.0001 is 
split. If both regimens are considered active, then a test of the regimens against the reference 
will not be done. Instead, this test will wait to compare the two experimental regimens, and 
only if that test is significant (H3OS is rejected).  
 
To characterize the power of this part of the study, we used a proportional hazards model as 
shown below.  
 
The hazard rate is defined through the following function: 
 
𝜆𝜆= exp {𝛽𝛽0 + 𝛽𝛽1𝑋𝑋𝑡𝑡+ 𝛽𝛽2𝑋𝑋𝑏𝑏+ 𝛽𝛽3𝑋𝑋𝑡𝑡∙𝑋𝑋𝑏𝑏} 
 
where 𝑋𝑋𝑡𝑡 is the treatment indicator, 𝑋𝑋𝑏𝑏 is the biomarker value which is 1 if the patient is PD-
L1(+) and zero otherwise, and 𝑋𝑋𝑡𝑡∙𝑋𝑋𝑏𝑏 is the interaction term between the treatment and 
biomarker values. If a patient is on the experimental regimen, 𝑋𝑋𝑡𝑡= 1 and 0 otherwise. The 
𝛽𝛽′𝑠𝑠 are the log HR values. See the table below for various parameter settings. For sake of 
providing an example, we will assume the analysis occurred when 128 deaths are observed on 
the reference regimen. Simulations were conducted assuming exponential survival times. The 
results were obtained through simulation of 10,000 runs using SAS’ proc phreg.  
 
 
 
 
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Row 
HR 
Rx 
HR 
Bio 
HR 
Rx*Bio 
P(Bio(+)) 
(%) 
𝐻𝐻𝐻𝐻
෢ 
Power 
Rx 
Power 
Bio(-) 
Power 
Bio(+) 
1 
1.000 1.000 
1.000 
10 1.013 
1.05 
0.51 
0.04 
2 
1.000 1.000 
1.000 
30 1.013 
1.00 
0.27 
0.13 
3 
1.000 1.000 
1.000 
50 1.012 
0.93 
0.22 
0.13 
4 
0.625 1.000 
1.000 
10 0.633 
90.72 
80.17 
6.56 
5 
0.625 1.000 
1.000 
30 0.634 
91.26 
66.54 
25.00 
6 
0.625 1.000 
1.000 
50 0.634 
90.37 
47.12 
47.59 
7 
1.000 1.000 
0.625 
10 0.965 
2.52 
0.50 
0.40 
8 
1.000 1.000 
0.625 
30 0.879 
11.08 
0.54 
6.86 
9 
1.000 1.000 
0.625 
50 0.802 
30.65 
0.55 
25.31 
10 
1.000 1.000 
0.400 
10 0.923 
5.54 
0.52 
2.56 
11 
1.000 1.000 
0.400 
30 0.775 
39.96 
0.54 
38.32 
12 
1.000 1.000 
0.400 
50 0.653 
86.40 
0.53 
86.01 
 
The column titled HR Rx is the treatment hazard ratio, HR Bio is the hazard ratio associated 
with the biomarker (often used when prognostic), and the HR Rx*Bio is the hazard ratio for 
the interaction. This hazard ratio can also be defined as the hazard ratio of treatment to 
reference among PD-L1(+) patients divided by the hazard ratio of treatment to reference 
among PD-L1(-) patients. The column titled 𝐻𝐻𝐻𝐻
෢ is an estimate of the apparent hazard ratio for 
the treatment effect when the biomarker is ignored (marginal HR). The value is the mean of 
10,000 cases. Rows 1 – 3 show the power of the procedure when the null hypothesis is true 
and there are no prognostic effects or interactions with the biomarker. The power for the 
treatment effect is within 1.24%, and the power of the subset analyses are always bounded 
above by the power of the treatment effect (i.e. Power Rx). Rows 4 – 6 show the power of the 
procedures when the treatment is equally effective across both strata of biomarkers, and the 
biomarker has no influence on survival. The power of the treatment effect is about 90% as 
designed. As the proportion of patients with PD-L1(+) increases, the power of the test within 
that subset increases as well. Rows 7 – 12 give examples when the treatment is ineffective in 
the PD-L1(-) patients but adequately or substantially effective in the PD-L1(+) patients. When 
the HR is 0.625 in the PD-L1 (+) patients only, the power of the treatment effect runs from 
3% to 31% as the proportion moves from 10% to 50% of the population. In this instance, the 
study is not adequately powered to detect this effect. If there is a strong effect in the PD-L1(+) 
group (HR=0.4), then the subset can drive the primary hypothesis to reject Ho. This would 
likely be followed by a rejection of Ho in the subset where the treatment is effective (but not 
in the other group). 
 
In summary, the procedure will limit the probability of declaring the regimen active to the 
advertised level when the null hypothesis is true and will yield sufficient power to detect 
treatment activity when PD-L1 is not predictive. In these cases, the power of the subset 
analysis is heavily dependent on the sample size and typically underpowered. When PD-L1 is 
predictive (and shows inactivity in one group), then the power of the entire study as well as 
the subset analyses are underpowered unless the HR is of such a magnitude as to drive the 
study. In the latter case, a substantial proportion must be PD-L1 (+), in which case the 
decision rules should be able to correctly identify the active cohorts. 
 
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We will define PD-L1(+) patients as those with IC1/2/3 for the analysis described above.  
 
14.6.4 Patient reported outcome (PROs) 
The analyses of PROs described here are not intended to be used for regulatory drug approval.  
These analyses are for research purposes. The primary objective of this component of the 
study is to assess patient-reported scores of disease-related symptoms (DRS) among the study 
treatments.  The primary measure for symptoms is the NFOSI-DRS-P (Disease Related 
Symptoms – Physical), which is a 9-item PRO.  The DRS-P score for the ith patient-
assessment is calculated as  
 
where δij is equal to 1 when the jth item has a valid response, otherwise it is equal to 0, sij is the 
response score of the jth item and M is the number of items in the subscale.  The response 
score for each item ranges from 0 to 4, where higher values indicate preferred states.  The 
DRS-P score for a particular patient-assessment time is considered valid if the patient 
provides valid responses to at least 5 of the subscale items, otherwise it is considered 
incomplete and, for the purposes of analyses, it is treated as if it is missing.   
 
A repeated measures model will be used to estimate and compare the mean DRS-P scores for 
the treatment groups.  Model covariates will include the patients’ randomly assigned study 
treatment, age at enrollment onto the study, initial performance status, pre-treatment DRS-P 
score, assessment time and treatment-by-time interaction.  The primary analyses will include 
only those treatments selected at the end of the phase II study and all of the patients assigned 
to one of these treatments during either stage 2 of the safety lead-in, phase II or phase III 
component of the study regardless of their compliance with the study treatment or eligibility 
status, provided at least one baseline (pre-treatment) and one follow-up assessment is 
available. For the primary analysis, patients will be grouped by their randomly assigned study 
treatment.  
 
The primary analysis of disease related symptoms will use a repeated measures model to 
compare the mean DRS-P scores for each experimental regimen to the reference regimen at 
each of the assessment times during the first year.  The type I error allocated to each of these 
two treatment comparisons is 0.025 (0.05/2, two-tail test).  The type I error will not be 
reallocated in the event that only one experimental arm is selected following the phase II 
component of the study.  Hochberg’s step-up multiple testing procedure (Hochberg, 1988) 
will be used to control type I error across the 6 post-baseline assessment times during the first 
year (see Section 11.1).       
 
Exploratory analyses will include an assessment of the model residuals in order to evaluate 
the adequacy of modeling assumptions.  Additional descriptive analyses will assess whether 
the differences in mean scores between groups vary systematically with time in a linear or 
quadratic fashion.   
 
Statistical Power for NFOSI-DRS-P 
∑
∑
=
=
=
1
1
)
*
(
*
j
ij
j
ij
ij
i
s
M
S
δ
δ
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A previously conducted study involving 51 patients indicates that the expected mean and 
standard deviation of the DRS-P are approximately 51.6 and 10.7, respectively.  The primary 
analysis of DRS-P will focus on the 6 assessments scheduled during the first year following 
enrollment onto the study.  For the purposes of estimating power, it is assumed that there will 
be a 10% attrition of patients at the first reassessment time and 15% at each subsequent 
assessment time, due to death or non-compliance.  Also, it is assumed that the correlation 
between two consecutive assessments on the same individual will be 0.60, and between two 
assessments separated by 1 and 2 assessments will be 0.40 and 0.20, respectively.  The 
correlation between scores more than 2 assessments apart is assumed to be 0.10.  A simulation 
of 1000 trials indicates that the probability of rejecting the null hypothesis (no difference in 
mean DRS-P scores) for at least one assessment time when there is a constant 5 unit 
difference between treatment groups (experimental vs reference) is approximately 99%.  The 
probabilities of rejecting the null hypothesis at each of the 6 post-baseline assessment times 
are: 98.5%, 94.6%, 82.8%, 73.5%, 67.4% and 62.7%).  The drop-off in power with each 
successive assessment point is due to the anticipated attrition of subjects over time.  
Alternatively, if the difference in DRS-P scores between treatment groups increases from 0 (at 
baseline) to 6 units over the first year, then there is an 80% chance of rejecting the null 
hypothesis for at least one post-baseline assessment time.  The probabilities of rejecting the 
null hypothesis at each assessment time are: 5.4%, 16.4%, 26.1%, 42.8%, 55.1% and 67.3%.  
In this case, the increase in power with each successive assessment point is due to the 
postulated increasing difference in mean DRS-P scores between treatment groups over time.    
 
Other PRO Scales 
Each of the other general PRO scales will be analyzed with repeated measures models using 
procedures similar to those described above for the DRS-P.  
 
Missing PRO information 
Patient death, noncompliance, missed clinic appointments, and patient illiteracy, can cause 
observations to be missed.  One or more of the PRO assessments may be missing for an 
individual on any occasion.  Missing information is troublesome particularly in studies 
involving repeated patient assessments.  The frequency that assessments are missed will be 
monitored every 6 months throughout the study.  Study Coordinators will be working with the 
Study Team and the NRG’s Patient Centered Outcomes Research Committee to identify 
reasons that data are missing and recommending remedial actions when possible. 
    
The PRO instruments used in this study have been translated to several different languages.  
Women who are unable to read or have difficulty reading, will not be required to participate in 
the PRO component of this study, however, a woman may elect to have the items read to her 
and be assisted in completing the instruments. 
 
14.7 
Interim Analysis for All Other Endpoints (Goals) (24-FEB-2021) 
Kaplan-Meier estimates of the treatment-specific cumulative distribution of PFS will be 
provided to the DMC at the time of the Phase III interim analysis.  Tabulations of adverse 
events by treatment group will also be provided at that time.  However, these endpoints are 
not the primary focus of the interim analysis. 
 
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15. 
REFERENCES (30-OCT-2020) 
 
Antonia SJ et al, J Clin Oncol 32, 2014, Abstract 8113. 
 
Basen-Engquist et al. Reliability and validity of the functional assessment of cancer therapy-ovarian.  
JCO.  2001; 1809-1817 
 
Berk KN and Lachenbruch PA. Repeated measures with zeros. Stat Methods in Med Res 2003;11(4): 303-
316. 
 
Beesley VL et al.  Quality of life and treatment response among women with platinum-resistant 
versus platinum-sensitive ovarian cancer treated four progression.  A prospective analysis.  Gyn Onc.  
2014; 132:130-136. 
 
Blank, C., T.F. Gajewski, A. Mackensen. Interaction of PD-L1 on tumor cells with PD-1 on tumor-
specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer 
Immunol Immunother. 2005; 54:307-314. 
 
Cella et al. Patient reported outcomes in an era of immunotherapy drug development.  British Journal 
of Cancer.  2013; 108(8): 571-1578. 
 
Cox, DR. Regression Models and life tables (with discussion), J of the Royal Statistical Society B 1972; 
26: 103-110. 
 
Di Giacomo, A.M., M. Biagioli, M. Maio. The emerging toxicity profiles of anti−CTLA-4 antibodies 
across clinical indications. Semin Oncol. 2010; 37:499-507. 
 
Eisenhauer, E.A., P. Therasse, J. Bogaerts, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45:228-247. 
 
Friedlander ML et al.  Symptom burden and outcomes of patients with platinum resistant/refracotry 
recurrent ovarian cancer : a reality check: results of stage 1 of the gynecologic cancer intergroup 
symptom benefit study.  IJGC. 2014 Jun ; 24(5) : 857-64 
 
Hamanishi, J., M. Mandai, M. Iwasaki, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating 
CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA. 2007; 
104:3360-3365. 
 
Herbst, R.S., J-C. Soria, M. Kowanetz, et al. Predictive correlates of response to the anti-PD-L1 
antibody MPDL3280A in cancer patients. Nature. 2014; 515:563-567. 
 
Hino, R., K. Kabashima, Y. Kato, et al. Tumor cell expression of programmed cell death-1 ligand 1 is 
a prognostic factor for malignant melanoma. Cancer. 2010; 116:1757-1766. 
 
Hochberg, Y. A sharper Bonferoni procedure for multiple significance testing. Biometrika 1988; 75: 
800-902. 
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Investigator’s Brochure, Atezolizumab (MPDL3280A). Version 7, July 2015. 
 
Jensen SE et al. Content validity of the NCCN-FACT ovarian symptom index-18.  Gyn Onc 2014; 
136(2). 
 
Kaplan EL and Meier P. Nonparametric estimation from incomplete observations. J of the American 
Statistical Assoc 1958; 53: 457-481. 
 
Keir, M.E., M.J. Butte, G.J. Freeman, et al. PD-1 and its ligands in tolerance and immunity. Annual 
Rev Immunol. 2008; 26:677-704. 
 
Liu SV et al, J Clin Oncol 33, 2015, Abstract 8030. 
 
Okazaki, T., T. Honjo. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 
2007; 9:813-824. 
 
Page DB, Diab A, Yuan J, et al.. J Clin Oncol 2014; 32:(suppl; abstr 3021) 
 
Papadimitrakopoulou V et al J Clin Oncol 33, 2015, Abstract 8031. 
Porter ME. What is value in health care? N. Engl. J. Med. 2010; 363(26):2477-2481. 
 
Powles, T., J.P. Eder, G.D. Fine, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity 
in metastatic bladder cancer. Nature. 2014;515:558-562. 
 
Stockler, MR et al.  Patient-reported outcome results from the open-label phase III AURELIA trial 
evaluating bevacizumab-containing therapy for platinum-resistant ovarian cancer. JCO. 2014; 
32(13):1309-1316. 
 
Strickland, KC, Howitt, BE, Shukla, SA, et. al. Association and prognostic significance of BRCA1/2 
mutation status on neoantigen load, number of tumor-infiltrating lymphocytes and expression of 
PD1/PDl1 in high grade serous ovarian cancer.  Oncotarget 2016; 7(12):13587-13598. 
 
Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the 
tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 
2014;20(19):5064-5074. doi:10.1158/1078-0432. CCR-13-3271.  
 
Thompson, R.H., S.M. Kuntz, B.C. Leibovich, et al. Tumor B7-H1 is associated with poor prognosis 
in renal cell carcinoma patients with long-term follow-up. Cancer Res. 2006; 66:3381-3385. 
 
Webb, et al, Gyn Onc, 2016; Roche data on file. 
 
Wiggans AJ et al.  Poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian 
cancer.  Cochrane Database Syst Rev.  2015 May 20; (5) 
 
Wolchok, J.D., A. Hoos, S. O’Day, et al. Guidelines for the evaluation of immune therapy activity in 
solid tumors: immune-related response criteria. Clin Can Res. 2009; 15:7412-7420.  
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APPENDIX I – FIGO OVARIAN CANCER STAGING 2014  
 
STAGE I: Tumor confined to ovaries  
 
IA Tumor limited to 1 ovary, capsule intact, no rumor on surface, negative washings. 
 
IB Tumor involves both ovaries otherwise like 1A. 
 
IC Tumor limited to 1 or both ovaries 
 
IC1 
Surgical spill 
IC2 
Capsule rupture before surgery or tumor on ovarian surface 
IC3 
Malignant cells in the ascites or peritoneal washings 
 
STAGE II: 
Tumor involves 1 or both ovaries with pelvic extension (below the pelvic brim) 
 
or primary peritoneal cancer  
 
IIA Extension and/or implant on uterus and/or Fallopian tubes 
 
IIB Extension to other pelvic intraperitoneal tissues 
 
STAGE III: 
Tumor involves 1 or both ovaries with cytologically or histologically 
 
confirmed spread to the peritoneum outside the pelvis and/or metastasis to the 
 
retroperitoneal lymph nodes  
 
IIIA Positive retroperitoneal lymph nodes and/or microscopic metastasis beyond the 
pelvis 
 
 
IIIA1 Positive retroperitoneal lymph nodes only 
IIIA1(i)  
Metastasis ≤ 10 mm 
IIIA1(ii) 
Metastasis > 10mm 
 
 
IIIA2 
Microscopic, extrapelvic (above the brim) peritoneal involvement ± 
positive retroperitoneal lymph nodes 
 
IIIB Macroscopic, extrapelvic, peritoneal metastasis ≤ 2 cm ± positive retroperitoneal 
lymph nodes.  Includes extension to capsule of liver/spleen. 
 
IIIC Macroscopic, extrapelvic, peritoneal metastasis > 2 cm ± positive retroperitoneal 
lymph nodes.  Includes extension to capsule of liver/spleen. 
 
STAGE IV: Distant metastasis excluding peritoneal metastasis 
 
IVA 
Pleural effusion with positive cytology 
 
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IVB 
Hepatic and/or splenic parenchymal metastasis, metastasis to extra-abdominal 
organs (including inguinal lymph nodes and lymph nodes outside of the abdominal 
cavity). 
 
Other major recommendations are as follows: 
• Histologic type including grading should be designated at staging 
• Primary site (ovary, Fallopian tube or peritoneum) should be designated where possible 
• Tumors that may otherwise qualify for stage I but involved with dense adhesions justify 
upgrading to stage II if tumor cells are histologically proven to be present in the adhesions 
 
 
 
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APPENDIX II – PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
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APPENDIX III- NYHA CLASSIFICATION 
 
Congestive Heart Failure – New York Heart Association Classification 
 
Class 
Definition 
I 
No limitation: Ordinary physical activity does not cause undue fatigue, 
dyspnea, or palpitation 
II 
Slight limitation of physical activity: Such patients are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina. 
III 
Marked limitation of physical activity: Although patients are comfortable at 
rest, less than ordinary physical activity will lead to symptoms. 
IV 
Inability to carry on physical activity without discomfort: Symptoms of 
congestive heart failure are present even with rest. With any physical activity, 
increased discomfort is experienced. 
 
Source: Criteria Committee, New York Heart Association, Inc. Diseases of the heart and blood 
vessels. Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, Brown and Co, 1964: 114. 
 
 
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APPENDIX IV – GENERAL THERAPY GUIDELINES (29-JUN-2020) 
 
 
• For cycle lengths greater than or equal to 21 days , a patient will be permitted to have a 
new cycle of chemotherapy delayed up to 7 days (without this being considered to be a 
protocol violation) for major life events (e.g., serious illness in a family member, 
major holiday, vacation which is unable to be re-scheduled).  Documentation to justify 
this decision should be provided. 
• It will be acceptable for individual chemotherapy doses to be delivered within a “24-
hour window before and after the protocol-defined date” for “Day 1” treatment of  
cycle lengths greater than or equal to 21 days.  If the treatment due date is a Friday, 
and the patient cannot be treated on that Friday, then the window for treatment would 
include the Thursday (1 day earlier than due) through the Monday (day 3 past due). 
• It will be acceptable for individual chemotherapy doses to be delivered within a “24-
hour window,” for example; “Day 8 chemotherapy” can be delivered on Day 7, Day 8, 
or Day 9 and “Day 15 chemotherapy” can be given on Day 14, Day 15, or Day 16. 
(02/20/2019) 
• Chemotherapy doses can be “rounded” according to institutional standards without 
being considered a protocol violation (most institutions use a rule of approximately +/- 
5% of the calculated dose). 
• Chemotherapy doses are required to be recalculated if the patient has a weight change 
of greater than or equal to 10%.  Patients are permitted to have chemotherapy doses 
recalculated for < 10% weight changes. 
 
 
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APPENDIX V – TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES (10/16/2017) 
(02/20/2019) 
 
I. Obtaining a Bank ID for Translational Science Biospecimens 
Only one Bank ID (# # # # - # # - G # # #) is assigned per patient. All translational science 
biospecimens and accompanying paperwork must be labeled with this coded patient number. 
 
Translational science biospecimens should not be submitted until after patient registration and 
Bank ID assignment. 
 
A Bank ID is automatically assigned once the Specimen Consent is completed and indicates that a 
patient has agreed to participate in the translational science component. If a patient has previously 
been assigned a Bank ID, please ensure the Bank ID appearing in Rave is the same as the previously 
assigned Bank ID. 
 
Please contact Support if you need assistance or have assigned more than one Bank ID to a patient 
(Email: support@nrgoncology.org; Phone: 716-845-7767). 
 
II. Requesting Translational Science Biospecimen Kits 
Kits will be provided for the collection and shipment of frozen stool. 
 
Sites can order kits online via the Kit Management link (https://kits.bpc-apps.nchri.org/) . Each site 
may order two kit types per protocol per day (daily max = 6 kits). 
 
 
Please contact the NRG BB-Columbus if you need assistance (Email: 
BPCBank@nationwidechildrens.org; Phone: 866-464-2262). 
 
Be sure to plan ahead and allow time for kits to be shipped by ground transportation. Kits should 
arrive within 3-5 business days. 
 
Note: Unused materials and kits should be returned to the NRG BB-Columbus. 
 
III. FFPE Tissue Shipped to the NRG BB-Columbus 
Formalin-fixed, paraffin embedded (FFPE) tissue should be the most representative of the 
biospecimen type (e.g., primary tumor, metastatic tumor, recurrent tumor, persistent tumor).  
 
• Recurrent and persistent tumor should be collected prior to the study treatment. Recurrent or 
persistent tumor collected from the site of primary disease should be labeled recurrent primary 
(FRP01) or persistent primary (FPP01), respectively. Recurrent or persistent tumor collected 
from a site other than the site of primary disease (e.g., lymph node) should be labeled recurrent 
metastatic (FRM01) or persistent metastatic (FPM01), respectively. 
 
• Primary (FP01) and metastatic (FM01) tumor should be collected prior to all treatment. 
 
• Primary neoadjuvant (FPT01) and metastatic neoadjuvant (FMT01) tumor should be 
collected after the patient receives neoadjuvant treatment.  Neoadjuvant tumor should only be 
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submitted if tumor collected prior to receiving any treatment (FP01 or FM01) is not available. 
 
• Only one block may be submitted per tissue type. 
 
• All FFPE tissue should be submitted with the corresponding pathology report. 
 
Special Notes Regarding NRG GY009 FFPE Requirements 
• Due to the complexity of the FFPE requirements, only blocks will be accepted.  Please provide 
Appendix VII to your pathologist. 
 
• If patient consents to optional FFPE collection for exploratory biomarker studies (see Informed 
Consent, Additional Studies Section), the block submitted for the mandatory FFPE requirement 
will also be used to fulfill the optional requirement. 
 
Mandatory FFPE Biospecimen Requirement 
• A FFPE primary, metastatic, recurrent, or persistent tumor block must be submitted. The 
tumor block must contain at least 50% viable tumor and intact architecture. 
 
• Every attempt should be made to provide a block on a permanent basis; however, if a block 
cannot be provided on a permanent basis, the block must be submitted on a temporary* basis. 
 
*If requested, blocks will be returned after completion of the integrated biomarker testing and at 
the site’s expense. 
 
• The NRG BB-Columbus will use blocks to fresh cut (within 60 days) four consecutive unstained 
sections (charged, 4 µm) for shipment to a Genentech designated laboratory for immediate 
integrated biomarker testing.  
 
Optional FFPE Biospecimen Requirement 
• If the patient consents to optional FFPE collection for exploratory biomarker studies, the block 
submitted for the mandatory FFPE requirement will also be used to fulfill the optional 
requirement.  
 
• Every attempt should be made to provide a block on a permanent basis; however, if a block 
cannot be provided on a permanent basis, the block must be submitted on a temporary* basis. 
*If requested, blocks will be returned after completion of the integrated biomarker testing and at 
the site’s expense. 
 
• The NRG BB-Columbus will use blocks to fresh cut a scroll (thickness dependent on tumor size) 
and 10 consecutive unstained sections (charged, 5µm) to be used for exploratory biomarker 
testing. 
 
Completing Form TR for FFPE Biospecimens 
The type of biospecimen (block) should be specified on Form TR.  
 
Labeling FFPE Tissue 
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A waterproof permanent marker or printed label should be used to label each translational science 
biospecimen with: 
 
 
 
Failure to label biospecimens with all data fields shown in the sample label above may result in 
delayed processing and/or inability to utilize biospecimens. 
 
IV. Whole Blood Shipped to the NRG BB-Columbus 
1.  Label the lavender/purple top (EDTA) collection tube(s) as described below. Multiple tubes may 
be used to collect the required amount. 
2. Draw 7-10mL of blood into the labeled lavender/purple top tube(s). A minimum of 3mL is 
needed for processing. 
3.  Immediately after collection, gently invert the tube 5-10 times to mix the blood and EDTA. 
4. Ship whole blood to the NRG BB-Columbus the day the biospecimen is collected. If the whole 
blood absolutely cannot be shipped the day it is collected, the tube(s) should be refrigerated (4°C) 
and shipped within 24 hours. 
 
Labeling Whole Blood 
A waterproof permanent marker or printed label should be used to label each translational science 
biospecimen with: 
 
 
 
Failure to label biospecimens with all data fields shown in the sample label above may result in 
delayed processing and/or inability to utilize biospecimens. 
 
V. Stool Biospecimens Shipped to the NRG BB-Columbus—Phase II Portion ONLY (29-JUN-
2020) 
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1. Provide patient with stool collection kit several days prior to the treatment visit. Note: Label the 
SAMPLE and OUTER stool collection containers with the patient name, date of birth, and 
date and time of sample collection (as specified in the stool collection kit instructions) prior 
to providing the kit to the patient. The SAMPLE and OUTER stool collection containers 
must be relabeled as described below before sending to the NRG BB-Columbus. 
2. Review the EasySampler stool collection instructions (provided with the stool collection kit) with 
patient and instruct the patient to collect the sample within 24 hours of the treatment visit, as close 
to the visit as possible. Note: The patient must freeze the stool sample within one hour of 
collection (as specified in the patient collection instructions) and keep the sample frozen 
until it is returned to the clinic.  The patient should note the collection time and the time the 
sample was frozen (as specified in the patient collection instructions). 
3. Upon receipt in the clinic, record the collection date on the label provided and adhere it to the 
sealing bag. 
4. Place the frozen stool in a -70oC to -80oC freezer until ready to ship. If a -70oC to -80oC freezer is 
not available for storage, store and ship on dry ice within 24 hours of collection. 
5. When completing Form TR, the collection time noted by the patient should be recorded as 
“Collection Time.” The “Estimated Processing Time” should be recorded as the amount of time 
elapsed between sample collection and sample freeze (as noted by the patient). 
 
Labeling Stool Biospecimens 
A waterproof permanent marker or printed label should be used to label each translational science 
biospecimen with: 
 
 
Note: Collection date should be recorded on the label provided and adhered to the sealing bag after 
the patient returns the sample at the treatment visit. 
 
Failure to label biospecimens with all data fields shown in the sample label above may result in 
delayed processing and/or inability to utilize biospecimens. 
 
VI. Submitting Form TR 
An electronically completed copy of Form TR must accompany each biospecimen shipped to the 
NRG BB-Columbus. Handwritten forms will not be accepted. 
 
Note: A copy does not need to be sent to the NRG BB-Columbus if biospecimens are not collected. 
 
Form TR should be printed from the Translational Research Form screen in Rave using the “PDF 
File” link at the top of the form. Clicking this link will generate a single page PDF. Do not use the 
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“Printable Version” or “View PDF” links at the bottom of the form or any other method to print the 
form, as these formats will not be accepted. 
  
Retain a printout of the completed form for your records. 
  
Please contact User Support if you need assistance (Email: support@nrgoncology.org; Phone: 716-
845-7767). 
 
VII. Shipping Translational Science Biospecimens 
Translational science biospecimens should not be shipped until after patient registration and 
Bank ID assignment. 
 
An electronically completed copy of Form TR must be included for each translational science 
biospecimen.  
 
A. FFPE Tissue 
FFPE tissue, an electronically completed copy of Form TR, and a copy of the corresponding 
pathology report should be shipped using your own container at your own expense to: 
 
NRG BB-Columbus / Protocol NRG-GY009 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: 614-722-2865 
FAX: 614-722-2897 
Email: BPCBank@nationwidechildrens.org 
 
Do not ship FFPE tissue for Saturday delivery. 
 
B. Whole Blood 
Whole blood biospecimens should be shipped to the NRG BB-Columbus (address above). 
 
Whole blood biospecimens can be shipped to the NRG -Columbus Monday through Friday for Tuesday through 
Saturday delivery. Do not ship whole blood the day before a holiday. Use your own shipping container to ship 
biospecimens via FedEx priority overnight. 
 
When shipping whole blood biospecimens, your site must comply with IATA standards 
(www.iata.org). If you have questions regarding your shipment, contact the NRG BB-Columbus at 
BPCBank@nationwidechildrens.org or by phoning 866-464-2262.  
 
To ship whole blood biospecimens you will need (1) a sturdy shipping container (e.g., a cardboard or 
styrofoam box), (2) a leak proof biohazard envelope with absorbent material*, (3) a puncture and 
pressure resistant envelope (e.g. Tyvek envelope), (4) an Exempt Human Specimen sticker, and (5) a 
pre-paid FedEx air bill. 
 
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*If you will be shipping whole blood biospecimens from more than one patient, please put each 
biospecimen in a separate plastic zip-lock bag before placing the biospecimens in the shipping bag. 
You may include up to four different blood biospecimens in one biohazard envelope. 
 
If you do not have these materials available at your site, you may order them from any supplier (e.g., Saf-T-Pak; Phone: 
800-814-7484; Website: www.saftpak.com). 
 
Shipping Whole Blood Using Your Own Shipping Container 
1. Place the whole blood biospecimen in a biohazard envelope containing absorbent material. Expel 
as much air as possible before sealing the bag. 
2. Wrap the biohazard envelope in bubble wrap or another padded material. 
3. Place the padded tube(s) into a Tyvek envelope. Expel as much air as possible before sealing the 
envelope. 
4. Place the Tyvek envelope in a sturdy shipping container (e.g., cardboard FedEx box). 
5. Insert a copy of Form TR for each biospecimen.  
6. Attach an Exempt Human Specimen sticker to the outside of the shipping container. 
7. Print a pre-paid FedEx air bill using the Kit Management link (https://kits.bpc-apps.nchri.org/.  ). 
Attach the air bill. 
8. Make arrangements for FedEx pick-up through your site’s usual procedure or by calling 800-238-
5355. 
 
C. Frozen Stool 
Frozen stool should be shipped on dry ice using the insulated container and shipping instructions 
provided to the NRG BB-Columbus (address above). 
 
Frozen biospecimens should be shipped Monday through Thursday for Tuesday through Friday 
delivery. Do not ship frozen biospecimens on Friday or the day before a holiday. Note: Saturday 
delivery is not available for frozen biospecimens.  
 
Frozen biospecimens should be stored in an ultra-cold freezing/storage space (i.e., ultra-cold ≤-70oC 
freezer, liquid nitrogen, or direct exposure with dry ice) until the biospecimens can be shipped. 
 
VIII. Banking Translational Science Biospecimens for Future Research 
Biospecimens will remain in the NRG BB-Columbus and made available for approved research 
projects if the patient has provided permission for the use of her biospecimens for future health 
research. 
 
Note: Testing of banked biospecimens will not occur until an amendment to this treatment protocol 
(or separate correlative science protocol) is reviewed and approved in accordance with National 
Clinical Trials Network (NCTN) policies. 
 
The patient’s biospecimen consent choices will be recorded on the signed informed consent document 
and electronically via Specimen Consent form. At the time of biospecimen selection for project 
distribution, the most recent consent information will be used. 
 
Sites can amend a patient’s choices regarding the future use of her biospecimens at any time if 
the patient changes her mind. 
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If the patient revokes permission to use her biospecimens, the NRG BB-Columbus will destroy or 
return any remaining biospecimens. The patient’s biospecimens will not be used for any further 
research; however, any biospecimens distributed for research prior to revoking consent cannot be 
returned or destroyed. In addition, the patient cannot be removed from any research that has been 
done with her biospecimens distributed prior to revoking consent. 
 
Note: If return of biospecimens is requested, shipping will be at the site’s expense. 
 
 
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APPENDIX VI – COLLABORATIVE AGREEMENT 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the terms 
of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study.  Collaborator(s) data for 
Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by 
the investigators.  The protocol documents for studies utilizing Agents contain confidential 
information and should not be shared or distributed without the permission of the NCI.  If a copy 
of this protocol is requested by a patient or patient’s family member participating on the study, the 
individual should sign a confidentiality agreement.  A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with (an)other 
Agent(s), each the subject of different Collaborative Agreements, the access to and use of data by 
each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be 
referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and nature 
of any agreements governing their collaboration with NCI, the design of the proposed 
combination protocol, and the existence of any obligations that would tend to restrict NCI's 
participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by 
any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in 
writing prior to the commencement of the trials that it will use the Multi-Party Data solely for 
development, regulatory approval, and commercialization of its own Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be 
made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional 
disclosure is required by law or court order as described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm).  Additionally, all 
Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all 
applicable federal statutes and regulations for the protection of human subjects, including, if 
applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 
45 C.F.R. Part 164. 
 
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4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or 
PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC 
for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group 
office for Cooperative Group studies or by the principal investigator for non-Cooperative Group 
studies for immediate delivery to Collaborator(s) for advisory review and comment prior to 
submission for publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to an additional 30 
days in order to ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator(s)’s intellectual property rights, are protected.  Copies of abstracts must be provided 
to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably 
at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings.  Press releases and other media presentations must also be 
forwarded to CTEP prior to release.  Copies of any manuscript, abstract and/or press release/ 
media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
 
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APPENDIX VII - LETTER TO PATHOLOGISTS (10/16/2017) 
 
Dear Pathologist, 
 
Your site is a participant in NRG-GY009, a randomized, phase II/III study of pegylated 
liposomal doxorubicin and CTEP-supplied atezolizumab versus pegylated liposomal 
doxorubicin/bevacizumab and CTEP-supplied atezolizumab versus pegylated liposomal 
doxorubicin/bevacizumab in platinum resistant ovarian cancer. 
 
This study includes CTEP-approved integrated biomarker testing. This approved testing will 
use formalin-fixed, paraffin-embedded (FFPE) tumor to stain for PD-L1 at a sponsor-designated 
laboratory. The PD-L1 testing requirements mandate that slides used for testing must be fresh 
cut. 
 
Additionally, this study includes several exploratory biomarkers, including analysis of T cell 
receptor repertoires and neoantigen assessment. DNA and RNA freshly isolated from FFPE 
tumor will be used for this testing. 
 
Given the biospecimen requirements for the approved and exploratory biomarker testing, NRG-
GY009 requires all sites submit FFPE blocks only (i.e., unstained slides will not be 
accepted). The block submitted must contain at least 50% viable tumor and intact 
architecture. Blocks may be submitted on a permanent or temporary basis. 
 
If submitted on a temporary basis, blocks will be returned after the completion of the integrated 
biomarker testing. The NRG Biospecimen Bank (BB)-Columbus will hold blocks until requested 
by the study team for the integrated biomarker testing. At that time, the NRG BB-Columbus will 
fresh cut four consecutive unstained sections (4μm each) for shipment to the sponsor-designated 
laboratory for immediate integrated biomarker testing. 
 
If return of the block is requested, the NRG BB-Columbus will contact your institution for 
a Fed Ex Account number and shipping address after completion of the integrated 
biomarker testing. 
 
If you should have any questions, please so not hesitate to contact Drs. Roisin O’Cearbhaill (PI) 
and 
(Translational Research Scientist). 
 
We thank you in advance for your participation in this trial and your commitment to the 
successful completion of this study’s translational research objectives. 
 
Sincerely, 
 MD 
, PhD, MPH 
 
 
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APPENDIX VIII - EXAMPLES ON HOW TO ASSESS TUMOR RESPONSES (10/16/2017) 
The methods used to assess tumor response follow to a large extent RECIST 1.1 but are modified 
especially at week 8 to allow for temporary inflammation of the tumors that could result from 
activation of an immune response system. Below are examples of hypothetical cases which can be 
used as a guide for evaluating your patient.  
The protocol specifies continuation of treatment in cases of radiologic progression at the first 8 
week (+/- 7 days) CT if all of the following criteria are satisfied:  
• 
No decrease in performance status  
• 
No requirement for immediate alternative treatment or urgent palliative treatment  
• 
Progression limited to an increase of 40% in the sum of diameters of target lesions  
• 
No more than 4 new lesions included in the sum.  
For patients who continue treatment in the case of radiologic progression at the first 8 
week (+/- 7 days) CT:  
• 
At any subsequent CT scan patients who have stable disease as compared to the 8 week (+/- 7 
days) CT scan will be allowed to continue on study treatment.  
• 
Patients who continue treatment in the case of radiologic progression at the first 8 week (+/- 7 
days) CT, and later experience a PR or CR (as compared to baseline CT) will be recorded as 
delayed responses.  
Example 1 
Patient obtains a baseline measurement on 12/31/2015, enrolls onto study, and starts therapy on 
01/01/2016. 
……………………………………………………………………………………………… 
Date of Evaluation: 12/31/2015  Baseline Tumor Measurement  
Site of Lesion 
Tumor Size 
Site 1 
5 cm 
Site 2 
5 cm 
Total 
10 cm 
Notes: The nadir is 10 cm. Partial response will occur if the total is ≤ 7 cm (> 30% or greater decrease 
from nadir of 10). Progression will occur if the total is > 14 cm (>40% or greater increase from nadir 
of 10). ................................................................................................................................................ 
 
 
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Date of Evaluation: 2/26/2016  
 
Eight Week Assessment  
 
Site of Lesion 
Tumor Size 
Site 1 
6 cm 
Site 2 
7 cm 
Total 
13 cm 
Time point response: Neither progression nor response since 7cm < total < =14 cm. Although the 
total > 12 cm (> 20% or greater increase from nadir of 10), an allowance is made for this type of 
therapy at this time. The nadir is revised to 13 cm. The threshold for progression is now > 15.6 cm (> 
20% or greater increase from nadir of 13). Partial response can be obtained if the total is ≤ 7 cm, same 
as before. 
............................................................................................................................................................ 
Date of Evaluation: 4/22/2016  
 
 
16 Week Assessment  
Site of Lesion 
Tumor Size 
Site 1 
8 cm 
Site 2 
8 cm 
Total 
16 cm 
Time point response: Progression since 16 cm > 15.6 cm. The date of progression is 2/26/2016, not 
4/22/2016.  
Example 2 
Patient obtains a baseline measurement on 12/31/2015, enrolls onto study, and starts therapy on 
01/01/2016. 
............................................................................................................................................................  
Date of Evaluation: 12/31/2015  
 
Baseline Tumor Measurement  
Site of Lesion 
Tumor Size 
Site 1 
5 cm 
Site 2 
5 cm 
Total 
10 cm 
 
Notes: The nadir is 10 cm. Partial response will occur if the total is ≤ 7 cm (> 30% or greater decrease 
from nadir of 10). Progression will occur if the total is > 14 cm (> 40% or greater increase from nadir 
of 10). 
............................................................................................................................................................ 
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 Date of Evaluation: 2/26/2016   
 
Eight Week Assessment  
Site of Lesion 
Tumor Size 
Site 1 
5 cm 
Site 2 
5 cm 
Site 3 
4 cm 
Total 
14 cm 
Time point response: Neither progression nor response since 7 cm < total <= 14 cm. Up to 4 
additional target tumors are allowed. Nadir revised to 14 cm. The threshold for progression is revised 
to > 16.8 cm. 
............................................................................................................................................................ 
Date of Evaluation: 4/22/2016  
 
 
16 Week Assessment   
Site of Lesion 
Tumor Size 
Site 1 
4 cm 
Site 2 
4 cm 
Site 3 
3 cm 
Total 
11 cm 
Time point response: Neither progression nor response since 7 cm < total < 16.8 cm. Note, the 
nadir is revised to 11 cm. The threshold for progression is now > 13.2 cm. In order for the patient to 
respond, all 3 tumors must sum to ≤ 7 cm. 
............................................................................................................................................................ 
Date of Evaluation: 6/17/2016  
 
 
24 Week Assessment  
Site of Lesion 
Tumor Size 
Site 1 
2 cm 
Site 2 
2 cm 
Site 3 
2 cm 
Total 
6 cm 
Time point response: Partial Response since total ≤ 7 cm. The patient’s response will need to be 
confirmed ≥ 4 weeks later with a total ≤ 7 cm. If confirmed, her date of partial response will be 
6/17/2016. Note, the nadir is now 6 cm. Disease progression would occur if the total is ≥ 7.2 cm.  
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APPENDIX IX:  DIAGNOSTIC IMAGE COLLECTION SUMMARY (03/19/2018) (29-JUN-
2020) 
Approximate scan collection per subject: 
a. ~7 scans per year up to 12 months or until progression 
b. After 12 months: ~4 scans per year until progression 
 
1. CT scan or MRI performed once every 8 weeks (+/- 7 days), and at any other time if clinically 
indicated based on symptoms or physical signs suggestive of progressive disease.  Imaging 
assessments can be discontinued if disease progression. 
2. If a patient discontinues study treatment for any reason other than progression, imaging 
studies should continue every 8 weeks (+/- 7 days) until progression.   
3. After 1 years of protocol therapy or follow-up (measured from approximately cycle 1, day 1), 
imaging studies will be conducted every 12 weeks (+/- 7 days).   
 
TRIAD Digital Image Submission: 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s (ACR) image 
exchange application. TRIAD provides sites participating in clinical trials a secure method to transmit 
images. TRIAD anonymizes and validates the images as they are transferred. 
 
1. TRIAD Access Requirements: 
• A valid CTEP-IAM account.  
• Registration type of: Associate (A), Associate Plus (AP), Non-Physician Investigator 
(NPIVR), or Investigator (IVR). Refer to the CTEP Registration Procedures section 
for instructions on how to request a CTEP-IAM account and complete registration in 
RCR. 
• TRIAD Site User role on an NCTN or ETCTN roster. 
All individuals on the Imaging and Radiation Oncology Core provider roster have access to 
TRIAD and may submit images for credentialing purposes, or for enrollments to which the 
provider is linked in OPEN. 
 
2. TRIAD Installations: 
To submit images, the individual holding the TRIAD Site User role will need to install the 
TRIAD application on their workstation. TRIAD installation documentation is available at 
https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM account and RCR 
registration. 
For questions, contact TRIAD Technical Support staff via email TRIAD-Support@acr.org 
or 1-703-390-9858. 
 
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APPENDIX X – PARTICIPATING INSTITUTIONS FOR SAFETY LEAD-INS (10/22/2018) 
 
 
 
NRG Oncology Participating Institutions for Safety Lead-Ins 
PA075 
Abramson Cancer Center at the University of Pennsylvania 
AZ151 
Arizona Cancer Center 
OH027 
Cleveland Clinic Foundation 
PA086 
Fox Chase Cancer Center 
MD017 
Johns Hopkins University/Sidney Kimmel Cancer Center 
GA020 
Georgia Regents University 
CT009 
Hartford Hospital 
TX035 
M.D. Anderson Cancer Center 
NY016 
Memorial Sloan Kettering Cancer Center 
WI013 
Froedtert and the Medical College of Wisconsin 
OH007 
Ohio State University 
OK003 
Oklahoma University 
NY158 
Roswell Park Cancer Institute 
PA121 
Thomas Jefferson University 
CA189 
UC Davis Medical Center 
CA088 
University of California Medical Center at Irvine-Orange Campus 
OH274 
UHHS – Chagrin Highlands Medical Center 
IL057 
University of Chicago 
CO070 
University of Colorado Cancer Center 
OH029 
Case Western Reserve University 
IA018 
University of Iowa Hospitals and Clinics 
PA015 
University of Pittsburgh Cancer Center 
VA009 
University of Virginia Health Systems 
VA010 
Virginia Commonwealth University 
MO011 
Washington University School of Medicine 
RI012 
Women’s and Infants Hospital 
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