Conditions: Ovarian Cancer Ovarian Neoplasms
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 18
Healthy volunteers: no

Brief summary:
The main purpose of this study is to validate a safe dose of atezolizumab with dose-dense paclitaxel and carboplatin when utilized with neoadjuvant chemotherapy and interval cytoreductive surgery followed by maintenance atezolizumab in women with advanced ovarian cancer.

Detailed description:
This is a Phase IB non-randomized, single-arm, open-label study of atezolizumab in combination with primary NACT-ICS in patients with advanced-stage epithelial ovarian cancer. The target population is women with previously untreated epithelial ovarian cancer (including fallopian tube and primary peritoneal cancer) with advanced stage (FIGO III-IV) disease suitable for NACT and ICS. The following regimen will be administered every 3 weeks for 3 cycles prior to ICS, then for 3 cycles following ICS:

* Carboplatin AUC = 5 or 6 IV, D1 of each cycle
* Paclitaxel 70 to 80mg/m2 IV, over one hour, on D1, 8, 15 of each cycle
* Atezolizumab 1200mg IV D1 of each cycle of chemotherapy and will be continued as maintenance therapy every 3 weeks until there is a lack of clinical benefit, unacceptable toxicity, or a total duration of 18 months.
* Bevacizumab (15 mg/kg IV every 3 weeks) may be added at cycle 5 of chemotherapy as per FDA approval. Those who opt for bevacizumab will receive chemotherapy, atezolizumab, and bevacizumab for cycles 5 and 6 followed by atezolizumab and bevacizumab maintenance. Maintenance bevacizumab will be given for a total duration of 16 cycles. Patients who have completed chemotherapy may opt for bevacizumab in the maintenance setting only if the amendment to add bevacizumab was not approved before after they started maintenance therapy.
* Upon completion of concurrent chemotherapy and atezolizumab therapy, patients will commence maintenance treatment with atezolizumab + bevacizumab for a total of up 16 cycles of maintenance therapy (22 total cycles of atezolizumab, and 18 total cycles of bevacizumab).

Each cycle is 21 days in duration and will be administered in the outpatient setting. Limited individualized flexibility in dose assignment (as noted) is permitted per physician discretion in regards to advanced-stage disease, nutritional status, ascites, non-physiologic creatinine measurements, and other comorbidities.

Three cycles of NACT with atezolizumab will be administered every 3 weeks prior to ICS (occurring between cycles 3 and 4) followed by 3 additional cycles (cycles 4-6) of chemotherapy with atezolizumab. Surgery must be performed after the third course of chemotherapy as soon as nadir counts permit, but preferably within six weeks after the completion of the third chemotherapy cycle. Fourth cycle of chemotherapy is to be administered as soon as possible, but preferably no more than six weeks after ICS.

Safety monitoring, including assessment for irAEs, will occur at each cycle and for 90 days after the last administration of atezolizumab or until start of next anti-cancer regimen, whichever occurs first. Image assessment by CT scan or MRI will be performed at baseline, prior to ICS to assess response, after completion of 6 cycles of chemotherapy with atezolizumab to assess response at end of chemotherapy treatment, and as clinically indicated during the maintenance phase and after completion of study treatment to assess PFS. Disease progression/recurrence will be defined per RECIST criteria and will not include isolated asymptomatic progression on the basis of CA125 levels. Immune function analysis will be performed on blood and tumor samples obtained at two time points: 1. confirmatory biopsy prior to start of therapy and 2. ICS.

It is estimated that 40 patients will be enrolled at an accrual rate of 3-5 patients/month and followed for a median of 3 years.

Arms:
arm 1: 1. Atezolizumab administered over 90 (± 15) minutes (for the first infusion, shortening to 60 (± 15) minutes and 30 ± 15) minutes for subsequent infusions as described below) followed by
2. Paclitaxel 70-80mg/m2 IV administered over approximately one hour followed by
3. Carboplatin IV administered over 15-30 minutes to achieve an initial target AUC of 5-6 mg/mL/Min (Calvert formula dosing).
4. (Optional, Physician choice) Bevacizumab IV maintenance administered starting at cycle 5 of chemotherapy over 30-90 minutes. For those who receive bevacizumab, it will be given for a total duration of 16 cycles

Interventions: intervention 1: Atezolizumab intervention 2: Carboplatin intervention 3: Paclitaxel intervention 4: Bevacizumab
Intervention descriptions: intervention 1: 1200mg IV q3weeks intervention 2: 5-6mg/ML IV q3 weeks intervention 3: 70-80 mg/m2 IV q1 week intervention 4: 15 mg/kg IV q3 weeks

Protocol document:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
 
This is a Duke University Medical Center document that contains confidential 
information.  It is intended solely for the recipient clinical investigator(s) and must not 
be disclosed to any other party.  This material may be used only for evaluating or 
conducting clinical investigations; any other proposed use requires written consent 
from Duke University Medical Center. 
 
MPDL3280ADuke 
Protocol ML 39266, Version 3-9 
1 
PROTOCOL 
TITLE: 
Atezolizumab in Combination with Neoadjuvant 
Chemotherapy and Interval Cytoreductive Surgery 
for Patients with Newly-Diagnosed Advanced-
Stage Epithelial Ovarian Cancer 
STUDY NUMBER: 
ML39266 
VERSION NUMBER: 
3-9 
TEST PRODUCTS: 
Atezolizumab  
INVESTIGATOR: 
Angeles Alvarez Secord, MD MS 
DUMC 3079 
Duke Cancer Institute 
Durham, NC 27710 
Telephone: 919-684-3765 
Fax: 919-684-8719 
Email: angeles.secord@duke.edu  
SUB-INVESTIGATORS: 
 
Stéphanie Gaillard, MD PhD 
Johns Hopkins Sidney Kimmel Cancer Center 
201 North Broadway 
Viragh 10 Box 6 
Baltimore, MD 21287 
Telephone:  410-955-3774 
Email:  stephanie.gaillard@jhmi.edu 
 
 
STUDY NURSE 
COORDINATOR: 
William Scott Andrews, RN 
SUPPORT PROVIDED BY: 
Genentech, Inc. 
PROTOCOL DATE: 
 October 22, 2019 
  
 NCT03394885 


 
CONFIDENTIAL 
 
This is a Duke University Medical Center document that contains confidential 
information.  It is intended solely for the recipient clinical investigator(s) and must not 
be disclosed to any other party.  This material may be used only for evaluating or 
conducting clinical investigations; any other proposed use requires written consent 
from Duke University Medical Center. 
 
MPDL3280ADuke 
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SUMMARY OF CHANGES 
 
 Protocol Version 3-9 
o Changes to the protocol include addition of modifications for 
patients who cannot have surgery at the specified time point as 
required in the protocol, modification for bevacizumab timing based 
on ICS modifications, edits to the eligibility checklist, and addition of 
language for patients with a germline or somatic BRCA mutations in 
regards to participation and maintenance


 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................ 11 
1.1 
Ovarian Cancer ..................................................................... 11 
 
Current Management ............................................................. 11 
1.2 
Background on Atezolizumab ................................................ 12 
 
Clinical Safety ........................................................................ 12 
 
Drug Interactions ................................................................... 13 
1.3 
Backbone Chemotherapy Regimen: Intravenous 
Carboplatin with Dose-dense Weekly Paclitaxel .................... 13 
 
Background ........................................................................... 13 
 
Safety Profile ......................................................................... 14 
1.4 
Study Rationale ..................................................................... 15 
2. 
OBJECTIVES .............................................................................................. 16 
2.1 
Primary .................................................................................. 16 
2.2 
Secondary ............................................................................. 17 
2.3 
Translational .......................................................................... 17 
3. 
STUDY DESIGN ......................................................................................... 17 
3.1 
Description of the Study ......................................................... 17 
3.2 
End of Study .......................................................................... 18 
3.3 
Rationale for Study Design .................................................... 19 
3.4 
Outcome Measures ............................................................... 19 
 
Primary Outcome Measure .................................................... 19 
 
Secondary Activity Outcome Measures ................................. 19 
 
Pharmacodynamic/Translational Outcome 
Measures 20 
4. 
MATERIALS AND METHODS .................................................................... 20 
4.1 
Study Population ................................................................... 20 
 
Inclusion Criteria .................................................................... 20 
 
Exclusion Criteria ................................................................... 22 
4.2 
Study Treatment .................................................................... 25 
 
Study Drug:  Atezolizumab .................................................... 25 
4.2.1.1  Formulation and Storage ...................................................... 25 


TABLE OF CONTENTS (CONT.) 
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Protocol-Specified Chemotherapy ......................................... 25 
4.2.2.1  Formulation and Storage ...................................................... 26 
  Dosage, Schedule, Administration, and 
Premedications ............................................................................. 26 
4.3 
Concomitant and Excluded Therapies ................................... 28 
 
Concomitant Therapy ............................................................ 28 
 
Excluded Therapy .................................................................. 28 
4.4 
General Plan to Manage Safety Concerns ............................ 29 
 
Dose Modification of Chemotherapy ...................................... 30 
  Management of Specific Safety Concerns with 
Atezolizumab................................................................................. 30 
  Guidelines for Atezolizumab Dosage Modification, 
Treatment Interruption, or Discontinuation .................................... 31 
4.4.3.1  Gastrointestinal Toxicity ....................................................... 32 
4.4.3.2  Hepatotoxicity ....................................................................... 33 
4.4.3.3  Dermatologic Toxicity ........................................................... 35 
4.4.3.4  Endocrine Toxicity ................................................................ 37 
4.4.3.5  Pulmonary Toxicity ............................................................... 40 
4.4.3.6  Potential Pancreatic Toxicity ................................................ 41 
4.4.3.7  Potential Eye Toxicity ........................................................... 41 
4.4.3.8  Potential Cardiac Toxicity ..................................................... 42 
4.4.3.9  Principles of Immunosuppression ........................................ 43 
4.4.3.10  Principles of Immunotherapy Rechallenge ......................... 44 
  Guidelines for Interval Cytoreduction Surgery 
Modification ................................................................................... 45 
4.5 
Patient Discontinuation .......................................................... 45 
4.6 
Study Treatment Discontinuation ........................................... 46 
4.7 
Study and Site Discontinuation .............................................. 46 
4.8 
Clinical and Laboratory Evaluations ...................................... 47 
 
Pretreatment Evaluations ...................................................... 47 
 
Study Assessments ............................................................... 47 
4.8.2.1  Medical History ..................................................................... 48 
4.8.2.2  Vital Signs ............................................................................ 48 
4.8.2.3  Physical Examination ........................................................... 48 


TABLE OF CONTENTS (CONT.) 
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4.8.2.4  Tumor and Response Evaluation ......................................... 48 
4.8.2.5  Laboratory Assessments ...................................................... 49 
  Treatment Discontinuation Visit and Safety Follow-up .................. 50 
 
Follow-Up Assessments ........................................................ 50 
 
Long-Term Follow-up ............................................................ 50 
5. 
STATISTICAL ANALYSES ......................................................................... 50 
5.1 
Definitions .............................................................................. 50 
5.2 
Study Design/Stopping Rule .................................................. 50 
5.3 
Populations ............................................................................ 51 
 
Safety Population .................................................................. 51 
 
Pharmacodynamic/Translational Population .......................... 51 
 
Efficacy Evaluable Population ............................................... 52 
5.4 
Statistical methodology .......................................................... 52 
 
Safety Analyses ..................................................................... 52 
 
Efficacy Analyses .................................................................. 52 
 
Translational Analyses........................................................... 52 
5.4.3.1  Correlation of PD-L1 expression to clinical         
outcomes .............................................................................. 52 
5.4.3.2  Other translational endpoints ............................................... 52 
5.5 
Sample size ........................................................................... 52 
6. 
ASSESSMENT OF SAFETY ....................................................................... 53 
6.1 
Risks Associated with Atezolizumab ..................................... 53 
6.2 
Safety Parameters and Definitions ........................................ 53 
 
Adverse Events ..................................................................... 53 
 
Serious Adverse Events ........................................................ 53 
6.3 
Methods and Timing for Assessing and 
Recording Safety Variables ................................................... 54 
 
Adverse Event Reporting Period ........................................... 54 
 
Assessment of Adverse Events ............................................. 54 
6.4 
Procedures for Eliciting, Recording, and 
Reporting Adverse Events ..................................................... 55 
 
Eliciting Adverse Events ........................................................ 55 
  Specific Instructions for Recording Adverse Events ...................... 55 


TABLE OF CONTENTS (CONT.) 
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6.4.2.1  Diagnosis versus Signs and Symptoms ............................... 55 
6.4.2.2  Deaths .................................................................................. 56 
6.4.2.3  Pre-existing Medical Conditions ........................................... 56 
6.4.2.4  Hospitalizations for Medical or Surgical 
Procedures ......................................................................................... 56 
6.4.2.5  Pregnancies in Female Patients ........................................... 56 
6.4.2.6  Post-Study Adverse Events .................................................. 57 
6.4.2.7  Safety Reconciliation ............................................................ 57 
6.4.2.8  Adverse Events of Special Interest ...................................... 57 
6.4.2.9  Adverse Event Reporting ..................................................... 59 
 
Additional Reporting Requirements for IND ........................... 61 
 
IND Annual Reports ............................................................... 61 
6.5 
Study Close-Out .................................................................... 61 
7. 
ETHICAL CONSIDERATIONS .................................................................... 62 
7.1 
Compliance with Laws and Regulations ................................ 62 
7.2 
Informed Consent .................................................................. 62 
7.3 
Institutional Review Board or Ethics Committee 
Approval ................................................................................ 63 
7.4 
Confidentiality ........................................................................ 63 
8. 
STUDY MEDICAL MONITORING REQUIREMENTS ................................. 64 
8.1 
Study Medication Accountability ............................................ 65 
8.2 
Data Collection ...................................................................... 65 
8.3 
Retention of Records ............................................................. 65 
9. 
TRANSLATIONAL STUDIES ...................................................................... 66 
9.1 
Biologic Samples For Biomarker And Correlative 
Studies ................................................................................... 66 
9.2 
BRCA Mutation Status ........................................................... 66 
9.3 
Tumor Mutation Profile .......................................................... 66 
10.  REFERENCES ........................................................................................... 66 
 


TABLE OF CONTENTS (CONT.) 
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LIST OF TABLES 
Table 1.3.1b 
Grade 3 or Greater Toxicities Reported in JGOG 3016 .............. 15 
Table 4.4.3.1   Dose Interruption Guidelines for Gastrointestinal Toxicity .......... 33 
Table 4.4.3.2  Dose Interruption Guidelines for Hepatotoxicity .......................... 34 
Table 4.4.3.3  Dose Interruption Guidelines for Dermatologic Toxicity .............. 36 
Table 4.4.4 
Dose Interruption Guidelines for Dermatologic Toxicity 
(cont.) .......................................................................................... 37 
Table 4.4.3.5   Dose Interruption Guidelines for Endocrine Toxicity ................... 38 
Table 4.4.3.6   Dose Interruption Guidelines for Endocrine Toxicity (cont.) ....... 39 
Table 4.4.3.7  Dose Interruption Guidelines for Pulmonary Toxicity .................. 40 
Table 4.4.3.8  Dose Interruption Guidelines for Pulmonary Toxicity (cont.) ....... 41 
Table 4.4.3.7  Dose Interruption Guidelines for Eye Toxicity .............................. 42 
 
 
LIST OF APPENDICES 
Appendix 1 
Study Flowchart .......................................................................... 69 
Appendix 2 
Initial Carboplatin Dose Recommendations based on IDMS 
Creatinine Values ........................................................................ 70 
Appendix 3 
Current National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE)................................... 71 
Appendix 4 
Response Evaluation Criteria in Solid Tumors (RECIST) ........... 72 
Appendix 5 
Immune-Related Response Criteria ............................................ 83 
Appendix 6 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scale ................................................................................ 85 
Appendix 7 
Anaphylaxis Precautions ............................................................. 86 
Appendix 8 
Safety Reporting Fax Cover Sheet ............................................. 87 
Appendix 9 
FDA MedWatch 3500 Form ........................................................ 88 
Appendix 10 
Eligibility Checklist ...................................................................... 89 
Appendix 12 
Investigator Signature Page ........................................................ 95 
Appendix 13    Dose Modifications and Day 1 Dosing Criteria ........................... 96 


 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 


 
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Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
anti-HBc 
antibody to hepatitis B core antigen 
ATA 
anti-therapeutic antibody 
AUC 
area under the concentration-time curve 
BSA 
body surface area 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CR 
complete response 
CRF 
Case Report Form 
CT 
computed tomography 
DLCO 
diffusion capacity of the lung for carbon 
monoxide 
DLT 
dose-limiting toxicity 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
U.S. Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FOLFOX 
leucovorin, 5-fluorouracil, oxaliplatin 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICS 
interval cytoreductive surgery 
IFN 
interferon 
Ig 
immunoglobulin 
IHC 
immunohistochemistry 
IL 
interleukin 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
IRF 
independent review facility 
IRR 
infusion-related reaction 
irRC 
immune-related response criteria  


 
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Abbreviation 
Definition 
IV 
intravenous 
LFT 
liver function test 
LPLV 
last patient, last visit 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NACT 
neoadjuvant chemotherapy 
NCI CTCAE 
National Cancer Institute Common Terminology 
Criteria for Adverse Events 
NCCN 
National Comprehensive Cancer Network 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
pCR 
pathologic complete response rate 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed death-1 
PD-L1 
programmed death-ligand 1  
PES 
polyethersulfone 
PET 
positron emission tomography 
PFS 
progression-free survival 
PI 
Package Insert 
PK 
pharmacokinetic 
PR 
partial response 
PUVA 
psoralen plus ultraviolet A radiation 
PVC 
polyvinylchloride 
qRT-PCR 
quantitative reverse-transcription polymerase 
chain reaction 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SD 
stable disease 
TNF 
tumor necrosis factor 
TSH 
thyroid-stimulating hormone 
UBC 
urothelial bladder cancer 
ULN 
upper limit of normal 
Vss 
volume at steady state 


 
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1. 
INTRODUCTION 
1.1 
Ovarian Cancer 
Ovarian cancer is the leading cause of death from gynecologic malignancies in 
the United States and Europe. The term “ovarian cancer” typically refers to a 
constellation of diseases including epithelial ovarian, fallopian, and peritoneal 
carcinomas. Within the US, approximately 24,000 women are diagnosed with 
ovarian cancer annually and 14,000 are expected to die each year of the disease 
[1]. While most women have an excellent response to first-line chemotherapy, 
the majority will experience disease recurrence and development of 
chemotherapy resistance, with increased susceptibility to disease-related 
complications, and death. Thus, there is a significant opportunity to improve long-
term treatment outcomes through the safe integration of effective targeted 
interventions during primary therapy.  
 
Current Management 
Standard first-line therapy for the management of advanced-stage ovarian 
cancer is cytoreductive surgery followed by postoperative systemic 
chemotherapy consisting of a combination of a platinum and taxane agent, 
usually carboplatin and paclitaxel. Various Phase III studies have shown 
progression-free survival rates of 10 – 28 months using various routes of 
administration (i.e. intraperitoneal vs intravenous), sequence of chemotherapy 
and cytoreductive surgery (i.e. neoadjuvant vs postoperative), and the addition of 
other agents [2-10]. As of 2016, no universal strategy is preferred and the 
National Comprehensive Cancer Network endorses multiple options for front-line 
therapy [11]. 
Neoadjuvant Chemotherapy 
Long-term clinical outcomes have been correlated with a number of prognostic 
factors, including stage, extent of residual disease following cytoreductive 
surgery, performance status, tumor grade, and presence of ascites. While the 
goal of primary cytoreductive surgery is resection of all macroscopic disease, not 
all patients are suitable candidates for aggressive primary surgery, based on 
distribution of disease, comorbidities, and other factors.   
Over the last 10 years, there has been increased interest in a tailored approach 
involving neoadjuvant chemotherapy (NACT) with consideration of interval 
cytoreductive surgery (ICS) for individual patients who were not good candidates 
for primary cytoreductive surgery. Two phase III randomized trials have validated 
this approach for selected patients, based on minimization of perioperative 
complications with similar long-term clinical outcomes (PFS and OS) [9, 10].  By 
2013, approximately 40% of patients at NCCN cancer centers received NACT-
ICS [12]. It has also been recognized that NACT-ICS offers an important 
opportunity to evaluate new agents in combination with standard therapy, while 


 
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also providing access to pre- and post-treatment biospecimens to evaluate 
molecular targeting, immunoregulatory function, and tumor response.  
1.2 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that 
targets PD-L1 and inhibits the interaction between PD-L1 and its receptors, PD-1 
and B7-1 (also known as CD80), both of which function as inhibitory receptors 
expressed on T cells.  Therapeutic blockade of PD-L1 binding by atezolizumab 
has been shown to enhance the magnitude and quality of tumor specific T cell 
responses, resulting in improved anti-tumor activity [13, 14].  Atezolizumab has 
minimal binding to Fc receptors, thus eliminating detectable Fc effector function 
and associated antibody-mediated clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer 
patients and is being investigated as a potential therapy in a wide variety of 
malignancies.  Atezolizumab is being studied as a single agent in the advanced 
cancer and adjuvant therapy settings, as well as in combination with 
chemotherapy, targeted therapy, and cancer immunotherapy. 
Atezolizumab is approved in the United States for the treatment of locally 
advanced or metastatic urothelial carcinoma and previously treated metastatic 
non-small cell lung cancer. 
Refer to the atezolizumab Investigator's Brochure and the atezolizumab package 
insert for details on nonclinical and clinical studies, and safety data including 
immune-related adverse events. 
 
Clinical Safety 
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.  These include potential dermatologic, 
hepatic, endocrine, and respiratory events as well as events of hepatitis/elevated 
liver function tests (LFTs) and influenza-like illness.  Expected adverse drug 
reactions associated with atezolizumab include the following:  
hepatitis/transaminitis, hypothyroidism, infusion-related reactions (IRRs), 
pneumonitis, influenza-like illness, and dermatologic reactions.  Potential adverse 
drug reactions include the following:  anti-therapeutic antibodies (ATAs), colitis, 
endocrine disorders, hypersensitivity, neurologic disorders, and pericardial 
effusion.   
For further details, see the atezolizumab Investigator’s Brochure. 


 
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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. 
 
1.3 
Backbone Chemotherapy Regimen: Intravenous Carboplatin 
with Dose-dense Weekly Paclitaxel 
 
Background 
Relative efficacy and safety was considered in the determination of the backbone 
chemotherapy regimen for this trial. Intravenous carboplatin with dose-dense 
weekly paclitaxel was selected based on the outcomes of two recent phase III 
studies evaluating weekly dose-dense paclitaxel vs every 3 week paclitaxel 
scheduling on outcomes. JGOG 3016 showed an impressive improvement using 
the dose-dense versus every 3 week administration, respectively, in both PFS 
(28 vs 17 months, p=0.004) and OS (100.5 vs 62.2 months, p=0.04) [15]. 
GOG262 also compared weekly dose-dense paclitaxel to every 3 week paclitaxel 
administration specifically in a population of patients whose residual disease 
post-cytoreductive surgery was >1cm or who opted for NACT [3]. Overall, there 
was no difference between the two treatment arms, suggesting that the results 
may have been influenced by the use of bevacizumab in >80% of patients 
enrolled. Of note, among the 112 patients who elected not to receive 
bevacizumab, there was improved PFS in the subset assigned to weekly 
paclitaxel, compared to the subset assigned to every 3 week paclitaxel (14.2 vs 
10.3 months, p=0.03). 
Differences in patient selection, and baseline population characteristics, along 
with the large proportion of patients who received primary bevacizumab in GOG 
262 may account for the differences between the two studies. In addition, within 
Japan, bevacizumab was not generally available for management of disease 
post-progression, while patients within the US would generally have access to 
commercial bevacizumab.  
There are additional details that further influenced the choice of chemotherapy 
for this trial. First, in GOG 262, 13% of patients elected to receive NACT followed 
by ICS and there were no safety issues identified. In addition, there was no 
apparent impact of the paclitaxel schedule on PFS in patients opting for NACT-
ICS versus primary cytoreduction. Second, maximal benefit of the weekly dose-
dense paclitaxel regimen in JGOG3016 was seen in patients with more 
advanced suboptimal disease, a population that would be anticipated to be 
similar to the planned population for this study. 


 
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From the perspective of feasibility, the dose-dense weekly regimen has been 
widely adopted at our centers following publication in 2013. Finally, this regimen 
offers two specific design advantages for the current trial: 1) more frequent 
opportunities for patient safety assessment during combination therapy, and 2) 
decreased prophylactic steroid requirement for weekly paclitaxel dosing. In view 
of the limited number of patients, as well as the potential influence of a specific 
chemotherapy regimen on efficacy and toxicity, the chemotherapy regimen will 
be held consistent across the entire study population. 
 
Safety Profile 
The most common dose-limiting adverse events associated with carboplatin and 
weekly dose-dense paclitaxel are hematologic. Frequency of grade 3 or greater 
adverse events by treatment group are listed in the tables below for GOG262 
(Table 1.3.2a) and JGOG3016 (Table 1.3.1b). In both studies, anemia was the 
only grade 3 or greater hematologic toxicity significantly worse in the dose-dense 
paclitaxel group. The risk of febrile neutropenia was not increased in either study. 
Overall, the dose-dense weekly paclitaxel regimen is well tolerated and its 
toxicity profile does not significantly overlap with the potential toxicities of 
atezolizumab. 
 
Table 1.3.2a Selected Grade 3 or Greater Toxicities Reported in GOG262 
 
Number (Percentage) of Grade 3-4 Adverse 
Events 
Adverse Event 
Weekly 
Paclitaxel 
N=340 
Q3Week 
Paclitaxel 
N=343 
p-value 
Anemia 
124 (37) 
54 (16) 
<0.001 
Diarrhea 
23 (7) 
11 (3) 
0.03 
Fatigue 
NR 
NR 
 
Febrile Neutropenia 
13 (4) 
16 (5) 
0.58 
Nausea 
20 (6) 
11 (3) 
0.10 
Neuropathy (Motor) 
3 (1) 
3 (1) 
0.99 
Neuropathy 
(Sensory) 
9 (3) 
7 (2) 
0.61 
Neutropenia 
246 (72) 
286 (83) 
<0.001 
Thrombocytopenia 
67 (20) 
54 (16) 
0.18 
Vomiting 
19 (6) 
15 (4) 
0.47 
 
 
 


 
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Table 1.3.1b Grade 3 or Greater Toxicities Reported in JGOG 3016 
 
Number (Percentage) of Grade 3-4 Adverse 
Events 
Adverse Event 
Weekly 
Paclitaxel 
N=312 
Q3Week 
Paclitaxel 
N=314 
p-value 
Anemia 
214 (69) 
137 (44) 
<0.0001 
Diarrhea 
10 (3) 
8 (3) 
0.64 
Fatigue 
15 (5) 
8 (3) 
0.14 
Febrile Neutropenia 
29 (9) 
29 (9) 
1.00 
Nausea 
32 (10) 
36 (11) 
0.70 
Neuropathy (Motor) 
15 (5) 
20 (6) 
0.56 
Neuropathy 
(Sensory) 
21 (7) 
20 (6) 
0.87 
Neutropenia 
286 (92) 
276 (88) 
0.15 
Thrombocytopenia 
136 (44) 
120 (38) 
0.19 
Vomiting 
9 (3) 
11 (4) 
0.82 
 
1.4 
STUDY RATIONALE 
A combination of carboplatin and paclitaxel remains the most widely used first-
line treatment option for patients with advanced-stage ovarian cancer. While 
optimized chemotherapy, cytoreductive surgery, high-resolution imaging, and 
better supportive care have contributed to improved clinical outcomes, this 
appears to have reached a plateau, without a change in disease-related 
mortality. This provides an important opportunity to integrate novel treatment 
interventions, such as immunotherapy, with primary treatment. 
Tumor cell killing by cytotoxic chemotherapy can reasonably be expected to 
expose the immune system to high levels of tumor antigens, and invigorating 
tumor-specific T-cell immunity in this setting by inhibiting PD-L1/PD-1 signaling 
may result in deeper and more durable responses compared to standard 
chemotherapy alone. Furthermore, PD-L1 expression is frequently increased on 
the surface of ovarian cancer cells and is thought to contribute to immune 
evasion.  
Limited data are available regarding the clinical activity of PD-1 and PD-L1 
inhibitors in ovarian cancer. Among patients with platinum-resistant recurrent 
disease and multiple prior therapies, response rates from small phase I-II studies 
have been reported between 10-15% [16-18]. However, due to extensive prior 
treatment, and limited immunologic capacity, these studies may underestimate 
the true proportion of patients that might benefit from these interventions.  
Evaluation of these agents in patients without prior therapy should maximize the 
opportunity to achieve clinical benefit while minimizing the risk of treatment-
related complications. We proposed to conduct a non-randomized trial of 
atezolizumab in combination with primary NACT-ICS followed by maintenance 


 
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atezolizumab for patients with untreated advanced-stage high-grade epithelial 
ovarian cancer (EOC) to validate a safe dose of the combination over multiple 
cycles of chemotherapy and cytoreductive surgery in women with advanced 
ovarian cancer. 
In December 21, 2018 the interim analysis of the Phase III JAVELIN Ovarian 100 
study comparing to incorporation of avelumab, a PD-L1 inhibitor, with paclitaxel 
and carboplatin in women with newly diagnosed ovarian cancer would did not be 
superior compared to platinum-based therapy alone [23]. Given these findings 
we propose to allow the option of bevacizumab after debulking surgery.  
 
On June 13, 2018, the Food and Drug Administration approved bevacizumab 
(Avastin, Genentech, Inc.), a monoclonal antibody that inhibits vascular 
endothelial growth factor (VEGF), for patients with epithelial ovarian, fallopian 
tube, or primary peritoneal cancer in combination with carboplatin and paclitaxel, 
followed by single-agent bevacizumab, for stage III or IV disease after initial 
surgical resection [24].There is data to support the combination of anti-VEGF 
therapy and immunotherapy. VEGF may decrease T cell infiltration [25] and thus 
VEGF inhibition may enhance intratumoral T-cell recruitment. This hypothesis 
has been tested in renal cell carcinoma (RCC). The combination of bevacizumab 
and atezolizumab in RCC led to increased CD8+ tumor-infiltrating lymphocytes 
and enhanced tumor reduction [26]. Bevacizumab may also promote T cell 
infiltration and immune-mediated tumor cell kill by normalizing tumor-associated 
vasculature [27].  
 
Patients will be treated with paclitaxel, carboplatin, and atezolizumab for cycles 
1-3.  Interval surgery will occur after Cycle 3. Within 6 weeks after interval 
surgery or when clinically appropriate patients will resume concurrent 
chemotherapy and atezolizumab. For cycle 5, patients have the option to include 
bevacizumab into their treatment regimen as per FDA approval. Those who opt 
for bevacizumab will receive chemotherapy, atezolizumab, and bevacizumab (15 
mg/kg IV every 3 weeks). Selection of patients for bevacizumab and treatment 
with this therapy will be performed as per institutional guidelines. Atezolizumab is 
being evaluated with chemotherapy and bevacizumab in the randomized phase 
III GOG3015 trial. GOG3015 includes an independent data monitoring committee 
and no significant safety concerns have been reported.  
 
Upon completion of concurrent therapy, patients will commence maintenance 
treatment with either atezolizumab alone or with bevacizumab and atezolizumab 
based on investigator and patient preference.  
 
2. 
OBJECTIVES 
2.1 
PRIMARY 
To validate a safe dose of the combination of atezolizumab with weekly dose-
dense paclitaxel and carboplatin when delivered over multiple cycles of NACT 


 
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with planned ICS (henceforth referred to as NACT-ICS), followed by concurrent 
paclitaxel, carboplatin, and atezolizumab +/- bevacizumab, followed by 
maintenance atezolizumab +/- bevacizumab in women with advanced ovarian 
cancer, as measured by frequency and severity of adverse events by Common 
Terminology Criteria for Adverse Events (CTCAE) v.5.0. 
2.2 
SECONDARY 
To estimate objective response rate (ORR), pathologic complete response rate 
(pCR) at interval cytoreduction, PFS, and OS in the study population. 
2.3 
TRANSLATIONAL 
 
Primary Translational: To correlate clinical outcomes (in particular median PFS) 
with PD-L1 expression. 
 
Secondary Translational: To correlate clinical outcomes (in particular median 
PFS) with tumor-infiltrating lymphocyte subpopulations, immune checkpoint 
receptor profiles, gene expression profiles associated with immunoactivation, 
cytokine expression profiles, BRCA mutation status, and tumor mutation profile. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a Phase IB non-randomized, single-arm, open-label study of atezolizumab 
in combination with primary NACT-ICS in patients with advanced-stage epithelial 
ovarian cancer. The target population is women with previously untreated 
epithelial ovarian cancer (including fallopian tube and primary peritoneal cancer) 
with advanced stage (FIGO III-IV) disease suitable for NACT and ICS. The 
following regimen will be administered every 3 weeks for 3 cycles prior to ICS, 
then for 3 cycles following ICS:  
 Carboplatin AUC = 5 or 6 IV, D1 of each cycle 
 Paclitaxel 70 to 80 mg/m2 IV, over one hour, on D1, 8, 15 of each cycle  
 Atezolizumab 1200 mg IV D1 of each cycle of chemotherapy and will be 
continued as maintenance therapy every 3 weeks until there is a lack of 
clinical benefit, unacceptable toxicity, or a total duration of 22 cycles (6 
concurrent with chemotherapy and 16 maintenance cycles). 
 Bevacizumab (15 mg/kg IV every 3 weeks) may be added at cycle 5 of 
chemotherapy as per FDA approval. Those who opt for bevacizumab will 
receive chemotherapy, atezolizumab, and bevacizumab for cycles 5 and 6 
followed by atezolizumab and bevacizumab maintenance. Maintenance 
bevacizumab will be given for a total duration of 16 cycles. Patients who 
have completed chemotherapy may opt for bevacizumab in the 


 
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maintenance setting only if the amendment to add bevacizumab was not 
approved before after they started maintenance therapy.  
 Upon completion of concurrent chemotherapy and atezolizumab therapy, 
patients will commence maintenance treatment with atezolizumab 
+ bevacizumab for a total of up 16 cycles of maintenance therapy (22 total 
cycles of atezolizumab, and 18 total cycles of bevacizumab). 
 
 
Each cycle is 21 days in duration and will be administered in the outpatient 
setting. Limited individualized flexibility in dose assignment (as noted) is 
permitted per physician discretion in regards to advanced-stage disease, 
nutritional status, ascites, non-physiologic creatinine measurements, and other 
comorbidities.  
Three cycles of NACT with atezolizumab will be administered every 3 weeks 
prior to ICS (occurring between cycles 3 and 4) followed by 3 additional cycles 
(cycles 4-6) of chemotherapy with atezolizumab. The addition of bevacizumab at 
cycle 5 is optional. Surgery must be performed after the third course of 
chemotherapy as soon as nadir counts permit, but preferably within six weeks 
after the completion of the third chemotherapy cycle. Fourth cycle of 
chemotherapy is to be administered as soon as possible, but preferably no more 
than six weeks after ICS.  
Safety monitoring, including assessment for irAEs, will occur at each cycle and 
for 90 days after the last administration of atezolizumab or until start of next anti-
cancer regimen, whichever occurs first. Image assessment by CT scan or MRI 
will be performed at baseline, prior to ICS to assess response, after completion 
of 6 cycles of chemotherapy with atezolizumab to assess response at end of 
treatment, and as clinically indicated during the maintenance phase and after 
completion of study treatment to assess PFS. Disease progression/recurrence 
will be defined per RECIST criteria and will not include isolated asymptomatic 
progression on the basis of CA125 levels. Immune function analysis will be 
performed on blood and tumor samples obtained at two time points: 1. 
confirmatory biopsy prior to start of therapy and 2. ICS. 
It is estimated that 40 patients will be enrolled at an accrual rate of 3-5 
patients/month and followed for a median of 3 years. 
 
3.2 
END OF STUDY 
The end of this study is defined as the date when the last patient, last visit 
(LPLV) occurs or safety follow-up is received from the last patient, whichever 


 
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occurs later.  Safety follow-up is expected to occur 27.5 months after enrollment 
opens. LPLV is dependent on time to progression. Median time to progression 
after completion of chemotherapy is estimated to be ~12 months. 
3.3 
RATIONALE FOR STUDY DESIGN 
NACT-ICS offers an opportunity to evaluate new agents in combination with 
standard therapy, while also providing access to pre- and post-treatment 
biospecimens to evaluate molecular targeting, immunoregulatory function, and 
tumor response. The study is designed to obtain safety data for atezolizumab 
when combined with carboplatin and weekly dose-dense paclitaxel NACT-ICS. 
Evaluating the safety of the combination in this setting will enable future tests of 
the hypothesis that the combination will result in more profound and durable 
responses, in larger randomized trials. The addition of bevacizumab in select 
patients will expand information on the safety, and anti-tumor activity of 
combination chemotherapy, atezolizumab, and bevacizumab.  
 
3.4 
OUTCOME MEASURES 
 
Primary Outcome Measure 
Safety/tolerability of the combination of atezolizumab + NACT-ICS, followed by 
atezolizumab + chemotherapy +/- bevacizumab, followed by maintenance 
atezolizumab +/- bevacizumab will be assessed using the following primary 
safety outcome measures: 
 Ability to undergo planned ICS (when clinically indicated) within 6 weeks 
of last dose of NACT, 
 Incidence, nature, and severity of adverse events and laboratory 
abnormalities as measured by frequency and severity of adverse events 
by NCI CTCAE v5.0, 
 Additional safety outcome measures will include the number of cycles and 
the dose intensity including starting dose and dose modifications of each 
component of the treatment regimen during and following the period of 
protocol-directed therapy.  
 
Secondary Activity Outcome Measures 
The following activity outcome measures will be assessed: 
 Response rate 
 Pathologic complete remission rate (at ICS) 
 PFS 
 OS 


 
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Response/progression will be determined using RECIST v1.1 (see Appendix 4) 
and irRC (see Appendix 5). 
 
Pharmacodynamic/Translational Outcome Measures 
1. Quantitation of pre- and post-treatment changes in: 
 PD-L1 expression 
2. Correlation of above markers, BRCA mutation status, and tumor mutation 
profile with clinical outcomes 
 tumor-infiltrating lymphocyte subpopulations 
 immune checkpoint receptor profiles 
 gene expression profiles associated with immunoactivation 
 cytokine expression profiles 
 angiogenic markers  
 
4. 
MATERIALS AND METHODS 
4.1 
STUDY POPULATION 
 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form (ICF) 
 
Ability and willingness to comply with the requirements of the study 
protocol 
 
Age  18 years 
 
No prior treatment for primary advanced (stage III or IV) epithelial 
ovarian, fallopian tube, or primary peritoneal carcinoma 
 
Confirmation of diagnosis and patients for whom the plan of 
management will include NACT followed by ICS. The decision to 
proceed with NACT will be at the treating physician’s discretion and 
include patients with advanced stage disease considered at low 
likelihood for optimal cytoreduction with primary debulking surgery.  
 
All patients must have measurable disease per RECIST v1.1 (see 
Appendix 4). Measurable disease is defined as at least one lesion that 
can be accurately measured in at least one dimension (longest diameter 
to be recorded). Each lesion must be ≥ 10mm when measured by CT, 
MRI or caliper measurement by clinical exam; or ≥ 20mm when 
measured by chest x-ray. Lymph nodes must be ≥ 15mm in short axis 
when measured by CT or MRI.   
Patients must meet the following criteria prior to initiation of study treatment: 


 
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 
Histology consistent with high-grade epithelial ovarian cancer (excluding 
mucinous carcinoma and clear cell carcinoma) 
 
An adequate pre-treatment tumor biopsy is required for the translational 
research component. Acceptable options include laparoscopic biopsy or 
image-guided core needle biopsy (minimum of two cores). Fine needle 
aspiration (FNA) biopsy or cytology from ascites may be adequate at the 
discretion of the sponsor.  
- 
Subjects for whom newly-obtained samples cannot be provided 
(e.g. inaccessible or subject safety concern) may submit an 
archived specimen of the types listed above only upon 
agreement of the sponsor. 
 
Adequate hematologic and end organ function, defined by the following 
laboratory results obtained within 14 days prior to the first study 
treatment (Cycle 1, Day 1): 
– 
ANC  1500 cells/L 
– 
Lymphocyte count  300/L 
– 
Platelet count  100,000/L  
– 
Hemoglobin  9.0 g/dL 
– 
Total bilirubin  1.5  upper limit of normal (ULN) with the 
following exception:  
Patients with known Gilbert disease who have serum 
bilirubin level  3  ULN may be enrolled. 
– 
AST and ALT  3.0  ULN with the following exception: 
Patients with liver involvement:  AST and/or ALT  5  ULN 
– 
Alkaline phosphatase  2.5  ULN with the following exceptions: 
Patients with documented liver involvement or bone 
metastases: alkaline phosphatase  5  ULN or  
Patients with isolated  5  ULN with elevation AST, ALT, or 
bilirubin 
– 
Creatinine clearance  50 mL/min on the basis of the Cockcroft-
Gault glomerular filtration rate estimation: 
(140  age)  (weight in kg)  (0.85 if female) 
72  (serum creatinine in mg/dL) 
– 
INR and aPTT  1.5  ULN  
This applies only to patients who do not receive therapeutic 
anticoagulation; patients receiving therapeutic 
anticoagulation (such as low-molecular-weight heparin or 
warfarin) should be on a stable dose. 


 
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 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 
1 or 2 (see Appendix 6) 
 
Peripheral neuropathy less than or equal to CTCAE Grade 1 
 
For female patients of childbearing potential, agreement (by patient) to 
use highly effective form(s) of contraception (i.e., one that results in a low 
failure rate [ 1% per year] when used consistently and correctly) and to 
continue its use at least until ICS or if ICS is not performed then 90 days 
post last dose of atezolizumab 
 
Patients who opt to receive bevacizumab must meet standard 
institutional treatment guidelines 
 
 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry. 
General Exclusion Criteria: 
 
Prior systemic chemotherapy for epithelial ovarian, fallopian tube, or 
primary peritoneal cancer.  
 
Prior invasive malignancy (except non-melanomatous skin cancer) 
unless disease free for a minimum of 3 years.  
- 
Exceptions include basal cell or squamous cell carcinoma of 
the skin, or in situ cervical cancer that has undergone 
potentially curative therapy.  
 
AEs from prior anticancer therapy that have not resolved to Grade  1 
except for alopecia 
 
Bisphosphonate therapy for symptomatic hypercalcemia 
– 
Use of bisphosphonate therapy for other reasons (e.g., bone 
metastasis or osteoporosis) is allowed. 
 
Known clinically significant liver disease, including active viral, alcoholic, 
or other hepatitis; cirrhosis; fatty liver; and inherited liver disease 
 
Known primary central nervous system (CNS) malignancy or 
symptomatic CNS metastases 
 
Pregnancy, lactation, or breastfeeding 
 
Known hypersensitivity to Chinese hamster ovary cell products or other 
recombinant human antibodies 
 
Inability to comply with study and follow-up procedures 
 
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, Bell’s palsy, 


 
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Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, 
vasculitis, or glomerulonephritis 
– 
Patients with a history of autoimmune hypothyroidism on a stable 
dose of thyroid replacement hormone may be eligible. 
– 
Patients with controlled Type 1 diabetes mellitus on a stable 
insulin regimen may be eligible. 
– 
Patients with eczema, psoriasis, lichen simplex chronicus of 
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%, aclometasone 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) 
 
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. 
 
Any other diseases, metabolic dysfunction, physical examination finding, 
or clinical laboratory finding giving reasonable suspicion of a disease or 
condition that contraindicates the use of an investigational drug or that 
may affect the interpretation of the results or render the patient at high 
risk from treatment complications 
 
History of HIV infection or active hepatitis B (chronic or acute) or 
hepatitis C infection 
– 
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. 


 
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 
Active tuberculosis 
 
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 
 
Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1 
 
Received oral or 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. 
 
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 
– 
Influenza vaccination should be given during influenza season 
only (approximately October to March).  Patients must not 
receive live, attenuated influenza vaccine (e.g., FluMist) within 4 
weeks prior to Cycle 1, Day 1 or at any time during the study. 
 
Medication-Related Exclusion Criteria: 
 
Prior history of treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CD137, anti-CTLA4 or any other antibodies targeting co-stimulation or 
checkpoint pathways 
 
Treatment with systemic immunostimulatory agents (including but not 
limited to interferon [IFN]- or interleukin [IL]-2) within 6 weeks or five 
half-lives of the drug (whichever is shorter) prior to Cycle 1, Day 1 
 
Treatment with investigational agent within 4 weeks prior to Cycle 1, Day 
1 (or within five half-lives of the investigational product, whichever is 
longer) 
 
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) may be enrolled. 
– 
The use of inhaled corticosteroids and mineralocorticoids (e.g., 
fludrocortisone) for patients with orthostatic hypotension or 
adrenocortical insufficiency is allowed. 
 
History of severe allergic, anaphylactic, or other hypersensitivity 
reactions to chimeric or humanized antibodies or fusion proteins 


 
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 
Patients with prior allogeneic bone marrow transplantation or prior solid 
organ transplantation 
 
 
4.2 
STUDY TREATMENT 
 
Study Drug:  Atezolizumab 
Once marketing authorization is received commercial atezolizumab will be used 
and will not be provided by Genentech for “on-label” studies.  For studies done 
before marketing authorization and/or "out of label", atezolizumab will be 
provided free of charge by Genentech but switched to commercial drug once 
marketing authorization is received.  Genentech will replace any atezolizumab 
drug that is not reimbursed.  For studies done “out of label,” atezolizumab will be 
provided free of charge by Genentech.  The Sponsor-investigator of the study will 
ensure maintenance of complete and accurate records of the receipt, 
dispensation, and disposal or return of all study drug in accordance with 21 Code 
of Federal Regulations (CFR), Part 312.57 and 312.62, and Genentech 
requirements. 
4.2.1.1 
Formulation and Storage 
 
The atezolizumab drug product is provided in a single-use, 20-cc USP/Ph. Eur. 
Type 1 glass vial as a colorless-to-slightly-yellow, sterile, preservative-free clear 
liquid solution intended for IV administration.  The vial is designed to deliver 20 
mL (1200 mg) of atezolizumab solution but may contain more than the stated 
volume to enable delivery of the entire 20 mL volume.  The atezolizumab drug 
product is formulated as 60 mg/mL atezolizumab in 20 mM histidine acetate, 
120 mM sucrose, 0.04% polysorbate 20, pH 5.8. 
Atezolizumab must be refrigerated at 2°C  8°C (36°F  46°F) upon receipt until 
use.  Atezolizumab vials should not be used beyond the expiration date provided 
by the manufacturer.  No preservative is used in the atezolizumab drug product; 
therefore, each vial is intended for single use only.  Discard any unused portion 
of drug left in a vial.  Vial contents should not be frozen or shaken and should be 
protected from direct sunlight. 
For further details, see the atezolizumab Investigator’s Brochure. 
 
Protocol-Specified Chemotherapy  
Carboplatin, paclitaxel, with or without bevacizumab will be administered 
according to the dose and schedule listed in Section 4.2.3. 


 
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4.2.2.1 
Formulation and Storage 
Sites will obtain carboplatin, paclitaxel, with or without bevacizumab through 
commercial supply and must refer to the package insert for detailed 
pharmacologic, storage, and safety information. 
 
 
Dosage, Schedule, Administration, and Premedications 
On days of scheduled atezolizumab, carboplatin, paclitaxel, with or without 
bevacizumab chemotherapy is to be administered, in the following manner: 
1. Paclitaxel 70-80 mg/m2 IV administered over approximately one hour 
followed by 
2. Carboplatin IV administered over 15-30 minutes to achieve an initial target 
AUC of 5-6 mg/mL/Min (Calvert formula dosing) followed by 
3. For patients who elect to receive bevacizumab, bevacizumab will be given 
15 mg/kg IV administered over 90 (± 15) minutes for the first infusion. If 
previous infusion is well tolerated by patient, then infusion period may be 
reduced to 60 (± 10) minutes. The infusion period time can be reduced to 
30 (± 10) minutes for subsequent infusions dependent on patient 
tolerability.  
4. Atezolizumab 1200 mg administered over 60 (± 15) minutes for the first 
infusion. If previous infusion is well tolerated by patient, then infusion 
period may be reduced to 30 (± 15) minutes for subsequent infusions 
Sites should follow their institutional standard of care for determining 
chemotherapy dose for obese patients and for dose adjustments in the event of 
patient weight changes. 
Carboplatin, paclitaxel, with or without bevacizumab will be administered per 
local institution standards with the following pre-medications administered prior to 
paclitaxel infusion:  
 an H1 blocker (such as diphenhydramine, loratadine, or fexofenadine) and  
 an H2 blocker (such as ranitidine or cimetidine).  
 Because steroids may attenuate the beneficial effect of atezolizumab, 
corticosteroid pre-medication will be minimized when possible (refer to 
Section 4.3.1 Concomitant Therapy). It is recommended that 
dexamethasone 10mg IV be administered prior to paclitaxel during cycle 
1D1. If there is no evidence of hypersensitivity reaction, dexamethasone 
should be reduced to 5 mg on C1D8 and omitted beginning with C1D15, 
unless hypersensitivity develops. Hypersensitivity reactions and 


 
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subsequent chemotherapy treatments should be managed according to 
institutional standards. In cases of atezolizumab related toxicity, steroids 
may be administered at the discretion of the treating investigator.  
The dose level of atezolizumab to be tested in this study is 1200 mg (equivalent 
to an average body weightbased dose of 15 mg/kg) administered by IV infusion 
every 3 weeks (21 [ 2] days).  Administration of atezolizumab will be performed 
in a setting with emergency medical facilities and staff who are trained to monitor 
for and respond to medical emergencies. 
Atezolizumab will be delivered in infusion bags with IV infusion lines that have 
product contacting surfaces of polyvinyl chloride (PVC) or polyolefin and 0.2 m 
in-line filters (filter membrane of polyethersulfone [Kehoe,  #8]).  No 
incompatibilities have been observed between atezolizumab and PVC or 
polyolefin infusion materials (bags or infusion lines).  
The initial dose of atezolizumab will be delivered over 60 (±15) minutes.  If the 
first infusion is tolerated without infusion associated AEs, subsequent infusions 
can be delivered over 30 (± 10) minutes.  Vital signs should be collected 
according to institutional standards during the infusion only if clinically indicated.  
Patients will be informed about the possibility of delayed post-infusion symptoms 
and instructed to contact their study physician if they develop such symptoms. 
The management of IRRs will be according to severity as follows: 
 
In the event that a patient experiences a mild (NCI CTCAE Grade 1) 
IRR, the infusion rate should be reduced to half the rate being given at 
the time of event onset.  Once the event has resolved, the investigator 
should wait for 30 minutes while delivering the infusion at the reduced 
rate.  If tolerated, the infusion rate may then be increased to the original 
rate. 
 
In the event that a patient experiences a moderate IRR (NCI CTCAE 
Grade 2) or flushing, fever, or throat pain, the infusion should be 
immediately interrupted and the patient should receive aggressive 
symptomatic treatment.  The infusion should be restarted only after the 
symptoms have adequately resolved to baseline grade.  The infusion 
rate at restart should be half of the infusion rate that was in progress at 
the time of the onset of the IRR. 
 
For severe or life-threatening IRRs (NCI CTCAE Grade 3 or 4), the 
infusion should be stopped immediately, and aggressive resuscitation 
and supportive measures should be initiated.  Patients experiencing 
severe or life-threatening IRRs will not receive further infusion and will be 
further managed as clinically indicated until the event resolves. 
 
For anaphylaxis precautions, see Appendix 7. 


 
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Guidelines for dosage modification, treatment interruption, or discontinuation and 
the management of specific adverse events are provided in Section 4.6 and 
Section 4.4.2, respectively. 
4.3 
CONCOMITANT AND EXCLUDED THERAPIES 
 
Concomitant Therapy 
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 related to atezolizumab 
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 2-adrenergic agonists; 
see Appendix 7). 
Systemic corticosteroids and TNF 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 stable dose level), or other allowed maintenance 
therapy (see Section 4.1.2) should continue their use.  Females of reproductive 
potential should use highly effective means of contraception.  
 
Excluded Therapy 
Any concomitant therapy, other than outlined within the protocol, 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. 
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 


 
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may result in unanticipated drug-drug interactions that may cause, or 
confound assessment of, toxicity. 
 
The use of a RANKL inhibitor (denosumab) must be discontinued during 
the study; this agent could potentially alter the activity and the safety of 
atezolizumab. 
 
Patients are not allowed to receive immunostimulatory agents, including but not 
limited to IFN-, IFN-, 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-TNF 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. 
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. 
4.4 
GENERAL PLAN TO MANAGE SAFETY CONCERNS 
Measures will be taken to ensure the safety of patients participating in this trial, 
including the use of stringent inclusion and exclusion criteria (see Section 4.1.1 and 
Section 4.1.2) and close monitoring (as indicated below and in Section 4.8.2).  See 
Section 6.3.2 for complete details regarding safety reporting for this study.  
Eligibility Criteria 
Eligibility criteria were selected to guard the safety of patients in this trial.  
Results from the nonclinical toxicology studies with atezolizumab, as well as the 
nonclinical/clinical data from other PD-L1/PD-1 inhibitors, were taken into 
account (see Section 4.1.2). 
Monitoring 
Safety will be evaluated in this study through the monitoring of all serious and 
non-serious AEs, defined and graded according to NCI CTCAE v5.0.  Patients 
will be assessed for safety (including laboratory values) according to the 
schedule in Appendix 1.  Patients will be followed for safety for 90 days following 
the last dose of study treatment or until receipt of another anticancer therapy, 
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General safety assessments will include serial interval histories, physical 
examinations, and specific laboratory studies, including serum chemistries and 
blood counts (see Appendix 1 for the list and timing of study assessments).  
All serious adverse events (SAEs) and protocol-defined events of special interest 
(see Section 6.2.2) will be reported in an expedited fashion (see Section 6.3).  In 
addition, the investigators will review and evaluate observed AEs on a regular 
basis. 
Patients who have an ongoing study treatmentrelated AE upon study 
completion or at discontinuation from the study will be followed until the event 
has resolved to baseline grade, the event is assessed by the investigator as 
stable, new anticancer treatment is initiated, the patient is lost to follow-up, the 
patient withdraws consent, or until it has been determined that study treatment or 
participation is not the cause of the AE. 
 
Dose Modification of Chemotherapy 
Reasons for dose modifications or delays, the supportive measures taken, and 
the outcomes will be documented in the patient’s chart and recorded on the 
eCRF. The severity of adverse events will be graded according to the NCI 
CTCAE v5.0 grading system. 
Dose modifications and interruptions should proceed in accordance with good 
clinical practice and institutional applicable guidelines (See Appendix 13 for Dose 
Modifications and Day 1 Dosing Criteria for hematologic dosing modifications). 
Patients enrolled may use colony stimulating factors, such as granulocyte colony-
stimulating factor (G-CSF) and erythropoietin, per guidelines of the American 
Society of Clinical Oncology (ASCO) and ASCO/American Society of 
Hematology (ASH) guidelines, respectively [19, 20]. Evidence supporting the use 
of long-acting (pegylated) forms of G-CSF in patients receiving weekly 
chemotherapy is limited, thus preference should be given to conventional 
formulations of G-CSF.  Use of G-CSF is at the discretion of the treating 
physician. 
When treatment is temporarily interrupted because of toxicity caused by 
chemotherapy, treatment cycles will be restarted such that the atezolizumab 
infusions remain synchronized and aligned with the chemotherapy schedule. 
If chemotherapy is discontinued secondary to toxicity, the patient may continue to 
receive atezolizumab as long as she is experiencing clinical benefit in the opinion 
of the investigator. 
Dosing for bevacizumab will be based on institutional standards.  
 
 
Management of Specific Safety Concerns with Atezolizumab 
Toxicities associated or possibly associated with atezolizumab treatment should 
be managed according to standard medical practice.  Additional tests, such as 


 
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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.  
Discontinuation of atezolizumab may not have an immediate therapeutic effect 
and, in severe cases, immune-related toxicities may require acute management 
with topical corticosteroids, systemic corticosteroids, mycophenolate, or TNF 
inhibitors. 
The primary approach to Grade 1 to 2 irAEs is supportive and symptomatic care 
with continued treatment with atezolizumab; for higher-grade irAEs, atezolizumab 
should be withheld and oral and/or parenteral steroids administered.  Recurrent 
Grade 2 irAEs may also mandate withholding atezolizumab or the use of 
steroids.  Assessment of the benefit-risk balance should be made by the 
investigator, with consideration of the totality of information as it pertains to the 
nature of the toxicity and the degree of clinical benefit a given patient may be 
experiencing prior to further administration of atezolizumab.  Atezolizumab 
should be permanently discontinued in patients with life-threatening irAEs. 
 
Guidelines for Atezolizumab Dosage Modification, Treatment 
Interruption, or Discontinuation 
Atezolizumab treatment will be given until there is unacceptable toxicity, lack of 
clinical benefit, or a total duration of 22 cycles. 
There will be no dose reduction for atezolizumab in this study.  Patients may 
temporarily suspend study treatment for up to 84 days 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 Section 6.3.1. 
If a patient must be tapered off steroids used to treat AEs, atezolizumab may be 
held for additional time beyond 84 days from the scheduled dose until steroids 
are discontinued or reduced to a prednisone dose (or dose equivalent) of  10 
mg/day. Post treatment steroids to reduce atezolizumab related adverse events 
are acceptable based on investigator discretion.  The acceptable length of 
interruption will be at the discretion of the investigator. 
Dose interruptions for reasons other than toxicity, such as surgical procedures, 
may be allowed.  The acceptable length of interruption will be at the discretion of 
the Sponsor. 


 
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Any toxicities associated or possibly associated with atezolizumab treatment 
should be managed according to standard medical practice.  Additional tests, 
such as autoimmune serology or biopsies, may be used to determine a possible 
immunogenic etiology.  Although most irAEs observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early 
and treated promptly to avoid potential major complications.  Discontinuation of 
atezolizumab may not have an immediate therapeutic effect, and there is no 
available antidote for atezolizumab.  In severe cases, immune-related toxicities 
may be acutely managed with topical corticosteroids, systemic corticosteroids, 
mycophenolate, or TNF inhibitors. 
Patients should be assessed clinically (including review of laboratory values) for 
toxicity prior to, during, and after each infusion.  If unmanageable toxicity due to 
atezolizumab occurs at any time during the study, treatment with atezolizumab 
should be discontinued. 
The atezolizumab Investigator's Brochure and the National Comprehensive 
Cancer Network (NCCN) guidelines provide guidelines for the management of 
patients who experience atezolizumab-associated IRRs and immune-related 
pulmonary, hepatitic, gastrointestinal, endocrine, ocular, pancreatic, 
dermatologic, neurologic, and meningoencephalitis events. The decision to 
withthold or discontinue atezolizumab may be made at the discretion of the 
investigator per the guidelines in the atezolizumab Investigator's Brochure,  
NCCN Guidelines, or Institutional guidelines. Management of 
hepatitis/transaminitis, colitis, rash, and hypothyroidism are presented in this 
section as they have been observed in prior studies and are potentially immune 
related.  See Section 4.4.3 for guidelines for the management of IRRs (see 
Appendix 7 for precautions for anaphylaxis). 
Further information regarding adverse event management is provided. 
Management can be based on atezolizumab Investigator’s Brochure, NCCN 
guidelines, and institutional guidelines at the discretion of the investigator. Data 
regarding immune related adverse events are increasing and management 
options are evolving. The incorporation of all these resources allow the 
investigator to use the most current management guidelines.  
4.4.3.1 
Gastrointestinal Toxicity 
Immune-mediated colitis has been associated with the administration of 
atezolizumab. 
Patients should be advised to inform the investigator if any diarrhea occurs, even 
if it is mild. 


 
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If the event is of significant duration or magnitude, or is associated with signs of 
systemic inflammation or acute phase reactants (e.g., increased CRP or platelet 
count or bandemia), sigmoidoscopy (or colonoscopy, if appropriate) with colonic 
biopsy is recommended. Ideally three to five specimens for standard paraffin 
block should be performed with one or two biopsy specimens snap frozen and 
stored if possible.     
Treatment may be restarted following the resolution of colitis.  In addition, if the 
patient is being managed with corticosteroids, treatment should not be restarted 
until the steroids have been tapered down to a prednisone dose  10 mg/day.  
Patients who resume treatment should be monitored closely for signs of renewed 
diarrhea.  Table 4.4.3.1 provides a summary of dose modification guidelines for 
gastrointestinal toxicities that may be used at investigator discretion. 
Table 4.4.3.1 Dose Interruption Guidelines for Gastrointestinal Toxicity 
*Immunotherapy is atezolizumab 
 
4.4.3.2 
Hepatotoxicity 
Immune-mediated hepatitis has been associated with the administration of 
atezolizumab. 
While in this study, patients presenting with right upper-quadrant abdominal pain 
and/or unexplained nausea or vomiting should have LFTs performed 
immediately, and LFTs should be reviewed before administration of the next 
dose of study drug. 


 
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If LFTs increase, neoplastic, concurrent medications, viral hepatitis, and toxic 
etiologies should be considered and addressed, as appropriate.  Imaging of the 
liver, gall bladder, and biliary tree should be performed to rule out neoplastic or 
other causes of increased LFTs.  Anti-nuclear antibody, perinuclear anti-
neutrophil cytoplasmic antibody, anti-liver kidney microsomal, and anti-smooth 
muscle antibody tests should be performed if an autoimmune etiology is 
considered. 
Patients with LFT abnormalities may be managed according to the guidelines in 
Table 4.4.3.2. at the discretion of the investigator. 
 
Table 4.4.3.2 Dose Interruption Guidelines for Hepatotoxicity 
*Immunotherapy is atezolizumab 
 


 
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Table 4.4.3.2 Dose Interruption Guidelines for Hepatotoxicity (cont.) 
 
  
4.4.3.3 
Dermatologic Toxicity 
Treatment-emergent rash has been associated with atezolizumab.  The majority 
of cases of rash were mild in severity and self-limited, with or without pruritus. 
Management of the skin rash may be performed based on guidelines and in 
Table 4.4.3.3 as well as per institutional standards. Consider alerting a 
dermatologist at your center so that patients can be seen quickly in the event of 
development of the rash which may occur suddenly. A skin biopsy may be helpful 
to further evaluate the etiology of the rash. For maculopapular rash on face, 
consider alclometasone 0.05% cream BID. For maculopapular rash on body, 
consider clobetasol 0.05% cream BID. 
For body fold rash, consider triamcinolone 0.1% cream plus Silvadene 1% mixed 
1:1 and applied BID. 
For pruritis grade 1, consider antipruritics such as hydroxyzine, cetirizine, 
diphenhydramine, loratadine, etc. For pruritis grade 2 or 3, antipruritics and 
consider Lyrica 25-50 mg BID, can increase as needed/tolerated up to 450 mg a 
day. 
 
 


 
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Table 4.4.3.3 Dose Interruption Guidelines for Dermatologic Toxicity 
*Immunotherapy is atezolizumab 
 
 
 


 
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Table 4.4.4 Dose Interruption Guidelines for Dermatologic Toxicity (cont.) 
 
 
 
4.4.3.4 
Endocrine Toxicity 
Hypothyroidism and hyperthyroidism has been associated with the administration 
of atezolizumab. 
Patients with unexplained symptoms such as fatigue, myalgias, impotence, 
mental status changes, or constipation should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies, as well as for hyponatremia or 
hyperkalemia.  An endocrinologist should be consulted if an endocrinopathy is 
suspected.   
Thyroid-stimulating hormone (TSH) and free T4 levels should be obtained to 
determine whether thyroid abnormalities are present.  TSH, prolactin, and a 
morning cortisol level will help to differentiate primary adrenal insufficiency from 
primary pituitary insufficiency. 
Hypothyroidism may be managed according to guidelines and in Table 4.4.3.4.as 
well as per institutional standards. 
 
 


 
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Table 4.4.3.5 Dose Interruption Guidelines for Endocrine Toxicity 
*Immunotherapy is atezolizumab 
 
 
 


 
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Table 4.4.3.6 Dose Interruption Guidelines for Endocrine Toxicity (cont.) 
 
 
 
 


 
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4.4.3.5 
Pulmonary Toxicity 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have 
been associated with the administration of atezolizumab and have primarily been 
observed in patients with underlying NSCLC. 
Mild-to-moderate events of pneumonitis have been reported with atezolizumab.  
All pulmonary events should be thoroughly evaluated for other commonly 
reported etiologies such as pneumonia/infection, lymphangitic carcinomatosis, 
pulmonary embolism, heart failure, chronic obstructive pulmonary disease 
(COPD), or pulmonary hypertension and the following should be performed: 
 
Measurement of oxygen saturation (i.e., arterial blood gas) 
 
High-resolution CT scan of the chest 
 
Bronchoscopy with bronchoalveolar lavage and biopsy 
 
Pulmonary function tests (with diffusion capacity of the lung for carbon 
monoxide [DLCO]) 
 
Patients will be assessed for pulmonary signs and symptoms throughout the 
study.  Patients will also have CT scans of the chest at every tumor assessment 
(see Section 4.8.2). 
Pulmonary toxicity may be managed according to guidelines and in Table 
4.4.3.5. as well as per institutional standards. 
Table 4.4.3.7 Dose Interruption Guidelines for Pulmonary Toxicity 
*Immunotherapy is atezolizumab
 


 
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Table 4.4.3.8 Dose Interruption Guidelines for Pulmonary Toxicity (cont.) 
 
 
4.4.3.6 
Potential Pancreatic Toxicity 
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with administration of other 
immunomodulatory agents.  The differential diagnosis of acute abdominal pain 
should include pancreatitis.  Appropriate workup may include an evaluation for 
obstruction, as well as serum amylase and lipase tests (see also 
Section 4.4.3.4). 
4.4.3.7 
Potential Eye Toxicity 
An ophthalmologist should evaluate visual complaints.  Uveitis or episcleritis may 
be treated with topical corticosteroid eye drops.  Atezolizumab should be 
permanently discontinued for immune-mediated ocular disease that is 
unresponsive to local immunosuppressive therapy. 
Ocular toxicity may be managed according to the guidelines in Table 4.4.3.7 as 
well as per institutional standards. 
 
 
 
 


 
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Table 4.4.3.7 Dose Interruption Guidelines for Eye Toxicity 
*Immunotherapy is atezolizumab 
 
 
4.4.3.8 
Potential Cardiac Toxicity 
Immune-related myocarditis has been associated with the administration of 
atezolizumab. Immune-related myocarditis should be suspected if any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not 
limited to, dyspnea, chest pain, palpitations, fatigue, decreased exercise 
tolerance, or syncope. Immune-related myocarditis needs to be distinguished 
from myocarditis resulting from infection (commonly viral, e.g., in a patient who 
reports a recent history of GI illness), ischemic events, underlying arrhythmias, 
exacerbation of preexisting cardiac conditions, or progression of malignancy. 
All patients with possible myocarditis should be urgently evaluated by performing 
cardiac enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a 
cardiac MRI as appropriate per institutional guidelines. A cardiologist should be 
consulted. An endomyocardial biopsy may be considered to enable a definitive 
diagnosis and appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, may be treated according to the guidelines, and in Table 
4.4.3.8 as well as per institutional standards. 


 
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Table 4.4.3.8 Dose Interruption Guidelines for Cardiac Toxicity 
*Immunotherapy is atezolizumab 
 
 
4.4.3.9 
Principles of Immunosuppression 
Please see below for references to Principles of Immunosuppression as related to the 
management of toxicities. 
 


 
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4.4.3.10 Principles of Immunotherapy Rechallenge 
Please see below for references to Principles of Immunotherapy Rechallenge as 
related to the management of toxicities. 
 


 
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Guidelines for Interval Cytoreduction Surgery Modification 
4.4.4.1 
In the event a patient is unable to get surgery after cycle 3 due to 
medical issues, the patient may still continue on study at the 
discretion of the treating physician and the Duke PI. 
4.4.4.2 
In the event a patient needs to have interval cytoreductive surgery 
earlier than the scheduled timeframe due to medical issues, the 
patient may have the surgery earlier and continue on study at the 
discretion of the treating physician and the Duke PI. 
4.4.4.3 
For patients with modified ICS timelines, optional bevacizumab timing 
will differ. Bevacizumab should not be given the cycle prior and the 
cycle after ICS. Timing of bevacizumab administration will be at the 
discretion of the treating physician. 
 
4.5 
PATIENT DISCONTINUATION 
Patients have the right to voluntarily withdraw from the study at any time for any 
reason.  In addition, the investigator has the right to withdraw a patient from the 
study at any time.  Reasons for withdrawal from the study may include, but are 
not limited to, the following: 
 
Patient withdrawal of consent at any time 
 
Any medical condition that the investigator or Sponsor determines may 
jeopardize the patient’s safety if he or she continues in the study 
 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Patient non-compliance with protocol or treatment 
 


 
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Every effort should be made to obtain information on patients who withdraw from 
the study.  The primary reason for withdrawal from the study should be 
documented on the appropriate Case Report Form (CRF).  However, patients will 
not be followed for any reason after consent has been withdrawn.  Patients who 
withdraw from the study will not be replaced. 
 
See Section 4.8.2 and Section 4.8.3 for assessments that are to be performed for 
patients who prematurely withdraw from the study during the treatment period. 
4.6 
STUDY TREATMENT DISCONTINUATION 
Patients must discontinue study treatment if they experience any of the following: 
 
Pregnancy 
 
Immune-related toxicities as outlined in Section 4.4.3 
 
Intercurrent illness, which in the judgment of the investigator, affects 
assessments of clinical status to a significant degree or requires 
discontinuation of study treatment 
 
Non-protocol anti-cancer therapy (including but not limited to 
chemotherapy, hormonal therapy, or immunotherapy) administered 
during study treatment (refer to Section 4.3) 
 
Wish to discontinue treatment. 
 
The primary reason for study treatment discontinuation should be documented 
on the appropriate CRF.  Patients who discontinue study treatment prematurely 
will not be replaced. Patients who discontinue for toxicity or choice can continue 
to be followed per protocol to assess study objectives.   
4.7 
STUDY AND SITE DISCONTINUATION 
The Sponsor has the right to terminate this study at any time.  Reasons for 
terminating the study may include, but are not limited to, the following: 
 
The incidence or severity of AEs in this or other studies indicates a 
potential health hazard to patients. 
 
Patient enrollment is unsatisfactory. 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the 
study.   
The Sponsor has the right to close a site at any time.  Reasons for closing a site 
may include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 


 
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 
Non-compliance with the International Conference on Harmonisation 
(ICH) guideline for Good Clinical Practice (GCP) 
 
No study activity (i.e., all patients have completed and all obligations 
have been fulfilled) 
 
4.8 
CLINICAL AND LABORATORY EVALUATIONS 
 
Pretreatment Evaluations 
Written documentation of full, unconditional IRB approval of the protocol and 
consent document must be on file before a patient can be screened. Patients will 
be assigned a study identification number upon signing consent.  
The following pretreatment evaluations must be performed within 4 weeks of 
initiation of study treatment: 
1. Signed patient informed consent 
2. Medical history 
3. Physical exam, including height, weight, and vital signs 
4. Serum pregnancy test, if applicable 
5. Baseline imaging (CT or MRI) 
6. Laparoscopic excisional or image-guided core biopsy to confirm diagnosis 
and obtain research specimens 
The following pretreatment evaluations must be performed within 14 days of 
initiation of study treatment: 
7. Laboratory evaluations including: CBC with auto differential, CMP, CA125, 
TSH, magnesium, phosphorus.  
 
Study Assessments 
The flowchart of scheduled study assessments is provided in Appendix 1.  
Patients will be closely monitored for safety and tolerability throughout the study.  
All assessments must be performed and documented for each patient. 
Patients should be assessed for toxicity prior to each dose; dosing will occur only 
if the clinical assessment and local laboratory test values are acceptable. 
If the timing of a protocol-mandated study visit coincides with a holiday and/or 
weekend that precludes the visit, the visit should be scheduled on the nearest 
following feasible date, with subsequent visits rescheduled accordingly. 


 
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4.8.2.1 
Medical History 
Medical history includes clinically significant diseases within the previous 5 years, 
smoking history, cancer history (including tumor characteristics such as hormone 
receptor status), prior cancer therapies and procedures, and all medications used 
by the patient within 7 days before the screening visit (including prescription, 
over-the-counter, and herbal/homeopathic remedies and therapies). 
4.8.2.2 
Vital Signs 
Vital signs may include measurements of heart rate, respiratory rate, systolic and 
diastolic blood pressures, and temperature. 
Vital signs should be collected during the infusion per institutional standard and 
as clinically indicated.  Patients will be informed about the possibility of delayed 
post-infusion symptoms and instructed to contact their study physician if they 
develop such symptoms. 
4.8.2.3 
Physical Examination 
A complete physical examination will be performed at screening and at the 
treatment discontinuation visit and may include the evaluation of head, eye, ear, 
nose, and throat and cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, and neurologic systems. 
A limited physical examination will be performed at other visits to assess 
changes from baseline abnormalities and any new abnormalities and to evaluate 
patient-reported symptoms.  New or worsened abnormalities should be recorded 
as AEs if appropriate. 
As part of tumor assessments, a physical examination will be performed. 
All patients should be monitored for symptoms of brain metastases.  Symptoms 
suggestive of new or worsening CNS metastases should prompt a full 
neurological examination.  A CT or magnetic resonance imaging (MRI) scan of 
the head should be done as clinically indicated to confirm or refute new or 
worsening brain involvement. 
If the screening exam is performed within 3 days of day#1 of cycle #1, the exam 
does not need to be performed again.  
4.8.2.4 
Tumor and Response Evaluation 
Any evaluable or measurable disease must be documented at screening and 
reassessed at each subsequent tumor evaluation.  For solid malignancy patients 
with measurable disease, response will be assessed by the investigator per 
RECIST v1.1 (see Appendix 4) and immune-related response criteria (irRC; see 
Appendix 5).  


 
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Imaging (CT or MRI) will be performed as follows: 
1. during the screening period, to document measurable disease 
2. after 3 cycles of chemotherapy with atezolizumab (prior to ICS) to 
assess response and suitability for ICS,  
3. after completion of 6 cycles of chemotherapy with atezolizumab to 
assess response at end of chemotherapy treatment,  
4. as clinically indicated during the maintenance therapy with 
atezolizumab alone and after completion of study treatment (to assess 
PFS).  
4.8.2.5 
Laboratory Assessments 
Samples for hematology, serum chemistries, coagulation, urinalysis, and the 
pregnancy test will be analyzed at the study site’s local laboratory.  See Study 
Flowchart for timing of laboratory assessments (Appendix 1). 
Local laboratory assessments will include the following: 
 
Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC 
count with differential [neutrophils, eosinophils, lymphocytes, monocytes, 
basophils, and other cells], and platelet count) 
 
Serum chemistries (glucose, BUN, creatinine, sodium, potassium, 
magnesium, chloride, bicarbonate, calcium, phosphorus, total bilirubin, 
ALT, AST, alkaline phosphatase, total protein, and albumin) 
 
CA-125 
 
Coagulation (aPTT and INR) 
 
Pregnancy test (for women of childbearing potential, including women 
who have had a tubal ligation) if/when indicated 
 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood) 
 
Thyroid function testing (TSH and free T4, if TSH is elevated), hepatitis B 
virus (HBV) serology (HBsAg, antibodies against HBsAg, hepatitis B core 
antigen), and HCV serology (anti-HCV) as clinically indicated 
- 
HBV DNA test is required for patients who have known 
positive serology for anti-HBc  
- 
HCV RNA test is required for patients who have known positive 
serology for anti-HCV 
  
Refer to Section 9 and the laboratory manual for additional details on 
translational laboratory assessments and sample handling. 


 
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Treatment Discontinuation Visit and Safety Follow-up 
Patients who discontinue from treatment will be asked to return to the clinic no 
more than 30 days after the last treatment for a treatment discontinuation visit.  
The visit at which a response assessment shows progressive disease may be 
used as the treatment discontinuation visit. Patients will be followed for safety for 
90 days following the last dose of atezolizumab or until receipt of another 
anticancer therapy, whichever comes first.   
 
Follow-Up Assessments 
If the maintenance atezolizumab is completed or discontinued before disease 
recurrence, the patient will be followed for recurrence according to NCCN 
guidelines [11]. Specifically, patients should be evaluated with physical exam at 
routine intervals and if there is concern for clinical relapse or serially rising 
CA125, imaging studies as clinically indicated should be obtained. Disease 
assessments will be recorded on the patient CRF until treatment with another 
anticancer therapy for recurrence is initiated. 
 
Long-Term Follow-up 
After disease recurrence, survival data will be collected every 6 months (+/- 1 
month) from the treating physician, research coordinator, public records, or by 
direct contact with the patient by the investigator for a maximum of 5 years from 
Cycle 1 Day 1. Information about further treatments for ovarian cancer will also 
be collected as possible by the investigator. 
 
5. 
STATISTICAL ANALYSES 
 
5.1 
DEFINITIONS 
Progression Free Survival: All patients will be evaluated for progression free 
survival from the date of first treatment to the date of first observation of 
progressive disease or death due to any cause or will be censored at date of last 
follow-up for those still alive without disease progression. 
 
Overall Survival: All patients will be evaluated for overall survival from the date of 
first treatment on protocol to the date of death due to any cause and will be 
censored at date of last follow-up for those still alive. 
 
Sample Size: It is estimated that 40 patients will be enrolled at an accrual rate of 
3-5 patients/month and followed for a median of 3 years 
 
5.2 
STUDY DESIGN/STOPPING RULE 
This study is a phase Ib trial with the endpoint of validating the safety of the 
combination of atezolizumab in combination with weekly dose-dense paclitaxel 


 
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and carboplatin for treatment of ovarian cancer in the neoadjuvant setting. The 
primary adverse event of interest is the inability of patients to proceed to planned 
ICS within the specified timeframe (≤6 weeks from last dose of NACT) as a 
result of atezolizumab-related toxicities. With NACT, approximately 12% of 
patients are unable to proceed to surgery due to lack of response or 
comorbidities [21]. Thus, there is a ≥ 90% chance that ≤ 2 patients out of 10 
would be unable to proceed to surgery and a ≥ 90% chance that ≤ 5 patients 
out of 25 would be unable to proceed to surgery. Thus, we have set the following 
as stopping rules for the study combination: 
 
 If there are 3 or more patients out of the first 10 patients who are unable to 
proceed to surgery within the expected timeframe due to adverse events, 
enrollment will be paused. The chance of stopping the trial is less than 
10% if the combination causes fewer patients to be unable to proceed to 
surgery than standard care. Under this stopping rule, the chance of 
stopping the trial is 44% if true rate of patients who are unable to proceed 
to surgery is 24%; 
 If there are 6 or more patients, out of the first 25 patients evaluable in the 
safety population, unable to proceed to surgery within the expected time 
frame due to adverse events, enrollment will be paused. The chance for 
stopping the trial is less than 10% if the combination causes fewer patients 
to be unable to proceed to surgery than standard care. Under this 
stopping rule, the chance of stopping the trial is 58% even if true rate of 
patients who are unable to proceed to surgery is 24%. 
 
In the event of unacceptable atezolizumab-related toxicity that interferes with 
performance of ICS, an amendment to the dose and/or schedule of 
chemotherapy will be considered to improve tolerability, and the new 
dose/schedule will be evaluated according to the same decision rules. We will 
provide an estimate of the proportion unable to go to surgery and its 95% 
binomial exact confidence interval. 
 
5.3 
POPULATIONS 
 
Safety Population 
Data from all subjects who receive any protocol therapy will be included in the 
safety analyses. Subjects who entered the study and did not receive any protocol 
therapy, and had this confirmed, will not be evaluated for safety. 
 
Pharmacodynamic/Translational Population 
The pharmacodynamic/translational population will consist of all subjects with 
any evaluable translational study results (including PD-L1 expression, tumor-
infiltrating lymphocyte subpopulations, immune checkpoint receptor profiles, 
gene expression profiles associated with immunoactivation, cytokine expression 
profiles, BRCA mutation status, tumor mutation profiles, and angiogenic markers. 


 
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Efficacy Evaluable Population 
The efficacy population will include all subjects who receive at least 1 dose of 
study drug. Patients without a post-dose efficacy assessment will be considered 
non-responders for response analysis. All progression of disease or death during 
follow-up period will be included as events for PFS and OS analysis.  
5.4 
STATISTICAL METHODOLOGY 
 
Safety Analyses 
Safety evaluation will include physical examinations, vital sign measurements, 
laboratory assessments, and monitoring for adverse events. The severity of 
toxicities will be graded according to the NCI CTCAE v5.0, whenever possible. 
Adverse events and clinically significant laboratory abnormalities (meeting Grade 
3-5 criteria according to CTCAE) will be summarized by maximum intensity and 
relationship to study drug. Simple descriptive statistics will be utilized to display 
the data on toxicity observed from the combination of atezolizumab with weekly 
dose-dense paclitaxel and carboplatin. 
 
 
Efficacy Analyses 
All efficacy endpoints will be summarized descriptively using frequency 
distributions. In addition, 95% confidence intervals will be provided for the 
proportion of each response. PFS and OS will be determined using the Kaplan-
Meier method. Median and 2-year survivals will be estimated along with 95% 
confidence intervals. 
 
Translational Analyses 
5.4.3.1 
Correlation of PD-L1 expression to clinical outcomes 
Expression of PD-L1 will be correlated with clinical outcomes. Efficacy analyses 
will be repeated based on PD-L1 expression levels. The population will be 
divided into two categories of high versus low expression based on IHC staining. 
The cut-point will be determined with input from the Genentech development 
team. 
5.4.3.2 
Other translational endpoints 
The other translational endpoints are exploratory and hypothesis generating. 
They will be summarized with descriptive statistics and correlated to the clinical 
outcomes of interest. 
5.5 
SAMPLE SIZE 
The sample size for the study was primarily determined based on feasibility of 
accrual and level of support. However, the sample size is sufficient to determine 
the safety and primary translational endpoints as outlined above. 
 


 
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6. 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and reporting AEs and SAEs that 
are considered related to atezolizumab, all events of death, and any study-
specific issue of concern. 
6.1 
RISKS ASSOCIATED WITH ATEZOLIZUMAB 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such 
therapy may increase the risk of immune-related AEs, specifically the induction 
or enhancement of autoimmune conditions.  AEs with potentially immune-related 
causes, including rash, hypothyroidism, hepatitis/transaminitis, colitis, myositis, 
and myasthenia gravis, have been observed in Study PCD4989g.   
Although most immune-related AEs observed with immunomodulatory agents 
have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications [22].   
A more detailed safety profile of atezolizumab is provided in the atezolizumab 
Investigator’s Brochure. 
6.2 
SAFETY PARAMETERS AND DEFINITIONS 
 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other 
protocol-imposed intervention, regardless of attribution. 
This includes the following: 
 
AEs not previously observed in the patient that emerge during the 
protocol-specified AE reporting period, including signs or symptoms of 
ovarian cancer that were not present prior to the AE reporting period 
 
Complications that occur as a result of protocol-mandated interventions 
(e.g., invasive procedures such as cardiac catheterizations) 
 
If applicable, AEs that occur prior to assignment of study treatment 
associated with medication washout, no treatment run-in, or other 
protocol-mandated intervention 
 
Pre-existing medical conditions (other than the condition being studied) 
judged by the investigator to have worsened in severity or frequency or 
changed in character during the protocol-specified AE reporting period 
 
 
Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
 
It results in death (i.e., the AE actually causes or leads to death) 


 
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 
It is life threatening (i.e., the AE, in the view of the investigator, places 
the patient at immediate risk of death.  It does not include an AE that, 
had it occurred in a more severe form, might have caused death.) 
 
It requires or prolongs inpatient hospitalization 
 
It results in persistent or significant disability/incapacity (i.e., the AE 
results in substantial disruption of the patient’s ability to conduct normal 
life functions) 
 
It results in a congenital anomaly/birth defect in a neonate/infant born to 
a mother exposed to the IMP 
 
It is considered a significant medical event by the investigator based on 
medical judgment (e.g., may jeopardize the patient or may require 
medical/surgical intervention to prevent one of the outcomes listed 
above) 
 
6.3 
METHODS AND TIMING FOR ASSESSING AND RECORDING 
SAFETY VARIABLES  
The investigator is responsible for ensuring that all AEs and SAEs that are 
observed or reported during the study are collected and reported to the U.S. 
Food and Drug Administration (FDA), appropriate Institutional Review Boards 
(IRBs), and Genentech, Inc., in accordance with CFR 312.32 (Investigational 
New Drug [Nixon,  #24] Safety Reports).  
 
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after 
informed consent is obtained and initiation of any study procedures and ends 90 
days following the last administration of study treatment or until receipt of another 
anticancer therapy, whichever comes first. After this period, investigators should 
only report SAEs that are attributed to prior study treatment. 
 
Assessment of Adverse Events 
All AEs and SAEs, whether volunteered by the patient, discovered by study 
personnel during questioning, or detected through physical examination, 
laboratory test, or other means, will be reported appropriately.  Each reported AE 
or SAE will be described by its duration (i.e., start and end dates), regulatory 
seriousness criteria if applicable, suspected relationship to atezolizumab (see 
following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators 
should apply the following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and 
administration of atezolizumab, and the AE cannot be readily explained by 


 
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the patient’s clinical state, intercurrent illness, or concomitant therapies; 
and/or the AE follows a known pattern of response to atezolizumab; and/or 
the AE abates or resolves upon discontinuation of atezolizumab or dose 
reduction and, if applicable, reappears upon re-challenge. 
No 
Evidence exists that the AE has an etiology other than atezolizumab (e.g., 
pre-existing medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal 
relationship to atezolizumab administration (e.g., cancer diagnosed 2 days 
after first dose of study drug). 
 
Expected AEs are those AEs that are listed or characterized in the Package 
Insert (PI) or current Investigator’s Brochure.  
Unexpected AEs are those not listed in the PI or current Investigator’s Brochure 
or not identified.  This includes AEs for which the specificity or severity is not 
consistent with the description in the PI or Investigator’s Brochure.  For example, 
under this definition, hepatic necrosis would be unexpected if the PI or 
Investigator’s Brochure only referred to elevated hepatic enzymes or hepatitis. 
6.4 
PROCEDURES FOR ELICITING, RECORDING, AND 
REPORTING ADVERSE EVENTS  
 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all patient evaluation time points 
should be adopted.  Examples of non-directive questions include:  
 
“How have you felt since your last clinical visit?” 
 
“Have you had any new or changed health problems since you were last 
here?”  
 
 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting 
AEs or SAEs.  Avoid colloquialisms and abbreviations. 
6.4.2.1 
Diagnosis versus Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather 
than jaundice, asterixis, and elevated transaminases).  However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a 
single diagnosis or syndrome at the time of reporting, it is acceptable to report 
the information that is currently available.  If a diagnosis is subsequently 
established, it should be reported as follow-up information. 


 
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6.4.2.2 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see 
Section 6.3.1), regardless of attribution, will be reported to the appropriate 
parties.  When recording a death, the event or condition that caused or 
contributed to the fatal outcome should be reported as the single medical 
concept.  If the cause of death is unknown and cannot be ascertained at the time 
of reporting, report “Unexplained Death.”   
6.4.2.3 
Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  
Such conditions should be reported as medical and surgical history.  A pre-
existing medical condition should be re-assessed throughout the trial and 
reported as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study.  When reporting such events, it is important 
to convey the concept that the pre-existing condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 
6.4.2.4 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE.  If a patient is hospitalized to undergo a 
medical or surgical procedure as a result of an AE, the event responsible for the 
procedure, not the procedure itself, should be reported as the SAE.  For 
example, if a patient is hospitalized to undergo coronary bypass surgery, record 
the heart condition that necessitated the bypass as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
 
Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for pre-existing conditions, 
 
Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study, or 
 
Hospitalization or prolonged hospitalization for scheduled therapy of the 
target disease of the study. 
 
6.4.2.5 
Pregnancies in Female Patients 
If a female subject becomes pregnant while receiving atezolizumab or within  5 
months after the last dose of atezolizumab, a report should be completed and 
expeditiously submitted to Genentech, Inc. Follow-up to obtain the outcome of 
the pregnancy should also occur. Abortion, whether accidental, therapeutic, or 
spontaneous, should always be classified as serious, and expeditiously reported 
as an SAE. Similarly, any congenital anomaly/birth defect in a child born to a 
female subject exposed to atezolizumab should be reported as an SAE. 


 
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6.4.2.6 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a patient 
has completed or discontinued study participation if attributed to prior 
atezolizumab exposure.  If the investigator should become aware of the 
development of cancer or a congenital anomaly in a subsequently conceived 
offspring of a female patient who participated in the study, this should be 
reported as an SAE.  
6.4.2.7 
Safety Reconciliation 
The Sponsor-investigator agrees to conduct reconciliation for the product.  
Genentech and the Sponsor-investigator will agree to the reconciliation 
periodicity and format, but agree at minimum to exchange quarterly line listings of 
cases received by the other party.  If discrepancies are identified, the Sponsor-
investigator and Genentech will cooperate in resolving the discrepancies.  The 
responsible individuals for each party shall handle the matter on a case-by-case 
basis until satisfactory resolution. The sponsor shall receive reconciliation 
guidance documents within the ‘Activation Package’. 
Following Case Transmission Verification, single case reports which 
have not been received by Genentech/Roche shall be forwarded by 
the Sponsor to Genentech/Roche within five (5) calendar days from 
request by Genentech/Roche. 
 
At the end of the study, a final cumulative Case Transmission 
Verification report will be sent to Genentech/Roche 
 
6.4.2.8 
Adverse Events of Special Interest  
Adverse events of special interest (AESIs) are defined as a potential safety 
problem, identified as a result of safety monitoring of the IMP. 
The following AEs are considered of special interest and must be reported to the 
Genentech Drug Safety expeditiously (see Section 6.4.2.9 for reporting 
instructions), irrespective of regulatory seriousness criteria:  
 Cases of potential drug-induced liver injury that include an elevated 
ALT or AST in combination with either an elevated bilirubin or clinical 
jaundice, as defined by Hy's Law and based on the following 
observations: 
o Treatment-emergent ALT or AST > 3 x baseline value in 
combination with total bilirubin > 2 x ULN (of which ≥ 35% is 
direct bilirubin) 
o Treatment-emergent ALT or AST > 3 x baseline value in 
combination with clinical jaundice 


 
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 Suspected transmission of an infectious agent by the study treatment, 
as defined below 
o Any organism, virus, or infectious particle (e.g., prion protein 
transmitting transmissible spongiform encephalopathy), 
pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected 
from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term 
applies only when a contamination of study treatment is 
suspected. 
Atezolizumab Adverse Events of Special Interest are: 
 
Pneumonitis 
 
Colitis 
 
Endocrinopathies:  diabetes mellitus, pancreatitis, hyperthyroidism or 
adrenal insufficiency, hypophysitis 
 
Hepatitis 
 
Transaminitis:  Grade  2 (AST or ALT  3  ULN and 
bilirubin  2  ULN) or AST/ALT  10  ULN  
 
Systemic lupus erythematosus 
 
Guillain-Barré syndrome  
 
Myasthenia gravis or myasthenic syndrome 
 
Meningoencephalitis 
 
Nephritis 
 
Events suggestive of hypersensitivity, cytokine release, influenza-like 
illness, systemic inflammatory response syndrome, systemic immune 
activation or infusion-reaction syndromes 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Myositis 
 
Myopathies, including rhabdomyolysis 
 
Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, 
pericarditis) 
 
Vasculitis 
 
Autoimmune hemolytic anemia 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, 
dermatitis bullous, toxic epidermal necrolysis) 
 


 
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6.4.2.9 
Adverse Event Reporting 
Investigators must report all significant AEs as identified below to the Duke 
Cancer Institute Safety Surveillance Office, who will report on behalf of the study 
to Genentech within the timelines described below.   
 
Contact for AE reporting: 
Duke Cancer Institute Safety Surveillance Office:  
Fax: (919) 681-9357, Phone: (919) 681-9538,  
Email: dcccsafe@dm.duke.edu 
 
Relevant follow-up information should be submitted to Genentech Drug Safety by 
the Duke Safety Surveillance Office as soon as it becomes available. 
 Serious adverse events (SAEs), pregnancy reports and AEs of special 
interest (AESIs), where the patient has been exposed to the atezolizumab, 
will be sent on a MedWatch form to Genentech/Roche by the Duke Safety 
Surveillance Office. Transmission of these reports (initial and follow-up) will 
be either electronically or by fax and within the timelines specified below: 
SADRs: Serious AE reports that are related to the Product shall be 
transmitted to Genentech/Roche by the Duke Safety Surveillance Office 
within fifteen (15) calendar days of the awareness date. 
 
 Other SAEs: Serious AE reports that are unrelated to the Product shall 
be transmitted to Genentech /Roche by the Duke Safety Surveillance 
Office within thirty (30) calendar days of the awareness date. 
 
 AESIs: AESIs shall be forwarded to Genentech/Roche by the Duke 
Safety Surveillance Office within fifteen (15) calendar days of the 
awareness date. 
 
 Pregnancy reports: While such reports are not serious AEs or ADRs per 
se, as defined herein, any reports of pregnancy, where the fetus may have 
been exposed to the Product, shall be transmitted to Genentech/Roche by 
the Duke Safety Surveillance Office within thirty (30) calendar days of the 
awareness date. Pregnancies will be followed up until the outcome of the 
pregnancy is known, whenever possible, based upon due diligence taken 
to obtain the follow-up information. 
 
In addition to SAEs, pregnancy reports and AESIs, the following Special 
Situations Reports should be collected and transmitted to Genentech/Roche by 
the Duke Safety Surveillance Office even in the absence of an Adverse Event 
within thirty (30) calendar days: 
 


 
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 Data related to product usage during pregnancy or breastfeeding 
 Data related to overdose, abuse, misuse, inadvertent/erroneous 
administration, medication error or occupational exposure, with or without 
association with an AE/SAE unless otherwise specified in the protocol 
 Data related to a suspected transmission of an infectious agent via a 
medicinal product (STIAMP) 
 Lack of therapeutic efficacy 
In addition, reasonable attempts should made to obtain and submit the age or 
age group of the patient, in order to be able to identify potential safety signals 
specific to a particular population 
 
Aggregate Reports 
 
Dr. Secord will forward a copy of the Final Study Report to Roche upon 
completion of the Study or will forward periodically listings of non-serious AEs 
originating from the Study to Roche or will forward a copy of the Publication to 
Roche upon completion of the Study.  
 
The Sponsor- Investigator of the Study, will be responsible for the preparation of 
their own Development Safety Update Report (DSUR) for the Study and for the 
submission of the report to the regulatory authorities and Ethics Committees of 
the concerned Member States, where applicable. The Sponsor- Investigator 
agrees to share a copy of their own DSUR with Genentech/Roche as soon as 
reasonably possible after completion. Genentech/Roche agrees to forward to the 
Sponsor- Investigator an executive summary of the Genentech/Roche DSUR 
upon request. Furthermore, Genentech/Roche agrees that the Sponsor- 
Investigator may cross-reference the executive summary of the 
Genentech/Roche DSUR, as applicable. 
 
Note:  Investigators should also report events to their IRB as required. 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect 
medication information, the report should include the following information within 
the Event Description (item 5) of the MedWatch 3500A form: 
 
Protocol description (and number, if assigned) 
 
Description of event, severity, treatment, and outcome if known 
 
Supportive laboratory results and diagnostics 
 
Investigator’s assessment of the relationship of the AE to each 
investigational product and suspect medication 
 


 
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Follow-Up Information 
Additional information may be added to a previously submitted report by any of 
the following methods: 
 
Adding to the original MedWatch 3500A report and submitting it as 
follow-up 
 
Adding supplemental summary information and submitting it as follow-up 
with the original MedWatch 3500A form  
 
Summarizing new information and faxing it with a cover letter including 
patient identifiers (i.e., date of birth, initial, patient number), protocol 
description and number, if assigned, brief AE description, and notation 
that additional or follow-up information is being submitted.  (The patient 
identifiers are important so that the new information is added to the 
correct initial report.) 
Occasionally Genentech may contact the reporter for additional information, 
clarification, or current status of the patient for whom and AE was reported.  For 
questions regarding SAE reporting, you may contact the Genentech Drug Safety 
representative noted above or the Medical Science Liaison assigned to the study.  
Relevant follow-up information should be submitted to Genentech Drug Safety as 
soon as it becomes available and/or upon request. 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm 
 
Additional Reporting Requirements for IND 
Study is IND exempt. Not applicable. 
 
 
IND Annual Reports 
Not Applicable 
 
6.5 
STUDY CLOSE-OUT 
Any literature articles that are a result of the study should be sent to Genentech.  
Copies of such reports should be mailed to the assigned Clinical Operations 
contact for the study: 
Atezolizumab Protocols 
Email:  anti-pdl-1-mpd3280a-gsur@gene.com,  noska.april@gene.com and 
ctvist_drugsafety@gene.com 
 
QUERIES 
 
Queries related to the Study will be answered by the Sponsor- 
Investigator. However, responses to all safety queries from regulatory 
authorities or for publications will be discussed and coordinated 
between the Parties. The Parties agree that Genentech/Roche shall 


 
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have the final say and control over safety queries relating to the 
Product. The Sponsor - Investigator agrees that it shall not answer 
such queries from regulatory authorities and other sources relating to 
the Product independently but shall redirect such queries to 
Genentech/Roche. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses 
to urgent requests for information or review of data are met. The Parties will 
clearly indicate on the request the reason for urgency and the date by which a 
response is required. 
 
SAFETY CRISIS MANAGEMENT 
 
In case of a safety crisis, e.g., where safety issues have a potential 
impact on the indication(s), on the conduct of the Study, may lead to 
labeling changes or regulatory actions that limit or restrict the way in 
which the Product is used, or where there is media involvement, the 
Party where the crisis originates will contact the other Party as soon 
as possible. 
 
The Parties agree that Genentech/Roche shall have the final say and 
control over safety crisis management issues relating to the Product. 
The Sponsor Investigator agrees that it shall not answer such 
queries from media and other sources relating to the Product but 
shall redirect such queries to Genentech/Roche. 
 
7. 
ETHICAL CONSIDERATIONS 
7.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
Patients who comply with the requirements of the protocol, are tolerating study 
treatment, and may be receiving benefit will be offered dosing beyond Cycle 1 at 
the investigator’s discretion after a careful assessment and thorough discussion 
of the potential risks and benefits of continued treatment with the patient.  Such 
patients may have the option to receive atezolizumab treatment as long as they 
continue to experience clinical benefit in the opinion of the investigator until the 
earlier of unacceptable toxicity, symptomatic deterioration attributed to disease 
progression, completion of planned protocol treatment, or any of the other 
reasons for treatment discontinuation listed in Section 4.4.4. 
7.2 
INFORMED CONSENT 
The informed consent document must be signed by the subject or the subject’s 
legally authorized representative before her participation in the study.  The case 
history for each subject shall document that informed consent was obtained prior 
to participation in the study.  A copy of the informed consent document must be 


 
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provided to the subject or the subject's legally authorized representative.  If 
applicable, it will be provided in a certified translation of the local language. 
Signed consent forms must remain in each subject’s study file and must be 
available for verification by study monitors at any time. 
7.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
APPROVAL 
This protocol, the informed consent document, and relevant supporting 
information must be submitted to the IRB for review and must be approved 
before the study is initiated.  The study will be conducted in accordance with 
FDA, applicable national and local health authorities, and IRB requirements. 
The Principal Investigator is responsible for keeping the IRB apprised of the 
progress of the study and of any changes made to the protocol as deemed 
appropriate, but in any case, the IRB must be updated at least once a year.  The 
Principal Investigator must also keep the IRB informed of any significant AEs. 
Investigators are required to promptly notify their respective IRB of all adverse 
drug reactions that are both serious and unexpected.  This generally refers to 
SAEs that are not already identified in the Investigator’s Brochure and that are 
considered possibly or probably related to the molecule or study drug by the 
investigator.  Some IRBs may have other specific AE requirements to which 
investigators are expected to adhere.  Investigators must immediately forward to 
their IRB any written safety report or update provided by Genentech (e.g., IND 
safety report, Investigator’s Brochure, safety amendments and updates, etc.). 
7.4 
CONFIDENTIALITY 
Patient medical information obtained by this study is confidential and may be 
disclosed to third parties only as permitted by the ICF (or separate authorization 
to use and disclose personal health information) signed by the patient or unless 
permitted or required by law. 
Medical information may be given to a patient’s personal physician or other 
appropriate medical personnel responsible for the patient’s welfare for treatment 
purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other regulatory agencies, national and local 
health authorities, Genentech representatives and collaborators, and the 
IRB/Ethics Committee (EC) for each study site, if appropriate. 


 
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8. 
STUDY MEDICAL MONITORING REQUIREMENTS 
This clinical research study will be monitored both internally by the PI, 
institutionally by the Duke Cancer Institute (DCI), and externally by the IRBs at 
Duke University Medical Center and participating sites.  External site monitoring 
will be performed in accordance with the External Site Monitoring Plan, which 
accompanies this protocol. Please refer to this document for specifics regarding 
monitoring procedures. In terms of internal review, the PI will continuously 
monitor and tabulate AEs.  Appropriate reporting to the IRBs at Duke University 
Medical Center and additional sites will be made. If an unexpected frequency of 
Grade III or IV events occur, depending on their nature, action appropriate to the 
nature and frequency of these adverse events will be taken. This may require a 
protocol amendment, dose de-escalation, or potentially closure of the study.  The 
PI of this study will also continuously monitor the conduct, data, and safety of this 
study to ensure that: 
 
Interim analyses occur as scheduled, 
 
Stopping rules for toxicity and/or response are met, 
 
Risk/benefit ratio is not altered to the detriment of the subjects, 
 
Appropriate internal monitoring of AEs and outcomes is done, 
 
Over-accrual does not occur, 
 
Under-accrual is addressed with appropriate amendments or actions, 
and 
 
Data are being appropriately collected in a reasonably timely manner. 
 
DCI review and monitoring of this protocol occurs in accordance with the NCI-
approved Data and Safety Monitoring Plan.  Briefly, protocol review begins with 
an initial review by the Cancer Protocol Committee (CPC), which assesses the 
ethics and safety of the protocol.  Documentation of these assessments will be 
maintained.  Formal, independent monitoring will be conducted by the DCI 
Monitoring Team after the first 3 subjects are enrolled, followed by annual 
monitoring of 1-3 subjects until the study is closed to enrollment and subjects are 
no longer receiving study interventions that are more than minimal risk.  DCI 
Monitoring Team reports and additional data/safety/toxicity reports submitted by 
the PI will be reviewed by the Safety Oversight Committee (SOC) on an annual 
basis.  Additional monitoring may be prompted by findings from monitoring visits, 
unexpected frequency of serious and/or unexpected toxicities, or other concerns.  
Monitoring visits may also be initiated upon request by DUHS and DCI 
Leadership, CPC, SOC, a sponsor, an investigator, or the IRB. 
Routine monitoring will be carried out via a periodic team conference among 
investigators during which toxicity data, including all SAEs, will be reviewed and 
other issues relevant to the study such as interim assessment of accrual, 


 
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outcome, and compliance with study guidelines, will be discussed.  Monitoring 
will be carried out on an ongoing basis.  The severity, relatedness, and whether 
or not the event is expected will be reviewed. 
8.1 
STUDY MEDICATION ACCOUNTABILITY 
If study drug will be provided by Genentech, the recipient will acknowledge 
receipt of the drug by returning the INDRR-1 form indicating shipment content 
and condition.  Damaged supplies will be replaced. 
Accurate records of all study drug dispensed from and returned to the study site 
should be recorded by using the institution’s drug inventory log or the National 
Cancer Institute drug accountability log. 
All partially used or empty containers should be disposed of at the study site 
according to institutional standard operating procedure.  Return unopened, 
expired, or unused study drug with the Inventory of Returned Clinical Material 
form as directed by Genentech. 
8.2 
DATA COLLECTION 
The study coordinator and investigators are responsible for ensuring that the 
eligibility checklist is completed in a legible and timely manner for every patient 
enrolled in the study, and that data are recorded on the appropriate forms and in 
a timely manner.  Any errors on source data should be lined through, but not 
obliterated, with the correction inserted, initialed, and dated by the study 
coordinator or PI.  All source documents will be available for inspection by the 
FDA and the local IRB. 
8.3 
RETENTION OF RECORDS 
FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see 
Section 4.9 of the guideline) require that records and documents pertaining to the 
conduct of clinical trials and the distribution of investigational drug, patient 
records, consent forms, laboratory test results, and medication inventory records, 
must be retained for 2 years after the last marketing application approval in an 
ICH region or after at least 2 years have elapsed since formal discontinuation of 
clinical development of the investigational product.  All state and local laws for 
retention of records also apply.  
For studies conducted outside the U.S. under a U.S. IND, the Principal 
Investigator must comply with the record retention requirements set forth in the 
FDA IND regulations and the relevant national and local health authorities, 
whichever is longer. 


 
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9. 
TRANSLATIONAL STUDIES 
9.1 
BIOLOGIC SAMPLES FOR BIOMARKER AND CORRELATIVE 
STUDIES 
During the course of this trial, biologic samples will be collected at two time 
points for biomarker and correlative studies, including immunohistochemistry, 
RNAseq, immune checkpoint profiling, and cytokine expression profiling. Please 
refer to the laboratory manual for details on specimen requirements, collection 
time points, and shipping instructions.  
 
9.2 
BRCA MUTATION STATUS 
BRCA germline mutation status will be collected when available at baseline, or 
when it becomes available during study participation. If results are not available, 
testing will not be mandated. 
Patients with germline or somatic BRCA mutations may continue on study or 
discontinue to receive a PARP inhibitor at their discretion and after discussing 
with their primary treating care provider. 
 
9.3 
TUMOR MUTATION PROFILE 
Tumor mutation profile information will be collected if it becomes available during 
study participation. If results are not available, testing will not be mandated. 
 
10. 
REFERENCES 
 
1. 
Siegel, Miller, and Jemal, Cancer statistics, 2015. CA Cancer J Clin, 2015. 
65(1): p. 5-29. PMID: 25559415. 
2. 
Katsumata, Yasuda, et al., Dose-dense paclitaxel once a week in 
combination with carboplatin every 3 weeks for advanced ovarian cancer: 
a phase 3, open-label, randomised controlled trial. Lancet, 2009. 
374(9698): p. 1331-8. PMID: 19767092. 
3. 
Chan, Brady, et al., Weekly vs. Every-3-Week Paclitaxel and Carboplatin 
for Ovarian Cancer. N Engl J Med, 2016. 374(8): p. 738-48. PMID: 
26933849. 
4. 
Armstrong, Bundy, et al., Intraperitoneal cisplatin and paclitaxel in ovarian 
cancer. N Engl J Med, 2006. 354(1): p. 34-43. PMID: 16394300. 
5. 
Bookman, Brady, et al., Evaluation of new platinum-based treatment 
regimens in advanced-stage ovarian cancer: a Phase III Trial of the 
Gynecologic Cancer Intergroup. J Clin Oncol, 2009. 27(9): p. 1419-25. 
PMID: 19224846. 


 
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6. 
Ozols, Bundy, et al., Phase III trial of carboplatin and paclitaxel compared 
with cisplatin and paclitaxel in patients with optimally resected stage III 
ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol, 2003. 
21(17): p. 3194-200. PMID: 12860964. 
7. 
Burger, Brady, et al., Incorporation of bevacizumab in the primary 
treatment of ovarian cancer. N Engl J Med, 2011. 365(26): p. 2473-83. 
PMID: 22204724. 
8. 
Perren, Swart, et al., A phase 3 trial of bevacizumab in ovarian cancer. N 
Engl J Med, 2011. 365(26): p. 2484-96. PMID: 22204725. 
9. 
Vergote, Trope, et al., Neoadjuvant chemotherapy or primary surgery in 
stage IIIC or IV ovarian cancer. N Engl J Med, 2010. 363(10): p. 943-53. 
PMID: 20818904. 
10. 
Kehoe, Hook, et al., Primary chemotherapy versus primary surgery for 
newly diagnosed advanced ovarian cancer (CHORUS): an open-label, 
randomised, controlled, non-inferiority trial. Lancet, 2015. 386(9990): p. 
249-57. PMID: 26002111. 
11. 
Ovarian Cancer including fallopian tube cancer and primary peritoneal 
cancer, in Clinical Practice Guidelines in Oncology (NCCN Guidelines). 
2015, National Comprehensive Cancer Network. 
12. 
Meyer, Cronin, et al., Use and Effectiveness of Neoadjuvant 
Chemotherapy for Treatment of Ovarian Cancer. J Clin Oncol, 2016. 
PMID: 27601552. 
13. 
Fehrenbacher, Spira, et al., Atezolizumab versus docetaxel for patients 
with previously treated non-small-cell lung cancer (POPLAR): a 
multicentre, open-label, phase 2 randomised controlled trial. Lancet, 2016. 
387(10030): p. 1837-46. PMID: 26970723. 
14. 
Rosenberg, Hoffman-Censits, et al., Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed 
following treatment with platinum-based chemotherapy: a single-arm, 
multicentre, phase 2 trial. Lancet, 2016. 387(10031): p. 1909-20. PMID: 
26952546. 
15. 
Katsumata, Yasuda, et al., Long-term results of dose-dense paclitaxel and 
carboplatin versus conventional paclitaxel and carboplatin for treatment of 
advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer 
(JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol, 
2013. 14(10): p. 1020-6. PMID: 23948349. 
16. 
Hamanishi, Mandai, et al., Safety and Antitumor Activity of Anti-PD-1 
Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer. 
J Clin Oncol, 2015. PMID: 26351349. 
17. 
Disis, Patel, et al., Avelumab (MSB0010718C), an anti-PD-L1 antibody, in 
patients with previously treated, recurrent or refractory ovarian cancer: A 
phase Ib, open-label expansion trial. Journal of Clinical Oncology, 2015. 
33((suppl; abstr 5509)). PMID:  
18. 
Varga, Piha-Paul, et al., Antitumor activity and safety of pembrolizumab in 
patients (pts) with PD-L1 positive advanced ovarian cancer: Interim results 
from a phase Ib study. Journal of Clinical Oncology, 2015. 33((suppl; abstr 
5510)). PMID:  


 
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19. 
Smith, Bohlke, et al., Recommendations for the Use of WBC Growth 
Factors: American Society of Clinical Oncology Clinical Practice Guideline 
Update. J Clin Oncol, 2015. 33(28): p. 3199-212. PMID: 26169616. 
20. 
Rizzo, Brouwers, et al., American Society of Clinical Oncology/American 
Society of Hematology clinical practice guideline update on the use of 
epoetin and darbepoetin in adult patients with cancer. J Clin Oncol, 2010. 
28(33): p. 4996-5010. PMID: 20975064. 
21. 
Vergote, Trope, et al., Neoadjuvant chemotherapy or primary surgery in 
stage IIIC or IV ovarian cancer. N Engl J Med, 2010. 363(10): p. 943-53. 
PMID: 20818904. 
22. 
Di Giacomo, Biagioli, and Maio, The emerging toxicity profiles of anti-
CTLA-4 antibodies across clinical indications. Semin Oncol, 2010. 37(5): 
p. 499-507. PMID: 21074065. 
23. 
EMD Group. Merck KGaA, Darmstadt, Germany, and Pfizer Provide 
Update on JAVELIN Ovarian 100 Trial of Avelumab in Previously 
Untreated Advanced Ovarian Cancer. EMD Group. 
https://www.emdgroup.com/en/news/javelin-ovarian-100-21-12-2018.html. 
Published December 21, 2018. 
24.  
Center for Drug Evaluation and Research. Approved Drugs - FDA 
approves bevacizumab in combination with chemotherapy for ovarian 
cancer. U S Food and Drug Administration. 
https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm6106
64.htm. Published June 13, 2018. 
25. 
Chen and Mellman, Oncology meets immunology: The cancer-immunity 
cycle. Immunity, 2013 39: p. 1-10. PMID: 23890059. 
26. 
Sznol, McDermott, Fields, et al., Phase Ib evaluation of MPDL3280A 
(anti-PD-L1) in combination with bevacizumab (bev) in patients (pts) with 
metastatic renal cell carcinoma (mRCC) [abstract]. J Clin Oncol, 2015. 
33:abstract 410. 
27. 
Tolaney, Boucher, Duda, et al. Role of vascular density and normalization 
in response to neoadjuvant bevacizumab and chemotherapy in breast 
cancer patients. PNAS, 2015. 112(46): p. 14325-30. PMID: 26578779 
 
 
 


 
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Appendix 1 
Study Flowchart 
  
Screening 
Treatment Period 
Study Completion/Early 
Term Visit 
Follow-Up 
Long-term 
follow-up 
Day 
-28 to 
-1 
-14 
to -1 
C1-3 
ICS14 
C4-6 
Maintenance 
Atezolizumab 
≤30 days after last 
treatment 
per NCCN guidelines 
until recurrence 
every 6 
months 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
Window 
  
  
+/-3 
+/-
1 
+/-1 
Within 42 days 
from C3D1 
+/- 
3 
+/-1 
+/-1 
+/-3 
  
  
+/- 1 month 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Demographic data 
X 
  
  
  
  
  
  
  
  
  
  
  
  
General med history & 
baseline conditions 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Vital signs 1 
X 
  
X 
  
  
  
X 
  
  
X 
X 
  
  
Weight & height 7 
X 
  
X 
  
  
  
X 
  
  
X 
X 
  
  
Physical examination12 
X 
  
X 
  
  
  
X 
  
  
X 
X 
  
  
Concomitant medications 
  
X 
X 
  
  
  
X 
  
  
X 
X 
  
  
Hematology 2 
  
X 
X11 
X 
X 
  
X 
X 
X 
X 
X 
  
  
Chemistry 3 
  
X 
X11 
  
  
  
X 
  
  
X 
X 
  
  
Coagulation studies4 
  
X 
  
  
  
  
  
  
  
  
  
  
  
CA125 
  
X 
X9, 11 
  
  
  
X 
  
  
X 
X 
X 
  
TSH 
  
X 
X11 
  
  
  
X 
  
  
X 
X 
  
  
Serum pregnancy test 
X10 
  
X10 
  
  
X10 
  
  
  
  
  
  
  
Hepatitis serology6 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Urinalysis 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Baseline imaging/response 
assessment5 
X 
  
  
  
  
X 
  
  
  
X 
  
X 
  
Translational Studies 
Specimens 8 
X 
X  
  
  
  
X 
  
  
  
  
  
  
  
Atezolizumab administration 
  
  
X 
  
  
  
X 
  
  
X 
  
  
  
Carboplatin administration 
  
  
X 
  
  
  
X 
  
  
  
  
  
  
Paclitaxel Administration 
  
  
X 
X 
X 
  
X 
X 
X 
  
  
  
  
Bevacizumab Administration  
(Optional)13 
 
 
 
 
 
 
X13 
 
 
X 
 
 
 
Recurrence and Survival data 
  
  
  
  
  
  
  
  
  
  
  
  
X 
1 Heart rate, systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  
2 Hemoglobin, hematocrit, platelet count, RBC count, WBC count, percent and absolute differential count (neutrophils, bands, eosinophils, lymphocytes, monocytes, basophils, other cells). 
3 Sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, magnesium, total bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, phosphorus. 
4 INR and aPTT 
5 imaging of the chest, abdomen, and pelvis by CT or MRI, the same modality that was used for baseline imaging should be used for response assessment. Imaging at ICS is to be performed prior to surgery. Imaging is 
to be performed after completion of chemotherapy and then as clinically indicated during maintenance and follow-up periods. 
6 hepatitis serologies as clinically indicated, especially in high risk patients 
7 height should be obtained prior to C1D1, subsequent measurements as clinically indicated 
8 See Section 9 and laboratory manual for information regarding translational studies specimens. During the screening period, the pretreatment tumor sample and pretreatment research blood sample may be collected up 
to 28 days prior to cycle 1 day1 of therapy. For pre-treatment biopsy, only upon agreement of the Investigator an alternative sample should be provided as per inclusion criteria section 4.1.1 prior to initiation of study 
treatment, these cases may omit the need to biopsy for newly obtained pre-treatment specimen. The ICS research blood sample may be collected up to 14 days before ICS if not feasible on the day of surgery. 
.9 Only for cycles 2 and 3  
10 Pregnancy test not required for women of non-childbearing potential 
11 Screening labs may be used if collected within 7 days of C1D1 
12 Physical exam does not need to be repeated on D1 of C1 if performed within the last 3 days. 
13Optional Bevacizumab can be given starting at cycles 5 and 6 of adjuvant chemotherapy and throughout maintenance. For patients with ICS delayed or ICS performed earlier, bevacizumab timing will differ. 
Bevacizumab should not be given at the cycle prior and cycle after ICS. Timing of bevacizumab administration will be at the discretion of the treating physician. 
14Patients who have medical issues that may need to delay or have ICS performed earlier may still continue on study at the discretion of the treating physician and the Duke PI 


 
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Appendix 2 
Initial Carboplatin Dose Recommendations 
based on IDMS Creatinine Values 
 
Initial Carboplatin Dose Recommendations based on IDMS Creatinine 
Values (based on NCI and legacy GOG recommendations)* 
Calculate using Calvert formula**  
 
Estimate GFR using Cockcroft-Gault 
equation*** 
 
Body Weight: 
     For body mass index (BMI) <25, 
use actual body weight 
     For BMI >25****, use adjusted 
body weight 
 
For abnormally low serum creatinine 
values, GFR should be capped at a 
maximum value of 125 mL/min or 
estimated GFR can be calculated 
using the lower limit of normal for the 
serum creatinine test utilized 
(frequently set at 0.7mg/dL). 
Maximum Carboplatin Dose: 
AUC 6 = 900mg 
AUC 5 = 750 
AUC 4 = 600 
*Subsequent modifications are based on hematologic toxicity or recalculation in the event of a change in 
renal function or body weight. 
**Although developed with measured GFR, estimated GFR is routinely employed in clinical practice 
***Of note, although the Cockcroft-Gault equation was developed and validated for drug dosing using 
pre-IDMS creatinine values, it is the preferred formula for estimating GFR. 
****The BMI cut-off for using adjusted body weight is under review, revised guidelines with a higher cut-
off are expected.  
 
Reference: 
Ivy SP, Zwiebel J, Mooney M. Follow-up for Information Letter Regarding AUC-
Based Dosing of Carboplatin. Investigational Drug Branch, Cancer Therapy 
Evaluation Program, Division of Cancer Treatment and Diagnosis, National 
Cancer Institute. 
http://ctep.cancer.gov/content/docs/Carboplatin_Information_Letter.pdf. 
Accessed December 10, 2015. 


 
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Appendix 3 
Current National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) 
 
Please use the following link to the NCI CTCAE website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 


 
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Appendix 4 
Response Evaluation Criteria in Solid Tumors 
(RECIST) 
Modified Excerpt from Original Publication 
Selected sections from the Response Evaluation Criteria in Solid Tumors 
(RECIST), Version 1.11 are presented below, with slight modifications and the 
addition of explanatory text as needed for clarity.2 
Measurability of Tumor at Baseline 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows: 
a. 
Measurable Tumor Lesions 
Tumor Lesions.  Tumor lesions must be accurately measured in at least 
one dimension (longest diameter in the plane of measurement is to be recorded) 
with a minimum size of:  
 
10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no 
greater than 5 mm) 
 
10-mm caliper measurement by clinical examination (lesions that cannot 
be accurately measured with calipers should be recorded as non-
measurable) 
 
20 mm by chest X-ray 
 
Malignant Lymph Nodes.  To be considered pathologically enlarged and 
measurable, a lymph node must be  15 mm in the short axis when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 5 mm).  
At baseline and in follow-up, only the short axis will be measured and followed.  
See also notes below on “Baseline Documentation of Target and Non-Target 
Lesions” for information on lymph node measurement. 
b. 
Non-Measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 
mm or pathological lymph nodes with  10 to  15 mm short axis), as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include:  
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, peritoneal spread, and 
abdominal masses/abdominal organomegaly identified by physical examination 
that is not measurable by reproducible imaging techniques.
                                            
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: Revised 
RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47. 
2 For consistency within this document, the section numbers and cross-references to other sections within 
the article have been deleted and minor formatting changes have been made. 


Appendix 4 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
MPDL3280ADuke 
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c. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy 
require particular comment, as outlined below. 
Bone lesions: 
 
Bone scan, positron emission tomography (PET) scan, or plain films are 
not considered adequate imaging techniques to measure bone lesions.  
However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft 
tissue components, that can be evaluated by cross-sectional imaging 
techniques such as CT or MRI can be considered measurable lesions if 
the soft tissue component meets the definition of measurability described 
above. 
 
Blastic bone lesions are non-measurable. 
 
Cystic lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts 
should not be considered malignant lesions (neither measurable nor 
non-measurable) since they are, by definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described 
above.  However, if non-cystic lesions are present in the same patient, 
these are preferred for selection as target lesions. 
 
Lesions with prior local treatment: 
 
Tumor lesions situated in a previously irradiated area, or in an area 
subjected to other loco-regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the 
lesion.  Study protocols should detail the conditions under which such 
lesions would be considered measurable. 
 
Target Lesions:  Specifications by Methods of Measurements  
a. 
Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed.  All baseline evaluations should be performed as close as 
possible to the treatment start and never more than 4 weeks before the 
beginning of the treatment. 
b. 
Method of Assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during study.  
Imaging-based evaluation should always be the preferred option. 


Appendix 4 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
MPDL3280ADuke 
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Clinical Lesions.  Clinical lesions will only be considered measurable when they 
are superficial and  10 mm in diameter as assessed using calipers (e.g., skin 
nodules).  For the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is suggested. 
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when 
progression is an important endpoint, since CT is more sensitive than X-ray, 
particularly in identifying new lesions.  However, lesions on chest X-ray may be 
considered measurable if they are clearly defined and surrounded by aerated 
lung. 
CT, MRI.  CT is the best currently available and reproducible method to measure 
lesions selected for response assessment.  This guideline has defined 
measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5 mm or less.  When 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.  
If prior to enrollment it is known that a patient is unable to undergo CT scans 
with intravenous (IV) contrast due to allergy or renal insufficiency, the decision as 
to whether a non-contrast CT or MRI (without IV contrast) will be used to 
evaluate the patient at baseline and during the study should be guided by the 
tumor type under investigation and the anatomic location of the disease.  For 
patients who develop contraindications to contrast after baseline contrast CT is 
done, the decision as to whether non-contrast CT or MRI (enhanced or non-
enhanced) will be performed should also be based on the tumor type and the 
anatomic location of the disease and should be optimized to allow for comparison 
with the prior studies if possible.  Each case should be discussed with the 
radiologist to determine if substitution of these other approaches is possible and, 
if not, the patient should be considered not evaluable from that point forward.  
Care must be taken in measurement of target lesions on a different modality and 
interpretation of non-target disease or new lesions since the same lesion may 
appear to have a different size using a new modality. 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should 
not be used as a method of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The 
utilization of these techniques for objective tumor evaluation cannot generally be 
advised. 


Appendix 4 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
MPDL3280ADuke 
Protocol ML 39266, Version 3-9 
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Tumor Response Evaluation 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate 
the overall tumor burden at baseline and to use this as a comparator for 
subsequent measurements.  Measurable disease is defined by the presence of 
at least one measurable lesion, as detailed above. 
Baseline Documentation of Target and Non-Target Lesions 
When more than one measurable lesion is present at baseline, all lesions up 
to a maximum of five lesions total (and a maximum of two lesions per organ) 
representative of all involved organs should be identified as target lesions and 
will be recorded and measured at baseline.  This means in instances where 
patients have only one or two organ sites involved, a maximum of two lesions 
(one site) and four lesions (two sites), respectively, will be recorded.  Other 
lesions (albeit measurable) in those organs will be recorded as non-measurable 
lesions (even if the size is  10 mm by CT scan).   
Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and be representative of all involved organs, but additionally, 
should lend themselves to reproducible repeated measurements.  It may be the 
case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement, in which circumstance the next largest lesion that can be 
measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor.  As noted above, 
pathological nodes that are defined as measurable and may be identified as 
target lesions must meet the criterion of a short axis of  15 mm by CT scan.  
Only the short axis of these nodes will contribute to the baseline sum.  The short 
axis of the node is the diameter normally used by radiologists to judge if a node 
is involved by solid tumor.  Nodal size is normally reported as two dimensions in 
the plane in which the image is obtained (for CT scan, this is almost always the 
axial plane; for MRI the plane of acquisition may be axial, sagittal, or coronal).  
The smaller of these measures is the short axis.  For example, an abdominal 
node that is reported as being 20 mm  30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with 
short axis  10 mm but  15 mm) should be considered non-target lesions.  
Nodes that have a short axis  10 mm are considered non-pathological and 
should not be recorded or followed. 
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 
of diameters.  If lymph nodes are to be included in the sum, then, as noted 


Appendix 4 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
MPDL3280ADuke 
Protocol ML 39266, Version 3-9 
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above, only the short axis is added into the sum.  The baseline sum of diameters 
will be used as a reference to further characterize any objective tumor regression 
in the measurable dimension of the disease. 
All other lesions (or sites of disease), including pathological lymph nodes, 
should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements are not required and these lesions should be followed 
as “present,” “absent,” or in rare cases “unequivocal progression.” 
In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged 
pelvic lymph nodes” or “multiple liver metastases”). 
Response Criteria 
a. 
Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective 
tumor response for 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 diameters 
of target lesions, taking as reference the baseline sum of diameters 
 
Progressive disease (PD):  at least a 20% increase in the sum of 
diameters of target lesions, taking as reference the smallest sum on 
study (nadir), including baseline 
In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered 
progression. 
 
Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
on study 
 
b. 
Special Notes on the Assessment of Target Lesions 
Lymph Nodes.  Lymph nodes identified as target lesions should always have 
the actual short axis measurement recorded (measured in the same anatomical 
plane as the baseline examination), even if the nodes regress to  10 mm on 
study.  This means that when lymph nodes are included as target lesions, the 
sum of lesions may not be zero even if CR criteria are met since a normal 
lymph node is defined as having a short axis  10 mm. 
Target Lesions That Become Too Small to Measure.  While on study, all 
lesions (nodal and non-nodal) recorded at baseline should have their actual 


Appendix 4 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
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measurements recorded at each subsequent evaluation, even when very small 
(e.g., 2 mm).  However, sometimes lesions or lymph nodes that are recorded as 
target lesions at baseline become so faint on CT scan that the radiologist may 
not feel comfortable assigning an exact measure and may report them as being 
too small to measure.  When this occurs, it is important that a value be recorded 
on the CRF as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small 
to measure, a default value of 5 mm should be assigned and BML 
(below measurable limit) should be ticked.  (Note:  It is less likely that 
this rule will be used for lymph nodes since they usually have a definable 
size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and 
is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well and BML should also be ticked.) 
 
To reiterate, however, if the radiologist is able to provide an actual measure, 
that should be recorded, even if it is below 5 mm, and, in that case, BML should 
not be ticked. 
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions 
fragment, the longest diameters of the fragmented portions should be added 
together to calculate the target lesion sum.  Similarly, as lesions coalesce, a 
plane between them may be maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest 
diameter in this instance should be the maximal longest diameter for the 
coalesced lesion. 
c. 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor 
response for the group of non-target lesions.  While some non-target lesions may 
actually be measurable, they need not be measured and, instead, should be 
assessed only qualitatively at the time points specified in the protocol. 
 
CR:  disappearance of all non-target lesions and (if applicable) 
normalization of tumor marker level) 
All lymph nodes must be non-pathological in size ( 10 mm short axis). 
 
Non-CR/Non-PD:  persistence of one or more non-target lesion(s) and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
PD:  unequivocal progression of existing non-target lesions 


Appendix 4 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
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The appearance of one or more new lesions is also considered 
progression. 
 
d. 
Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be 
an overall level of substantial worsening in non-target disease in a magnitude 
that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy.  A modest 
increase in the size of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status.  The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD 
or PR of target disease will therefore be extremely rare. 
When the Patient Has Only Non-Measurable Disease.  This circumstance 
arises in some Phase III trials when it is not a criterion of study entry to have 
measurable disease.  The same general concepts apply here as noted above; 
however, in this instance, there is no measurable disease assessment to factor 
into the interpretation of an increase in non-measurable disease burden.  
Because worsening in non-target disease cannot be easily quantified (by 
definition:  if all lesions are truly non-measurable), a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if 
the increase in overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease, that is, an increase in tumor burden 
representing an additional 73% increase in volume (which is equivalent to a 
20% increase in diameter in a measurable lesion).  Examples include an 
increase in a pleural effusion from “trace” to “large” or an increase in lymphangitic 
disease from localized to widespread or may be described in protocols as 
“sufficient to require a change in therapy.”  If unequivocal progression is seen, 
the patient should be considered to have had overall PD at that point.  While it 
would be ideal to have objective criteria to apply to non-measurable disease, the 
very nature of that disease makes it impossible to do so; therefore, the increase 
must be substantial. 
e. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; 
therefore, some comments on detection of new lesions are important.  There are 
no specific criteria for the identification of new radiographic lesions; however, the 
finding of a new lesion should be unequivocal, that is, not attributable to 
differences in scanning technique, change in imaging modality, or findings 
thought to represent something other than tumor (for example, some “new” bone 
lesions may be simply healing or flare of pre-existing lesions).  This is particularly 
important when the patient’s baseline lesions show partial or complete response.  


Appendix 4 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
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For example, necrosis of a liver lesion may be reported on a CT scan report as a 
“new” cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease 
progression. 
If a new lesion is equivocal, for example because of its small size, continued 
therapy and follow-up evaluation will clarify if it represents truly new disease.  If 
repeat scans confirm there is definitely a new lesion, then progression should be 
declared using the date of the initial scan. 
Evaluation of Response 
a. 
Time point Response (Overall Response) 
It is assumed that at each protocol-specified time point, a response assessment 
occurs.  Table 1 provides a summary of the overall response status calculation 
at each time point for patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 
is to be used. 
Table 1.  Time point Response:  Patients with Target Lesions (with or without Non-
Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not 
all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial response; 
SD  stable disease. 
 


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(RECIST) (cont.) 
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Table 2.  Time point Response:  Patients with Non-Target Lesions Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised. 
 
b. 
Missing Assessments and Not-Evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the 
patient is not evaluable at that time point.  If only a subset of lesion 
measurements are made at an assessment, usually the case is also considered 
not evaluable at that time point, unless a convincing argument can be made that 
the contribution of the individual missing lesion(s) would not change the assigned 
time point response.  This would be most likely to happen in the case of PD.  For 
example, if a patient had a baseline sum of 50 mm with three measured lesions 
and, during the study, only two lesions were assessed, but those gave a sum of 
80 mm; the patient will have achieved PD status, regardless of the contribution of 
the missing lesion.  
If one or more target lesions were not assessed either because the scan was not 
done or the scan could not be assessed because of poor image quality or 
obstructed view, the response for target lesions should be “unable to assess” 
since the patient is not evaluable.  Similarly, if one or more non-target lesions are 
not assessed, the response for non-target lesions should be “unable to assess” 
except where there is clear progression.  Overall response would be “unable to 
assess” if either the target response or the non-target response is “unable to 
assess,” except where this is clear evidence of progression as this equates with 
the case being not evaluable at that time point. 


Appendix 4 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
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Table 3.  Best Overall Response When Confirmation Is Required 
Overall Response at 
First Time point 
Overall Response at 
Subsequent Time point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR a 
CR 
SD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
CR 
PD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
CR 
NE 
SD, provided minimum duration 
for SD was met; otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
PR 
NE 
SD, provided minimum duration 
for SD was met; otherwise, NE 
NE 
NE 
NE 
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial response; 
SD  stable disease. 
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, 
even disease meeting PR criteria relative to baseline, qualifies as PD at that point 
(since disease must have reappeared after CR).  Best response would depend on whether 
the minimum duration for SD was met.  However, sometimes CR may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had 
PR, not CR, at the first timepoint.  Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
  
c. 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes 
decrease to “normal” size ( 10 mm), they may still have a measurement 
reported on scans.  This measurement should be recorded even though the 
nodes are normal in order not to overstate progression should it be based on 
increase in size of the nodes.  As noted earlier, this means that patients with CR 
may not have a total sum of “zero” on the CRF. 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be reported as “symptomatic deterioration.”  Every effort should be made to 
document objective progression even after discontinuation of treatment.  
Symptomatic deterioration is not a descriptor of an objective response; it is a 
reason for stopping study therapy.  The objective response status of such 


Appendix 4 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
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patients is to be determined by evaluation of target and non-target disease as 
shown in Tables 1  3. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; 
cystic changes or necrosis in existing lesions), treatment may continue until the 
next scheduled assessment.  If at the next scheduled assessment progression is 
confirmed, the date of progression should be the earlier date when progression 
was suspected. 
In studies for which patients with advanced disease are eligible (i.e., primary 
disease still or partially present), the primary tumor should also be captured as a 
target or non-target lesion, as appropriate.  This is to avoid an incorrect 
assessment of complete response if the primary tumor is still present but not 
evaluated as a target or non-target lesion.


 
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Appendix 5 
Immune-Related Response Criteria 
INTRODUCTION 
Increasing clinical experience indicates that traditional response criteria 
(e.g., Response Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST v1.1] 
and World Health Organization [WHO]) may not be sufficient to characterize fully 
activity in the new era of target therapies and/or biologics.  In studies with 
cytokines, cancer vaccines, and monoclonal antibodies, complete response, 
partial response, or stable disease has been shown to occur after an increase in 
tumor burden as characterized by progressive disease by traditional response 
criteria.  Therefore, conventional response criteria may not adequately assess 
the activity of immunotherapeutic agents because progressive disease (by initial 
radiographic evaluation) does not necessarily reflect therapeutic failure.  
Long-term effect on the target disease must also be captured.  The 
immune-related response criteria1 (irRC) are criteria that attempt to do that by 
enhancing characterization of new response patterns that have been observed 
with immunotherapeutic agents (i.e., ipilimumab).  (Note:  The irRC only index 
and measurable new lesions are taken into account.) 
GLOSSARY 
Term 
Definition 
SPD 
sum of the products of the two largest perpendicular diameters 
Tumor burden 
SPDindex lesions  SPDnew, measurable lesions 
Nadir 
minimally recorded tumor burden 
irCR 
immune-related complete response 
irPD 
immune-related progressive disease 
irPR 
immune-related partial response 
irSD 
immune-related stable disease 
irBOR 
immune-related best overall response 
 
BASELINE ASSESSMENT USING irRC 
Step 1. Identify the index lesions (five lesions per organ, up to ten visceral 
lesions and five cutaneous lesions).   
Step 2. Calculate the SPD of all of these index lesions: 
SPD  
(Largest diameter of lesion i)  (Second largest diameter of lesion i). 
                                            
1  Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Can Res 2009;15:741220. 

i


Appendix 5 
Immune-Related Response Criteria (cont.) 
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POST-BASELINE ASSESSMENTS USING irRC 
Step 1. Calculate the SPD of the index lesions.   
Step 2. Identify new, measurable lesions ( 5  5 mm; up to five new lesions per 
organ:  five new cutaneous lesions and ten visceral lesions).   
Step 3. Calculate the SPD of the new, measurable lesions. 
Step 4. Calculate the tumor burden: 
Tumor burden   SPDindex lesions  SPDnew, measurable lesions 
Step 5. Calculate the change in tumor burden relative to baseline and the change 
in tumor burden relative to nadir. 
Step 6. Derive the overall response using the table below. 
Overall Response Criterion 
irCR 
Complete disappearance of all lesions (whether measurable or 
not, and no new lesions) confirmed by a repeat, consecutive 
assessment  4 weeks from the date first documented 
irPR 
Decrease in tumor burden  50% relative to baseline confirmed by 
a consecutive assessment  4 weeks from the date first 
documented 
irSD 
Criteria for irCR, irPR, and irPD are not met; does not require 
confirmation 
irPD 
Increase in tumor burden  25% relative to nadir confirmed by a 
consecutive assessment  4 weeks from the date first 
documented 
irCR  immune-related complete response; irPD  immune-related progressive disease; 
irPR  immune-related partial response; irSD  immune-related stable disease. 
 
DETERMINATION OF irBOR 
Once a patient has completed all tumor assessments, his/her irBOR may be 
determined: 
Condition 
irBOR 
At least one irCR 
irCR 
At least one irPR and no irCR 
irPR 
At least one irSD and no irCR and no irPR 
irSD 
At least one irPD and no irCR, no irPR, and no irSD 
irPD 
irBOR  immune-related best overall response; irCR  immune-related complete response; 
irPD  immune-related progressive disease; irPR  immune-related partial response; 
irSD  immune-related stable disease. 
 


 
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Appendix 6 
Eastern Cooperative Oncology Group (ECOG) 
Performance Status Scale 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light housework or office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about  50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair  50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair 
5 
Dead 
 


 
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Appendix 7 
Anaphylaxis Precautions 
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 study drug 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. 
 


 
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Appendix 8 
Safety Reporting Fax Cover Sheet                      
Send to Duke Safety Surveillance Office:                                                            
Email: dcccsafe@dm.duke.edu, Fax: (919) 681-9357, Phone: (919) 681-9538 
 
GENENTECH SUPPORTED RESEARCH 
AE/SAE FAX No:  (650) 225-4682 
Alternate Fax No:  (650) 225-4630 
 
Page 1 of ___ 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
Initial Report Date 
 
 
/ 
/ 
 
 
dd / mmm / yyyy 
Follow-up Report Date 
 
 
/ 
/ 
 
 
dd / mmm / yyyy 
Patient Initials 
(Please enter a dash if the 
patient has no middle name) 
____ - ____ -____ 
 
SAE or Safety Reporting questions, contact Duke Cancer Institute Safety 
Surveillance Office: Fax: (919) 681-9357, Phone: (919) 681-9538 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER 
SHEET. 


 
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Appendix 9 
FDA MedWatch 3500 Form 
This form is included in the study start-up zip file to be sent to sites via email.  
 
 
 
 
 


 
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Appendix 10 
Eligibility Checklist 
Study #: Pro00079313                                                                                           Subject ID #: 
Inclusion Criteria 
Yes 
No 
N/A 
Site Coordinator 
Confirmation (Initial/Date) 
Patient is willing and able to provide written informed consent for the trial 
  
  
  
 
Patient has ability and willingness to comply with the requirements of the 
study protocol 
 
 
 
 
Patient is ≥ 18 years of age on day of signing informed consent 
  
  
  
 
Patient has no history of prior treatment for primary advanced (stage III or 
IV) epithelial ovarian, fallopian tube, or primary peritoneal carcinoma 
  
  
  
 
Patient has confirmation of diagnosis and patients for whom the plan of 
management will include NACT followed by ICS. The decision to proceed 
with NACT will be at the treating physician’s discretion and include patients with 
advanced stage disease considered at a low likelihood for optimal 
cytoreduction with primary debulking surgery 
  
  
  
 
Patient has measurable disease per RECIST v1.1. Measurable disease is 
defined as at least one lesion that can be accurately measured in at least one 
direction (longest diameter recorded). Each lesion must be ≥ 10mm when 
measured by CT, MRI or caliper measurement by clinical exam; or ≥ 20mm 
when measured by chest x-ray. Lymph nodes must be ≥ 15mm in short axis 
when measured by CT or MRI 
 
 
 
 
Patient has histology consistent with high-grade epithelial ovarian cancer  
 
 
 
 
Patient has an adequate pre-treatment tumor biopsy. Includes laparoscopic 
biopsy or image-guided core needle biopsy (minimum of two cores). Fine 
needle aspiration (FNA) biopsy or cytology form ascites may be adequate at 
the discretion of the investigator. Subjects for whom newly-obtained samples 
cannot be provided (e.g. inaccessible or subject safety concern) may submit an 
archived specimen only upon agreement of the investigator. 
**Sponsor approval required for FNA, archival, or cytology specimens** 
 
 
 
 
Patient has adequate hematologic and end organ function within 14 days 
prior to first study treatment (Cycle 1, Day 1):  
  
  
  
 
• Absolute Neutrophil Count ≥ 1,500/mcl  
  
  
  
 
• Lymphocyte Count ≥ 300/mcl 
 
 
 
 
• Platelets ≥ 100,000/mcl.  
  
  
  
 
• Hemoglobin ≥ 9.0 g/dL  
  
  
  
 
• Bilirubin ≤ 1.5 X ULN  If patient has known Gilbert disease who have serum 
bilirubin level ≤ 3 ULN may be enrolled 
 
 
 
 
• AST & ALT ≤ 3.0 X ULN  If patient has liver involvement: AST & ALT ≤ 5 X 
ULN 
 
 
 
 
• Alkaline phosphatase ≤ 2.5 X ULN. If patient has documented liver 
involvement or bone metastases: alkaline phosphatase ≤ 5 X ULN. Isolated 
alkaline phosphatase ≤ 5 X ULN with normal AST, ALT, and bilirubin is 
acceptable based on investigator discretion.  
 
 
 
 
• Creatinine Clearance ≥ 50 mL/min 
 
 
 
 
• International Normalized Ratio (INR) and Activated Partial 
Thromboplastin Time (aPTT)  ≤1.5 X ULN unless subject is receiving 
anticoagulant therapy; patients receiving therapeutic anticoagulation should be 
on stable dose 
 
 
 
 
Patient has ECOG Performance Status of 0, 1 or 2 
  
  
  
 
Patient has peripheral neuropathy less than or equal to CTCAE Grade 1 
 
 
 
 
If patient is of childbearing potential: should be willing to use highly effective 
form(s) of contraception and to continue its use at least until ICS or if ICS if not 
performed then 90 days post last dose of atezolizumab. Subjects of 
childbearing potential are those who have not been surgically sterilized or have 
not been free from menses for > 1 year 
  
  
  
 
Patients who opt to receive bevacizumab must meet standard institutional 
treatment guidelines 
 
 
 
 


 
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Study #: Pro00079313                                                                      Subject ID #: 
 
Exclusion Criteria 
Yes 
No 
N/A 
Site Coordinator 
Confirmation (Initial/Date) 
Patient has mucinous, low-grade histology, or clear cell carcinoma 
  
  
  
 
Patient has prior systemic chemotherapy for epithelial ovarian, fallopian 
tube, or primary peritoneal cancer 
  
  
  
 
Patient has prior invasive malignancy (except non-melanomatous skin 
cancer) unless disease free for a minimum of 3 years.  
Exceptions include basal cell or squamous cell carcinoma of the skin, or in situ 
cervical cancer that has undergone potentially curative therapy 
  
  
  
 
Patient has AEs from prior anticancer therapy that have not resolved to 
Grade ≤ 1 except for alopecia 
  
  
  
 
Patient uses bisphosphonate therapy for symptomatic hypercalcemia.  
Use of biophosphonate therapy for other reasons allowed (e.g. bone metastasis 
or osteoporosis) 
  
  
  
 
Patient has known clinically significant liver disease, including active viral, 
alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver 
disease  
  
  
  
 
Patient has known primary central nervous system (CNS) malignancy or 
symptomatic CNS metastases 
  
  
  
 
Patient is pregnant or breastfeeding 
  
  
  
 
Patient has known hypersensitivity to Chinese hamster ovary cell products 
or other recombinant human antibodies 
  
  
  
 
Patient is unable to comply with study and follow-up procedures 
  
  
  
 
Patient has a 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, Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, 
autoimmune thyroid disease, vasculitis, or glomerulonephritis 
  
  
  
 
• Patients with a history of autoimmune hypothyroidism on a stable dose of 
thyroid replacement therapy hormone may be eligible 
  
  
  
 
• Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen 
may be eligible 
 
 
 
 
• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are permitted provided they meet the following conditions 
 
 
 
 
     - Patients with psoriasis must have a baseline ophthalmologic exam to rule 
out ocular manifestations       manifestations 
 
 
 
 
     -  Rash must cover less than 10% of the body surface area (BSA) 
 
 
 
 
     -  Disease is well controlled at baseline and only requiring low potency topical 
steroid (e.g. hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, 
flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)       
hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, 
desonide 0.05%, aclometasone 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)) 
 
 
 
 
Patient has a history of idiopathic pulmonary fibrosis, pneumonitis 
(including drug-induced), organizing pneumonia (i.e. bronchiolitis 
obliterans, crytogenic organizing pneumonia, etc.) or evidence of active 
pneumonitis on screening CT scan 
 
 
 
 
• Patients with history of radiation pneumonitis in the radiation field (fibrosis) are 
permitted 
 
 
 
 
Patient has any other diseases, metabolic dysfunction, physical 
examination finding, or clinical laboratory finding giving reasonable 
suspicion of a disease or condition that contraindicates the use of an 
  
  
  
 


 
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investigational drug or that may affect the interpretation of results or 
render the patient at high risk of treatment complications 
Study #: Pro00079313                                                                      Subject ID #:  
Exclusion Criteria 
Yes 
No 
N/A 
Site Coordinator 
Confirmation (Initial/Date) 
Patient has history of HIV infection or active hepatitis B (chronic or acute) 
or hepatitis C infection 
  
  
  
 
• 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 
  
  
  
 
Patient has active tuberculosis 
 
 
 
 
Patient has 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 
 
 
 
 
Patient has signs or symptoms of infection within 2 weeks prior to Cycle 1, 
Day 1 
 
 
 
 
Patient has received oral or 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 
 
 
 
 
Patient has received a live vaccine within 4 weeks of Cycle 1, Day 1 or 
anticipation of such a live, attenuated vaccine will be required during the 
study 
  
  
  
 
• Note: Influenza vaccination should be given during influenza season only 
(approximately October to March). Patients must not receive live, attenuated 
influenza vaccine (e.g., Flu-Mist®) within 4 weeks prior to Cycle 1, Day 1 or at 
any time during the study 
 
 
 
 
Patient has prior history of treatment with anti-PD-1, anti-PD-L1, anti-PD-
L2, anti-CD137, anti-CTLA4 or any other antibodies targeting co-
stimulation or checkpoint pathways 
 
 
 
 
Patient has treatment with systemic immunostimulatory agents (including 
but not limited to interferon [Disis,  #15]-α or interleukin [IL]-2) within 6 
weeks or five half-lives of the drug (whichever is shorter) prior to Cycle 1, 
Day 1 
 
 
 
 
Patient has treatment with investigational agent within 4 weeks prior to 
Cycle 1, Day 1 (or within five half-lives of the investigational product, 
whichever is longer) 
 
 
 
 
Patient has 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) may be 
enrolled 
 
 
 
 
• The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) 
for patients with orthostatic hypotension or adrenocortical insufficiency is allowed 
 
 
 
 
Patient has history of severe allergic, anaphylactic, or other 
hypersensitivity reactions to chimeric or humanized antibodies or fusion 
proteins 
 
 
 
 
Patient has had prior allogeneic bone marrow transplantation or prior solid 
organ transplantation 
 
 
 
 
 
 
____________________________________________ 
Signature of Coordinator/Research Nurse                                               ________________ 
 
_____________________ 
Date 


 
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____________________________________________ 
Signature of Investigator 
 
______________________ 
Date 


 
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Appendix 11 Registration Form
 


 
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Appendix 12 
Investigator Signature Page 
Investigator Signature Page 
 
 
Product:  Atezolizumab 
 
Protocol: Atezolizumab in Combination with Neoadjuvant Chemotherapy and 
Interval Cytoreductive Surgery for Patients with Newly-Diagnosed Advanced-
Stage Epithelial Ovarian Cancer 
 
 
Investigator’s Agreement 
 
I have read the attached protocol entitled “Atezolizumab in Combination with 
Neoadjuvant Chemotherapy and Interval Cytoreductive Surgery for Patients with 
Newly-Diagnosed Advanced-Stage Epithelial Ovarian Cancer”, and agree to 
abide by all provisions set forth therein. 
 
I agree to comply with the International Conference on Harmonization Tripartite 
Guideline on Good Clinical Practice and applicable FDA regulations/guidelines 
set forth in 21 CFR Parts 11, 50, and 56. 
 
I agree to ensure that the confidential information contained in this document will 
not be used for any purpose other than the evaluation or conduct of the clinical 
investigation. 
 
____________________________    
Signature 
 
 
 
                                                                             
____________________________  
 
        ______________________ 
Name of Principal Investigator 
 
 
 
 Date (DD Month YYYY) 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix 13 Dose Modifications and Day 1 Dosing Criteria 
 
General Modifications 
 
In order to maintain dose-intensity and cumulative dose-delivery on this study, 
reasonable efforts will be made to minimize dose reduction and treatment delays 
as specified. Any patient whose treatment is delayed must be evaluated on a 
weekly basis until adequate hematologic parameters have been met. Appendix 
13 offers guidelines regarding dose modifications for chemotherapy that may be 
used at the discretion of the treating investigator.  
 
1. Treatment decisions will be based on the absolute neutrophil count (ANC) 
rather than the total white cell count (WBC) 
 
2. Lower limits for ANC and Platelet Count- Day 1 Dosing 
 
a. Day 1 of a subsequent cycle of cytotoxic chemotherapy will not be 
administered until the ANC is ≥ 1,000 cells/mcl and the platelet 
count is ≥ 75,000/mcl. All treatment will be delayed for a maximum 
of three weeks until these values are achieved. Patients who fail to 
recover adequate counts within a three-week delay will no longer 
receive cytotoxic therapy. 
 
The day 8 and 15 paclitaxel dose will not be given unless the ANC 
is at least 500 cells/mcl and the platelet count is at least 
50,000/mcl. If not given, these doses are omitted and not made up 
 
3. Use of hematopoietic Cytokines and Protective Agents 
 
a.  It is anticipated that myelosuppression may be a significant side 
effect of the regimen. Myeloid growth factors (either filgrastim or 
pegfilgrastim) can be used (it is recommended that NCCN and/or 
ASCO guidelines be consulted). If myeloid growth factors are used, 
it is recommended that filgrastim (dose according to institutional 
standard) will be administered daily subcutaneously starting 24-72 
hours after the last dose of chemotherapy and continuing through 
hematopoietic recover or pegfilgrastim will be administered at 6 mg 
subcutaneously (one dose per treatment cycle) 24-72 hours after 
the last dose of chemotherapy. Administration of growth factors on 
the same day as chemotherapy is not recommended. Pegfilgrastim 
is not recommended for chemotherapy regimens given less than 
every two weeks 
 
b. Patients will NOT receive prophylactic thrombopoietic agents.  


 
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c. Patients may receive erythropoietin (EPO), iron supplements, 
and/or transfusions as clinically indicated for management of 
anemia. Treating physicians should be aware of the prescribing 
information for the erythropoiesis stimulating agents (including 
Aranesp, Epogen and Procrit) which note that there is a potential 
risk of shortening the time to tumor progression or disease-free 
survival, and that these agents are administered only to avoid red 
blood cell transfusions. They are not indicated in patients being 
treated with curative intent. They do not alleviate fatigue or increase 
energy. They should NOT be used in patients with uncontrolled 
hypertension. They can cause an increased incidence of thrombotic 
events in cancer patients on chemotherapy. The updated package 
inserts should be consulted. 
http://www.fda.gov/Medwatch/safety/2007/safety07.htm 
 
d. Patients may NOT receive amifostine or other protective agents. 
 
Modifications for Hematologic Toxicity (Nadirs) 
 
1. Dose-Limiting Neutropenia (DLT-ANC) is defined by the occurrence of 
febrile neutropenia, prolonged Grade 4 neutropenia persisting ≥ 7 days, 
delay of treatment for more than 7 days because of neutropenia, ANC 
<1000 cells/mcl on Day 1, or omission of day 8 or day 15 paclitaxel 
because of neutropenia. Febrile neutropenia is defined within CTCAE as a 
disorder characterized by an ANC <1000/mcl and a single temperature 
of >38.3 degrees C (101 degrees F) or a sustained temperature of ≥38 
degrees C (100.4 degrees F) for more than one hour 
 
2. Dose-limiting thrombocytopenia (DLT-PLT) is defined by any occurrence 
of Grade 4 thrombocytopenia (<25,000/mcl) or bleeding associated with 
Grade 3 thrombocytopenia (25,000 to <50,000/mcl), delay of treatment on 
day 1 of a cycle by more than 7 days because of thrombocytopenia, 
platelet count of <75,000/mcl on day 1, or inability to give day 8 or day 15 
paclitaxel due to thrombocytopenia. There will be no modifications for 
uncomplicated Grade 3 thrombocytopenia except as above. 
 
3. Initial occurrence of dose-limiting neutropenia or dose limiting 
thrombocytopenia will be handled according to the following table 
 
 
 
 


 
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Modification instructions for Dose-Limiting Hematologic Toxicity 
DLT 
ANC 
DLT 
PLT 
First Occurrence Second Occurrence Third Occurrence 
Yes 
No 
Reduce 
carboplatin one 
AUC unit 
Omit day 15 
paclitaxel and 
administer G-CSF 
starting after day 8 
paclitaxel 
Reduce carboplatin 
one AUC, and give G-
CSF after day 8 
paclitaxel 
 
Fourth occurrence: 
Discontinue protocol 
directed cytotoxic 
therapy 
Yes 
Yes 
Reduce 
carboplatin one 
AUC unit 
Omit day 15 
paclitaxel and 
administer G-CSF 
starting after day 8 
paclitaxel) and 
reduce carboplatin 
one AUC unit 
Discontinue protocol-
directed cytotoxic 
therapy 
No 
Yes 
Reduce 
carboplatin one 
AUC unit 
Decrease carboplatin 
one AUC unit 
Discontinue protocol-
directed cytotoxic 
therapy 
 
If treatment is delayed more than 21 days for reasons of toxicity, then protocol-
directed cytotoxic therapy is ended; however patient may, at discretion of treating 
physician, continue with protocol directed maintenance therapy if she is 
benefiting from treatment. 
 
In the event the patient has a third dose limiting hematologic toxicity but is still 
obtaining clinical benefit from chemotherapy, she may be treated with additional 
cycles of chemotherapy at the discretion of the investigator and with approval by 
Dr. Alvarez Secord. The need for additional dose modification will be determined 
on an individual basis.