A Phase II Evaluation of Pembrolizumab in Combination With IV Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Phase: PHASE2
Conditions: Fallopian Tube Clear Cell Adenocarcinoma, Fallopian Tube Endometrioid Adenocarcinoma, Fallopian Tube Mucinous Adenocarcinoma, Fallopian Tube Serous Adenocarcinoma, Ovarian Clear Cell Adenocarcinoma, Ovarian Endometrioid Adenocarcinoma, Ovarian Mucinous Adenocarcinoma, Ovarian Serous Adenocarcinoma, Primary Peritoneal Serous Adenocarcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma, Undifferentiated Fallopian Tube Carcinoma, Undifferentiated Ovarian Carcinoma
Sponsor: Roswell Park Cancer Institute

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TITLE: A Phase II Evaluation of Pembrolizumab in Combination with IV Bevacizumab 
and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Epithelial 
Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Roswell Park Cancer Institute1&7
Study Number:
I 270715
Initial Date:
Amendment#1:
Amendment#2:
Amendment #3:
Amendment #4:
06 November 2015
20 July 2016
25 August 2016
01 August 2017
19 December 2017
Amendment #5:
22 March 2019
Amendment #6:
25 April 2019
Amendment #7:
03 October 2019
IND Holder:
Roswell Park Cancer Institute
Principal Investigator:
Emese Zsiros, MD PhD
Roswell Park Cancer Institute
Elm & Carlton Streets
Buffalo, New York 14263
716-845-8337
Emese.Zsiros@RoswellPark.org 
Sponsor :
Roswell Park Cancer Institute
Industry/Other Supporter:
Merck & Co., Inc.
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and 
shall remain the exclusive property of the party (ies) mentioned above. The use of such 
confidential information must be restricted to the recipient for the agreed purpose and 
must not be disclosed, published, or otherwise communicated to any unauthorized persons, 
for any reason, in any form whatsoever without the prior written consent of the party (ies) 
above.
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Study Contacts 
Name
Institution
Email
Role
Protocol 
Section
Junko Matsuzaki, 
PhD
Roswell Park 
Cancer Institute, 
Buffalo, NY 
Junko.Matsuzaki@RoswellPark.org 
Immune Analysis 
Facility Director
8.8.1 
8.9.1, 
Anthony Miliotto
Roswell Park 
Cancer Institute, 
Buffalo, NY
Anthony.Miliotto@RoswellPark.org
Senior Research 
Associate
8.8.3
QualTek Molecular 
Laboratories, 
Newtown, PA
MISPsamples@qmlabs.com
IHC for PD-L1 
expression
8.11.1
Correlative 
Sciences 
Pathology Office 
(CSPO)
Roswell Park 
Cancer Institute, 
Buffalo, NY
Carol.Siegel@RoswellPark.org
Sample storage
8.9.1, 
8.9.2
Warren Davis, 
PhD
Roswell Park 
Cancer Institute, 
Buffalo, NY
Warren.Davis@RoswellPark.org
Microbiome 
sample processing 
and storage
8.10.2
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SYNOPSIS
Title / Phase
A Phase II Evaluation of Pembrolizumab in Combination with IV 
Bevacizumab and Oral Metronomic Cyclophosphamide in the 
Treatment of Recurrent Epithelial Ovarian, Fallopian Tube, or 
Primary Peritoneal Cancer.
Roswell Park Cancer Institute Study 
Number
I 270715
Roswell Park Cancer Institute Investigator
Emese Zsiros, MD PhD
Sponsor
Roswell Park Cancer Institute
Industry/ Other Supporter
Merck & Co., Inc.
Study Drug(s)
Pembrolizumab
Bevacizumab
Cyclophosphamide
Objectives
Primary:
•
To evaluate improvement in progression-free survival for 
patients treated with anti-PD1 pembrolizumab in 
combination with IV bevacizumab and oral metronomic 
cyclophosphamide as compared to a historical control.
Secondary:
•
To obtain pilot data on clinical response rates using both 
RECIST1.1 criteria (Response Evaluation Criteria in Solid 
Tumors) and immune related response criteria (irRECIST).
•
To obtain data on changes in tumor microenvironment 
prior to and subsequent to therapy and, to screen for 
potential biomarkers to predict clinical benefit
•
To determine the safety and tolerability of the treatment 
combination in the study population.
•
To evaluate overall survival in patients treated with anti-
PD1 pembrolizumab in combination with IV bevacizumab 
and oral metronomic cyclophosphamide.
•
To assess the impact of the combination of anti-PD1 
pembrolizumab, IV bevacizumab and oral metronomic 
cyclophosphamide on anti-tumor immune responses in 
ovarian cancer.
Study Design
This is an open label Phase II study (with a safety lead-in cohort of 
n=5) of anti-PD1 antibody pembrolizumab, in combination with IV 
bevacizumab and oral metronomic cyclophosphamide in patients 
with recurrent platinum sensitive, resistant or refractory epithelial 
ovarian, fallopian tube, or primary peritoneal cancer.
Target Accrual and Study Duration
The study will enroll approximately 40 evaluable patients in total. 
Accrual is expected to take 18 months.
Study Procedures
Disease Evaluation: CT at Baseline, after 3rd cycle, after 6th cycle 
then, after every 6th cycle (or sooner if disease progression)
Adverse Events: Day 1 of each cycle, end of treatment, safety 
follow-up.
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Hematology: Baseline, Day 1 of each cycle, end of treatment, 
safety follow-up
Chemistry: Baseline, Day 1 of each cycle, end of treatment, safety 
follow-up
Performance Status: Baseline, Day 1 of each cycle, end of 
treatment, post treatment evaluations
Full Physical Examination (including basic neurological 
examination, vital signs, and body weight): Baseline, Day 1 
Cycle 1, Day 1 of every 3rd cycle, end of treatment, post treatment 
evaluations
Directed Physical Examination (including basic neurological 
exam, vital signs, and body weight): On cycles not requiring a full 
physical examination (e.g. cycles 2 and 3, cycles 5 and 6)
Vital Signs: Baseline, Day 1 of each cycle, end of treatment, post 
treatment evaluations
Pregnancy test: Within 72 hours prior to receiving first dose of 
study treatment in patients of child bearing potential
PT/INR and APTT: Baseline, Cycle 6 Day 1, Cycle 12 Day 1, end 
of treatment, safety follow-up.
Urinalysis: Baseline, Cycle 1Day 1, every 2nd cycle after Cycle 1, 
end of treatment.
UPCR Ratio: Baseline, Cycle 1Day 1 and, Day 1 of every 2nd 
cycle.
T3, FT4, and TSH: Baseline, Cycle 3 Day 1 then Day 1 of every 
3rd cycle, end of treatment, safety follow-up
Tissue Biopsy: Baseline, 2-3 weeks after Cycle 3, end of treatment 
(optional)
Blood Collection (correlative studies): Baseline (within 2 weeks 
prior to treatment initiation), Cycle 2 – Day 1, Cycle 4- Day 1, 
Cycle 7- Day 1, Cycle 10 –Day 1, and at the end of study treatment 
or at time of discontinuation (within two weeks after the last 
treatment cycle is completed) or, at the time of disease progression 
or for any other reason that requires study treatment termination, 
whichever occurs sooner.
On those patients, who have already completed 10 cycles, the one 
additional correlative blood sample will be collected at the time of 
their next cycle. 
Human Microbiome collection (correlative studies): Stool, 
vaginal and skin samples with correlative questionnaires prior to 
cycle#1 (within 7 days of starting treatment, preferably on Day 1 of 
cycle 1 prior to staring chemotherapy), after 3 cycles (within 7 days 
of starting cycle 4, preferably on Day 1 of cycle 4 prior to starting 
chemotherapy), Cycle 10 –Day 1 (within 7 days of starting cycle  
10, preferably on Day 1 of cycle 10  prior to starting chemotherapy) 
and at the end of treatment (during the last physical exam at the 
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time of study termination, stool sample collection within 7 days of 
this visit)
On those patients, who have already completed 10 cycles, the one 
additional microbiome sample will be collected at the time of their 
next cycle. 
Study Questionnaires:
•
Microbiome Initial Assessment Questionnaire: Cycle 1-
Day 1
•
Microbiome Collection Questionnaire: Cycle 1-Day 1, 
Cycle 4-Day 1, Cycle 10 –Day 1 and  End of Treatment (or 
time of discontinuation)
•
EORTC QLQ-C30 and EORTC QLQ-OV28: Cycle 1-
Day 1, Cycle 4-Day 1, Cycle 7 – Day 1, Cycle 10 –Day 1, 
End of Treatment (or time of discontinuation)
•
Multidimensional Fatigue Symptom Inventory-Short Form 
(MFSI-SF): Cycle 1-Day 1, Cycle 4-Day 1, Cycle 7 – Day 
1, Cycle 10 –Day 1, End of Treatment (or time of 
discontinuation )
•
On those patients, who have already completed 10 cycles, 
the additional correlative questionnaires will be collected 
at the time of their next cycle. 
Dermatology: Recommended skin check at baseline, after Cycle 3 
and at end of study treatment – optional for patients
Statistical Analysis
Sample Size Determination:
The primary objective of the Phase II study is to evaluate the 
progression-free survival (PFS) for patients treated with 
pembrolizumab in combination with IV bevacizumab and oral 
metronomic cyclophosphamide in women with recurrent/persistent 
platinum –sensitive, -resistant, or -refractory ovarian, primary 
peritoneal, or fallopian tube cancers. The median PFS of platinum 
resistant ovarian cancer patients treated with standard chemotherapy 
is approximately 3.5 months. In a recent study platinum-resistant 
ovarian cancer patients treated with a combination of IV 
bevacizumab and oral metronomic cyclophosphamide had a median 
PFS and overall survival (OS) of 4.5 and 10.7 months, respectively. 
In another study, patients with recurrent ovarian cancer treated with 
bevacizumab plus low-dose metronomic oral cyclophosphamide 
had a median response duration of 3.9 months. Therefore we would 
consider a PFS of 7 months or greater to be of interest in this 
population.
Consider a sample size of n=40 patients, with up to 1 year of 
follow-up, and a maximum drop-out rate of 10%. If the true 7-
month PFS rate is 50% (a median PFS of 7 months) for the 
proposed treatment combination, then a one-sided Wald-type test 
has approximately an 86.1% chance of resulting in significance. A 
nominal significance level of 10% is considered.
Safety Analysis: The frequency of toxicities will be tabulated by 
grade across all dose levels and cycles. Toxicity rates will be 
estimated using 90% confidence intervals, which will be obtained 
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using Jeffreys prior method. All participants who receive any study 
treatment will be considered evaluable for toxicity.
The overall and progression free survival will be summarized using 
standard Kaplan-Meier methods, with estimates of median survival 
and given survival rates will be obtained with 90% confidence 
intervals.
Safety Lead-in Cohort: A safety lead-in cohort of n1=5 patients 
will enrolled and the safety/tolerability of the combination will be 
examined after each patient completes at least 3 cycles. If 2 or less 
patients have experienced a drug related toxicity requiring 
drug/treatment delay or suspension (as defined in Sections 6.4, 6.5, 
and 6.7.3), then an additional n2=35 patients are enrolled to 
complete the Phase II study. Otherwise, the study will be suspended 
and the research team will meet to discuss possible safety concerns 
and will decide what actions to take with respect to study 
continuation.
Efficacy Analysis: The overall and progression free survival will be 
summarized using standard Kaplan-Meier methods, with estimates 
of median survival and given survival rates will be obtained with 
90% confidence intervals.
Objective tumor response will be tabulated for all patients that 
completed at least three cycles of the proposed treatment 
combination. The response rate will be estimated using 90% 
confidence intervals, obtained using Jeffrey’s prior method.
Correlative Data Analysis: The blood, tumor, stool, vaginal and 
skin microbiome samples will be collected as biomarkers and will 
be reported using the appropriate descriptive statistics depending on 
clinical outcome. Associations between these markers and PFS will 
be evaluated using Cox regression models; while associations with 
tumor response will be evaluated using logistic regression models.
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Participant Name: ____________________________________________________________
Medical Record No.: __________________________________________________________
Title: A Phase II Evaluation of Pembrolizumab in Combination with IV Bevacizumab and 
Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Epithelial Ovarian, 
Fallopian Tube, or Primary Peritoneal Cancer
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
1.
Age ≥ 18 years of age on day of signing informed consent
2.
Have an ECOG Performance Status of 0 or 1 (Refer to Appendix A)
3.
Have measurable disease per RECIST 1.1 or irRECIST criteria present.
4.
Participant may have serous, endometrioid, clear cell, mucinous or 
undifferentiated type of recurrent epithelial ovarian, fallopian tube, or 
primary peritoneal cancer. 
o
Histologic confirmation of the original primary tumor is required via 
the pathology report.
5.
Participant can be either platinum-sensitive (platinum free interval 
(PFI) ≥ 6 months prior to recent recurrence) or platinum-resistant 
(PFI < 6 months prior to recent recurrence. If the participant has a 
platinum sensitive disease, she may only enroll in this clinical trial if 
there is a contraindication for her to receive further treatment with 
platinum-based chemotherapy (such as serious persistent toxicity or 
severe hypersensitivity to platinum agents or she declines standard of 
care). 
6.
Participant must be willing to undergo core or excisional biopsy of a 
tumor lesion within 4 weeks (28 days) prior to initiation of treatment on 
Day 1 and, after 3 cycles of study treatment. Participants for whom 
newly-obtained samples cannot be provided (e.g. inaccessible or subject 
safety concern) may submit an archived specimen only upon agreement 
from the Principal Investigator.
7.
Have the following clinical laboratory values:
•
Absolute neutrophil count (ANC): ≥ 1,500 /mcL
•
Platelets: ≥ 100,000 / mcL
•
Hemoglobin: ≥ 9 g/dL or 5.6 mmol/L without transfusion or EPO 
dependency (within 7 days of assessment)
•
Serum creatinine: ≤1.5 X upper limit of normal (ULN) OR 
measured or calculated creatinine clearance ≥ 60 mL/min for 
participant with creatinine levels > 1.5 X institutional ULN (refer to 
Appendix B). GFR can also be used in place of creatinine or CrCl.
•
Urine Protein Creatine Ratio (UPCR) < 1 prior to starting cycle 1 
(refer to Appendix C).
•
Serum total bilirubin: ≤ 1.5 X ULN OR direct bilirubin ≤ ULN for 
participants with total bilirubin levels > 1.5 ULN
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INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
•
AST (SGOT) and ALT (SGPT): ≤ 2.5 X ULN OR ≤ 5 X ULN for 
participants with liver metastases
•
Albumin: > 2.5 mg/dL
•
International Normalized Ratio (INR) or Prothrombin Time 
(PT): ≤1.5 unless participant is receiving anticoagulant therapy as 
long as PT or PTT is within therapeutic range of intended use of 
anticoagulants
•
Activated Partial Thromboplastin Time (aPTT): ≤1.5 X ULN unless 
participant is receiving anticoagulant therapy as long as PT or PTT 
is within therapeutic range of intended use of anticoagulants
8.
Participants of childbearing potential must have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study 
medication. If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required.
9.
Participants of childbearing potential must be willing to use 2 methods of 
birth control or be surgically sterile, or abstain from heterosexual activity 
for the course of the study through 120 days after the last dose of study 
medication (participants of childbearing potential are those who have not 
been surgically sterilized or have not been free from menses for > 1 
year). Should a woman become pregnant or suspect she is pregnant while 
she is participating in this study, she should inform her treating physician 
immediately.
10. Participant has recovered from toxicities of prior chemotherapy or other 
therapy (to grade 2 or less).
11. Participant may have received prior investigational therapy (including 
immune therapy).
12. Participant may have received prior hormonal therapy.
13. Participant may have received bevacizumab (or other antiangiogenic 
agent) and/or cyclophosphamide in the past.
14. Participant has had at least 4 weeks of postoperative recovery from 
surgery prior to enrollment to ensure complete wound healing. 
Participants with bowel resections at surgery should begin protocol at 
least 42 days after surgery.
15. Ability to swallow and retain oral medication.
16. Participant or legal representative must understand the investigational 
nature of this study and sign an Independent Ethics 
Committee/Institutional Review Board approved written informed 
consent form prior to receiving any study related procedure.
Participant meets all entry criteria:
  Yes
  No
If “NO”, do not enroll participant in study.
Investigator Signature: ___________________________________
Date: __________
Printed Name of Investigator: ________________________________________________
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Participant Name: ____________________________________________________________
Medical Record No.: __________________________________________________________
Title: A Phase II Evaluation of Pembrolizumab in Combination with IV Bevacizumab and 
Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Epithelial Ovarian, 
Fallopian Tube, or Primary Peritoneal Cancer
EXCLUSION CRITERIA
No
Yes
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
1.
Is currently participating and receiving study therapy or has participated 
in a study of an investigational agent and received study therapy or used 
an investigational device within 4 weeks of the first dose of treatment.
2.
Has a diagnosis of immunodeficiency or is receiving systemic steroid 
therapy or any other form of immunosuppressive therapy within 7 days 
prior to the first dose of trial treatment or, is taking any other medication 
that might affect immune function.
3.
Has a known history of active TB (Bacillus Tuberculosis).
4.
Hypersensitivity to bevacizumab, cyclophosphamide, pembrolizumab or 
any of its excipients.
5.
Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks 
prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to agents administered more than 4 
weeks earlier.
6.
Has had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to study Day 1 or who has not 
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a 
previously administered agent. Note: Participants with ≤ Grade 2 
neuropathy are an exception to this criterion and may qualify for the 
study. Note: If participant received major surgery, they must have 
recovered adequately from the toxicity and/or complications from the 
intervention prior to starting therapy and, has to be at least 28 days after 
the surgery.
7.
Has a known additional malignancy that is progressing or requires active 
treatment: exceptions include basal cell carcinoma of the skin or 
squamous cell carcinoma of the skin that has undergone potentially 
curative therapy or cervical cancer in situ that has undergone potentially 
curative therapy.
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EXCLUSION CRITERIA
No
Yes
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
8.
Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. Participants with previously treated brain 
metastases may participate provided they are stable (without evidence of 
progression by imaging for at least four weeks prior to the first dose of 
trial treatment and any neurologic symptoms have returned to baseline), 
have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment. This exception does not 
include carcinomatous meningitis, which is excluded regardless of 
clinical stability.
9.
Has active autoimmune disease that has required systemic treatment in the 
past 6 months (i.e. with use of disease modifying agents, corticosteroids 
or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, 
insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency) is not considered a form of systemic treatment.
10. Has known history of, or any evidence of active, non-infectious 
pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
participant’s participation for the full duration of the trial, or is not in the 
best interest of the patient to participate, in the opinion of the treating 
investigator.
13. Has known psychiatric or substance abuse disorders that would interfere 
with cooperation with the requirements of the trial.
14. Is pregnant or breastfeeding, or expecting to conceive within the projected 
duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment.
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 
agent.
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies).
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., 
HCV RNA [qualitative] is detected).
18. Has received a live vaccine within 30 days of planned start of study 
therapy. Note: Seasonal influenza vaccines for injection are generally 
inactivated flu vaccines and are allowed; however intranasal influenza 
vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not 
allowed.
19. Active or history of inflammatory bowel disease (colitis, Crohn's), 
diverticulitis, irritable bowel disease, celiac disease, or other serious, 
chronic, gastrointestinal conditions associated with diarrhea. Active or 
history of systemic lupus erythematosus or Wegener's granulomatosis.
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EXCLUSION CRITERIA
No
Yes
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
20. Participant has clinical symptoms or signs of partial or complete 
gastrointestinal obstruction or, requires parenteral hydration and/or 
nutrition.
21. Participant requires, or is likely to require, more than a two-week course 
of corticosteroids for intercurrent illness. Participant must complete the 
course of corticosteroids 2 weeks before screening to meet eligibility.
22. Participant has a serious, non- healing wound, ulcer, or bone fracture.
23. Participant has a clinically significant cardiovascular disease including:
•
Uncontrolled hypertension, defined as systolic > 150 mmHg or 
diastolic > 90 mmHg
•
Myocardial infarction or unstable angina within 6 months prior to 
enrollment
•
New York Heart Association (NYHA) Grade II or greater 
congestive heart failure (refer to Appendix F)
•
Participant has a grade II or greater peripheral vascular disease
•
Participant has a clinically significant peripheral artery disease (e.g. 
those with claudication, within 6 months)
24. Participant has organ allografts.
25. Participant is receiving medication(s) that might affect immune function.
26. Unwilling or unable to follow protocol requirements.
Investigator Signature: ___________________________________
Date: ___________
Printed Name of Investigator: _________________________________________________
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TABLE OF CONTENTS
1
Background ............................................................................................................................20
1.1
Advanced Solid Tumors and Immunotherapy....................................................................20
1.2
Antiangiogenic Therapy Improves Immune Therapy.........................................................21
1.3
PD-1 and PD-L1 Background.............................................................................................22
1.3.1
PD-1 and PD-L1 Pharmaceutical and Therapeutic Background ....................................22
1.3.2
PD-1 and PD-L1 Blockade in Ovarian Cancer ...............................................................23
1.4
Pembrolizumab...................................................................................................................23
1.4.1
Preclinical and Clinical Studies with Pembrolizumab....................................................23
1.5
Bevacizumab.......................................................................................................................23
1.5.1
Bevacizumab and Ovarian Cancer..................................................................................24
1.6
Cyclophosphamide .............................................................................................................25
1.6.1
Rational for Combining Bevacizumab with Cyclophosphamide in Ovarian Cancer .....25
1.7
Translational Science Background .....................................................................................26
1.7.1
PD-L1 Expression (Integrated Biomarker).....................................................................26
1.7.2
Analysis of Tumor Infiltrating Immune cells and Targetable Immune Activating and 
Immune Inhibitory Genes (Exploratory Biomarker) .....................................................................26
1.7.3
Neo-antigen Landscape (Exploratory Biomarker)..........................................................27
1.7.4
T Cell Receptor (TCR) Repertoires (Exploratory Biomarker) .......................................27
1.7.5
Tumor-Associated Antigen (TAA) Serologic Responses (Exploratory Biomarker)......27
1.7.6
Cytokine and Chemokine Landscape (Exploratory Biomarker).....................................27
1.7.7
Tumor Associated Lymphocytes in Ascites (Exploratory Biomarker)...........................27
1.7.8
Human microbiome collection (Exploratory Biomarker)...............................................27
1.8
Risks and/or Benefits..........................................................................................................29
1.8.1
Pembrolizumab ...............................................................................................................29
1.8.2
Bevacizumab...................................................................................................................29
1.8.3
Cyclophosphamide..........................................................................................................31
2
Rationale.................................................................................................................................31
2.1
Rationale for Dose Selection/Regimen/Modification for Pembrolizumab.........................31
2.2
Rationale for Endpoints ......................................................................................................32
3
Objectives...............................................................................................................................33
3.1
Primary Objectives .............................................................................................................33
3.2
Secondary Objectives .........................................................................................................33
4
Methodology ..........................................................................................................................33
4.1
Study Design.......................................................................................................................33
4.2
Study Endpoints..................................................................................................................34
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4.2.1
Primary Endpoints...........................................................................................................34
4.2.2
Secondary Endpoints.......................................................................................................34
4.2.3
Replacement of Participants............................................................................................34
4.3
Target Accrual and Study Duration....................................................................................35
5
Participant Selection...............................................................................................................35
5.1
Inclusion Criteria ................................................................................................................35
5.2
Exclusion Criteria ...............................................................................................................37
5.3
Inclusion of Women and Minorities...................................................................................38
6
Treatment Plan .......................................................................................................................39
6.1
Dosing and Administration.................................................................................................39
6.1.1
Dosing of Pembrolizumab ..............................................................................................40
6.1.2
Dosing of Bevacizumab..................................................................................................40
6.1.3
Dosing of Cyclophosphamide.........................................................................................40
6.2
Timing of Dose Administration..........................................................................................40
6.3
Prohibited Concomitant Therapeutic Modalities................................................................40
6.4
Dose-Limiting Toxicity and Dose Delays for Pembrolizumab ..........................................40
6.5
Dose Delays for Bevacizumab............................................................................................43
6.6
General Concomitant Medications/ Vaccinations ..............................................................46
6.6.1
Acceptable Concomitant Medications ............................................................................46
6.6.2
Prohibited Concomitant Medications..............................................................................46
6.7
Supportive Care Guidelines................................................................................................47
6.7.1
Pembrolizumab Supportive Care Guidelines..................................................................47
6.7.2
Bevacizumab Supportive Care Guidelines .....................................................................52
6.7.3
Cyclophosphamide Supportive Care Guidelines ............................................................52
6.8
Diet/Activity/Other Considerations....................................................................................52
6.8.1
Diet..................................................................................................................................52
6.8.2
Contraception..................................................................................................................52
6.8.3
Use in Pregnancy ............................................................................................................53
6.8.4
Use in Nursing Women...................................................................................................53
6.8.5
Skin Toxicity...................................................................................................................53
6.9
Duration of Treatment ........................................................................................................54
6.9.1
Assessing for Secondary Cytoreduction and additional tumor biopsies to evaluate for 
response to treatment .....................................................................................................................54
6.10
Treatment Discontinuation .................................................................................................54
6.11
Compliance.........................................................................................................................55
7
Investigational Products .........................................................................................................55
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7.1
Pembrolizumab...................................................................................................................55
7.1.1
Active Substance and Source..........................................................................................55
7.1.2
Drug Shipment ................................................................................................................56
7.1.3
Preparation ......................................................................................................................56
7.1.4
Storage and Stability .......................................................................................................56
7.1.5
Handling and Disposal....................................................................................................56
7.1.6
Overdose .........................................................................................................................57
7.2
Bevacizumab.......................................................................................................................57
7.3
Cyclophosphamide .............................................................................................................57
8
Study Procedures....................................................................................................................57
8.1
Administrative Procedures..................................................................................................62
8.1.1
Informed Consent............................................................................................................62
8.1.2
Inclusion/Exclusion Criteria ...........................................................................................62
8.1.3
Medical History...............................................................................................................62
8.1.4
Prior and Concomitant Medications Review ..................................................................62
8.1.5
Post-Study Anti-Cancer Therapy Status .........................................................................62
8.1.6
Survival Follow-Up.........................................................................................................63
8.2
Clinical Procedures/Assessments .......................................................................................63
8.2.1
Adverse Event (AE) Monitoring.....................................................................................63
8.2.2
Full Physical Examination ..............................................................................................63
8.2.3
Directed Physical Exam..................................................................................................63
8.2.4
Vital Signs.......................................................................................................................64
8.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale ..............................64
8.3
Laboratory Procedures/Assessments ..................................................................................64
8.4
Efficacy Measurements ......................................................................................................64
8.4.1
Tumor Imaging and Assessment of Disease...................................................................64
8.5
Tissue Collection, Correlative Blood Sampling and Microbiome Samples.......................64
8.6
End of Treatment/Withdrawal/Discontinuation .................................................................65
8.7
Post-Treatment Visits .........................................................................................................65
8.7.1
Safety Follow-Up Visit ...................................................................................................65
8.7.2
Follow-up Visits..............................................................................................................65
8.7.3
Survival Follow-Up.........................................................................................................65
8.8
Collection and Handling of Specimens ..............................................................................66
8.8.1
Blood Sample Collection and Processing for Correlative Studies..................................66
8.8.2
Tumor Tissue Collection.................................................................................................67
8.8.3
Ascites.............................................................................................................................67
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8.9
Pathology ............................................................................................................................68
8.9.1
Pre- and On-Treatment Biopsies.....................................................................................68
8.9.2
Pre-Treatment Formalin-Fixed Paraffin-Embedded (FFPE) Biopsy Samples ...............69
8.10
Human Microbiome collection...........................................................................................69
8.10.1
Assessing quality of life and emotional well-being and lifestyle using the EORTC 
QLQ-C30, QLQ-OV28, MFSI-SF and Microbiome questionnaires.............................................69
8.10.2
Microbiome collection time points .................................................................................70
8.10.3
Skin microbiome collection ............................................................................................71
8.10.4
Vaginal sample collection technique and specimen handling ........................................72
8.10.5
Fecal microbiome collection...........................................................................................72
8.11
Planned Correlative Studies................................................................................................73
8.11.1
Assessment of dynamic changes in tumor microenvironment prior to and subsequent to 
therapy 73
8.11.2
Exploration of peripheral blood biomarkers as early predictors of clinical benefit........74
8.11.3
Exploration of genetic predictors of response.................................................................75
8.11.4
Exploration of human microbiome as a predictor of clinical response and its association 
with potential side effects ..............................................................................................................76
8.11.5
Assessment of Biospecimens and Clinical data..............................................................77
9
Efficacy evaluations ...............................................................................................................77
9.1
Baseline...............................................................................................................................77
9.1.1
Measurable Lesion Definitions and Target Lesion Selection .........................................77
9.1.2
Non-measurable Lesion Definitions ...............................................................................78
9.1.3
Target and Non-Target Lymph Node Lesion Definitions...............................................78
9.1.4
Non-Target Lesion Selection ..........................................................................................78
9.1.5
Bone Lesions...................................................................................................................78
9.1.6
Cystic and Necrotic Lesions as Target Lesions ..............................................................79
9.1.7
Lesions with Prior Local Treatment................................................................................79
9.1.8
No Disease at Baseline....................................................................................................79
9.2
Follow-Up...........................................................................................................................79
9.2.1
Recording of Target and New Measurable Lesion Measurements.................................79
9.2.2
Definition of New Measurable Lesions ..........................................................................79
9.2.3
Non-Target Lesion Assessment ......................................................................................80
9.2.4
New Non-Measurable Lesions Definition and Assessment............................................80
9.2.5
irRECIST Overall Tumor Assessments ..........................................................................80
9.2.6
Confirmation Measurement ............................................................................................81
9.3
Guidelines for Evaluation of Measurable Disease..............................................................81
10
Safety Evaluation................................................................................................................82
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10.1
Adverse Events ...................................................................................................................82
10.1.1
Definition ........................................................................................................................82
10.1.1.1
Diagnosis Versus Signs and Symptoms ......................................................................83
10.1.1.3
Abnormal Laboratory Values......................................................................................83
10.1.1.4
Preexisting Medical Conditions (Baseline Conditions) ..............................................83
10.1.2
Grading and Relationship to Drug ..................................................................................84
10.1.3
Reporting Adverse Events ..............................................................................................88
10.2
Events of Clinical Interest (ECIs).......................................................................................88
10.3
Serious Adverse Events ......................................................................................................90
10.3.1
Definition ........................................................................................................................90
10.3.2
Reporting Serious Adverse Events .................................................................................90
10.3.3
Reporting Events of Clinical Interest (ECIs) ..................................................................91
10.3.4
Reporting of Overdose....................................................................................................91
10.3.5
Reporting of Pregnancy and Lactation............................................................................91
10.4
Follow-Up for Serious Adverse Events..............................................................................91
10.5
Follow-Up for Events of Clinical Interest ..........................................................................91
10.6
Unanticipated Problems......................................................................................................92
10.6.1
Definition ........................................................................................................................92
10.6.2
Reporting Unanticipated Problems .................................................................................92
10.7
FDA Reporting ...................................................................................................................93
11
Data and Safety Monitoring................................................................................................93
12
Statistical Methodology......................................................................................................94
12.1
Sample Size Determination ................................................................................................94
12.2
Demographics and Baseline Characteristics.......................................................................95
12.3
Phase II Analysis ................................................................................................................95
12.3.1
Safety Lead-in Cohort.....................................................................................................95
12.3.2
Primary Objective ...........................................................................................................96
12.3.3
Secondary Objectives......................................................................................................96
12.4
Interim Analysis and Criteria for Early Termination of the Study.....................................97
13
Ethical and Regulatory Standards.......................................................................................97
13.1
Ethical Principles................................................................................................................97
13.2
Informed Consent ...............................................................................................................97
14
Study Responsibilities ........................................................................................................98
14.1
Data Collection ...................................................................................................................98
14.2
Maintenance of Study Documents......................................................................................98
15
Administrative Rules ..........................................................................................................99
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15.1
Revisions to the Protocol....................................................................................................99
15.2
Termination of the Study....................................................................................................99
15.3
Confidentiality ....................................................................................................................99
16
Appendices .......................................................................................................................100
17
References.........................................................................................................................126
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IN-TEXT TABLES
Table 1
Study Treatment Regimen...........................................................................................39
Table 2
Pembrolizumab: Dose Modification Guidelines for Drug-Related Adverse Events ..41
Table 3
Infusion Reaction Treatment Guidelines.....................................................................51
Table 4
Schedule of Procedures and Observations ..................................................................58
Table 5
Analysis of Tumor Microenvironment........................................................................73
Table 6
Analysis of Peripheral Blood Biomarkers...................................................................75
Table 7
Analysis of Genetic Predictors....................................................................................75
Table 8
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies (Regardless of 
Expectedness) ................................................................................................................................88
Table 9
Events of Clinical Interest ...........................................................................................88
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APPENDICES
Appendix A
ECOG Performance Status Scores.....................................................................101
Appendix B
Calculation for Creatinine Clearance.................................................................102
Appendix C
Procedure for Obtaining a Urine Protein Creatinine Ratio (UPCR)..................103
Appendix D
Laboratory Tests ................................................................................................104
Appendix E
Medication Diary ...............................................................................................105
Appendix F
NYHA Functional Classification System ..........................................................107
Appendix G
EORTC QLQ-C30 .............................................................................................108
Appendix H
EORTC OLQ-OV28 ..........................................................................................110
Appendix I
Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) ..............112
Appendix J
Microbiome Collection Questionnaire...............................................................113
Appendix K
Microbiome Initial Assessment Questionnaire..................................................117
Appendix L
Collection Instructions: Skin..............................................................................119
Appendix M
Collection Instructions: Vaginal ........................................................................120
Appendix N
Collection Instructions: Stool.............................................................................121
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1
BACKGROUND
1.1
Advanced Solid Tumors and Immunotherapy
Despite advances in surgery and chemotherapy over the past two decades, epithelial ovarian 
cancer (EOC) is still the leading cause of death from gynecologic cancer in the United States. 
Most ovarian cancer patients present with advance stage disease at the time of the diagnosis, and 
although most of them respond to first-line chemotherapy, these responses are not durable and 
the majority of these women will die of their disease. The clinical course of ovarian cancer 
patients is marked by periods of remission and relapse of sequentially shortening duration until 
chemotherapy resistance develops or significant toxicity occurs. Second line chemotherapies 
achieve very limited clinical benefit; therefore, there is an enormous unmet need for the 
development of novel therapies.
Recent scientific evidence demonstrated that EOC is an immunogenic tumor that can be 
recognized by the host immune system, and the increased infiltration of cytotoxic T cells in 
tumor islets correlates with significantly longer survival (1, 2), while increased numbers of 
immunosuppressive cells such as CD4+CD25+FoxP3+ regulatory T cells (Tregs) or B7-H4 
expressing tumor macrophages predict poor survival (2-4). T cell responses to multiple antigens 
overexpressed by ovarian cancers, such as folate receptor α (FRα), New York-esophageal-1 
(NY-ESO-1), p53, human epidermal growth factor receptor 2 (Her2)/neu, survivin, sperm 
surface protein Sp17, WT1, MUC1, melanoma associated antigen-3 (MAGE3), human 
telomerase reverse transcriptase (hTERT) and insulin-like growth factor binding protein-2 have 
been described in several studies, which further supports the rationale for immunotherapy in 
ovarian cancer (5-7). The success of immunotherapy however heavily depends on the homing 
ability of cytotoxic T lymphocytes (CTLs) into tumors, which is a complex multistep process 
involving adhesive interactions with vascular cells and migration within the stroma. Much of this 
process is regulated by tumor endothelial cells (EC) and chemotactic gradients within the tumor 
microenvironment (8, 9). Even in case of successful CTL infiltration, antitumor immunity is 
counterbalanced by an immune-suppressive microenvironment, constituted in part by tumor 
cells, Tregs and tolerance-inducing myeloid cells.
Harnessing the immune system to treat cancer is the major goal of immunotherapy. Although the 
identification of several tumor-specific antigens in ovarian cancer has provided the foundation 
for designing successful immunotherapies, immune cells still have to overcome the immune 
escape of the tumor or cancer immunoediting. The mechanisms for immunomodulation 
(therapeutic intervention aimed at modifying the body's immune response) in ovarian cancer 
include activation of professional antigen-presenting cells (APCs) by engaging costimulatory 
receptors (such as CD40), activation of effector T lymphocytes by immunostimulatory 
monoclonal antibodies (mAb), improving effector T cell homing by normalizing tumor 
vasculature and finally depletion of Tregs or immunosuppressive machineries. All of these 
components are essential to achieve meaningful clinical outcome 
Thus, a renewed emphasis on immunotherapy has emerged over the last several years with the 
development 
and 
testing 
of 
a 
novel 
class 
of 
immunotherapeutic 
agents 
called 
checkpoint inhibitors. The use of immune checkpoint inhibitors, which work by targeting 
molecules that serve as checks and balances in the regulation of immune responses, might be a 
promising avenue of immunotherapeutic research in ovarian cancer. Checkpoint inhibitor 
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immunotherapy is still in early-phase testing for ovarian cancer. Understanding the pivotal role 
of the tumor microenvironment in suppressing anticancer immunity, the unique adverse effects 
profiles of these agents, and the exploration of combinatorial treatment regimens will ultimately 
lead to enhance the efficacy of ovarian cancer immunotherapies and improved patient care (10).
1.2
Antiangiogenic Therapy Improves Immune Therapy
Targeting tumor angiogenesis is an important complementary approach to improve outcomes of 
patients with solid tumors (11). Tumor  neovasculature  is characterized by disruption  of  
intercellular  adhesion  between  EC and disorganization of supportive pericytes, which results in 
increased permeability and effusion formation (ascites in ovarian cancer) as well as in release of 
tumor cells into lymphatic and vascular spaces (12, 13). Currently the VEGF pathway is the most 
widely studied angiogenic pathway in carcinogenesis, and is comprised of VEGF-A (also known 
as VEGF) and the two receptor tyrosine kinases, VEGFR1 and VEGFR2 (14). VEGF was first 
recognized as an adverse factor in ovarian cancer in the 1990s as patients with increased VEGF 
expression in early stage ovarian cancer were shown to have significantly worse clinical outcome 
(15).
Since then we understand that tumor EC often use VEGF to establish a substantial barrier to limit 
T cell infiltration as VEGF deregulates vascular cell adhesion molecule 1 (VCAM-1) and 
intercellular adhesion molecule 1 (ICAM-1) on EC, thus impedes T cell extravasation (16, 17). 
Blockade of VEGF has been shown to increase the amount of T cell infiltration in tumors, thus 
dismantling this tumor endothelial barrier is crucial to improve T cell trafficking to tumor 
microenvironment (18).
Besides modulating lymphocyte endothelial trafficking VEGF also has profound effects on 
immune regulatory cell function, specifically inhibiting DC maturation and antigen presentation 
via VEGFR-1 (19-22) VEGF blockade was shown to restore DC function and enhance 
immunotherapy (11, 23).
Also in recent studies selective expression of the death mediator Fas ligand (FasL, also called 
CD95L) was described in the vasculature of human and mouse solid tumors but not in normal 
vasculature (24, 25). In these tumors, FasL expression was associated with scarce 
CTL infiltration and a predominance of Tregs (24). Tumor-derived VEGF-A, interleukin 10 (IL-
10) and prostaglandin E2 (PGE2) cooperatively induced FasL expression on tumor EC, which 
was shown to kill effector CTLs but not Tregs because of their higher levels of c-FLIP 
expression (26). In mice pharmacologic and genetic inhibition of VEGF-A (with bevacizumab) 
produced a marked increase in the influx of tumor-rejecting CD8+ CTLs over FoxP3+ Tregs that 
was dependent on attenuation of FasL expression and led to CD8-dependent tumor growth 
suppression (26).
Current anti-angiogenic therapy using bevacizumab, or other second-generation multitargeted 
receptor tyrosine kinase inhibitors (RTKIs) such as sunitinib,(27-29) sorafenib (30, 31), or 
pazopanib (32), improves PFS for a period of time in most types of cancer, but the anti-tumor 
effects of these drugs are short-lived. Most patients who initially respond will eventually develop 
drug resistance, tumor recurrence, or metastases indicating that anti-angiogenic therapy alone are 
not sufficient to prevent tumor progression and cancer metastasis in a long run (33-37). Their 
modest efficacy is most likely a result of redundant and complementary angiogenic pathways, 
such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth 
factor (EGF), and other pathway that compensate for VEGF blockade and allow angiogenesis to 
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occur despite anti-VEGF treatment (37) . Hypoxia induced by anti-angiogenesis therapy 
also modifies some of the signaling pathways in tumor and stromal cells, which could further 
contribute to resistance to therapy (38). In the clinical setting improvements achieved in PFS do 
not translate to OS benefits for the majority of cancer patients, thus combination of 
antiangiogenic drugs are necessary to enhance their efficacy.
1.3
PD-1 and PD-L1 Background
1.3.1
PD-1 and PD-L1 Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades. Accumulating evidence shows a correlation between 
tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / 
FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term survival in 
many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related 
to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2). The structure of murine PD-1 has been 
resolved. PD-1 and family members are type I transmembrane glycoproteins containing an Ig 
Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and 
an immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic 
tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 
which are involved in the CD3 T-cell signaling cascade. The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins. PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer 
cells. Expression has also been shown during thymic development on CD4-CD8- (double 
negative) T-cells as well as subsets of macrophages and dendritic cells. The ligands for PD-1 
(PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, 
including non-hematopoietic tissues as well as in various tumors: Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region 
and contain short cytoplasmic regions with no known signaling motifs. Binding of either PD-1 
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is 
expressed at low levels on various non-hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-
cell function in peripheral tissues. Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor. PD-1 
has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma 
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(MEL). This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention.
1.3.2
PD-1 and PD-L1 Blockade in Ovarian Cancer
Programmed cell death 1 and its ligand (PD-1-PD-L1) is expressed in many ovarian cancer 
patients and showed the closest relation to unfavorable prognosis among other 
immunosuppressive molecules that have been tested in ovarian cancer (39). Checkpoint blocking 
antibodies, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and PD-1, 
have demonstrated significant recent promise in the treatment of an expanding list of 
malignancies, and each plays a non-redundant role in modulating immune responses (40). 
CTLA-4 attenuates the early activation of naïve and memory T cells, while PD-1 is primarily 
involved in modulating T cell activity in peripheral tissues via interaction with its ligands, PD-L1 
and PD-L2 (40, 41). The blockade of PD-1 or PD-L1 was shown to enhance T-cell function and 
tumor cell lysis in the tumor microenvironment (42), however has limited effect as a 
monotherapy as peripheral tolerance is also highly depended on the  on tumor endothelial death 
barrier and CTL infiltration to tumor microenvironment. Thus efforts to further enhance the 
efficacy of immune checkpoint blockade through rational treatment combinations are needed.
1.4
Pembrolizumab
Pembrolizumab (formerly MK-3475) is a potent and highly selective humanized monoclonal 
antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2.
Upon administration, pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed 
on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its 
ligands, which results in the activation of T-cell-mediated immune responses against tumor cells. 
The ligands for PD-1 include PD-L1, which is expressed on antigen presenting cells (APCs) and 
overexpressed on certain cancer cells, and PD-L2, which is primarily expressed on APCs. 
Activated PD-1 negatively regulates T-cell activation through the suppression of the PI3K/Akt 
pathway.
Pembrolizumab (KeytrudaTM) has recently been approved in the United States for the treatment 
of patients with unresectable or metastatic melanoma and disease progression following 
ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
1.4.1
Preclinical and Clinical Studies with Pembrolizumab
A detailed discussion of the preclinical and clinical pharmacology, pharmacokinetics, and 
toxicology of pembrolizumab can be found in the Investigator’s Brochure.
1.5
Bevacizumab
Bevacizumab (Avastin®) is a recombinant humanized monoclonal antibody that neutralizes 
VEGF and blocks its signal transduction through both VEGFR-1 and VEGFR-2 as demonstrated 
by the inhibition of VEGF-induced cell proliferation, survival permeability, nitric oxide 
production, migration and tissue factor production (43).
The FDA approved bevacizumab as a first-line treatment for patients with unresectable 
metastatic colorectal cancer in 2004, after a randomized double-blind phase III clinical trial 
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demonstrated significant survival benefit in those patients treated with the addition of 
bevacizumab to irinotecan, 5-fluorouracil, and leucovorin (44).
1.5.1
Bevacizumab and Ovarian Cancer
In early phase II trials in ovarian cancer patients bevacizumab yielded single-agent activity 
beyond that was seen in colorectal or lung cancer (45). The median PFS was 4.7 months, which 
was statistically superior (p< .0001) to median PFS of 1.8 months for a historical cohort of more 
than 300 similar patients entered onto previous GOG phase II trials of inactive cytotoxic agents. 
Clinical response rate was 18% (5% complete response) with median response duration of 10.5 
months. An additional 55% had stable disease. Single-agent bevacizumab was well tolerated 
with no hematologic events of grade 3 or higher (45).
To date, four phase III randomized clinical trials testing bevacizumab in ovarian cancer have 
been published.
In later clinical trials the use of bevacizumab added significant clinical benefit when combined 
with standard chemotherapy in four randomized, double-blind, phase III trials, both as front-line 
treatment (GOG-0218 and ICON7) and in patients with recurrent disease (OCEANS and 
AURELIA) (46, 47).
In two pivotal, well designed, phase III, clinical trials (GOG-0218 and ICON7) in women with 
advanced epithelial ovarian, fallopian tube or primary peritoneal cancer, first-line treatment with 
bevacizumab in combination with standard chemotherapy (carboplatin plus paclitaxel) followed 
by maintenance treatment with bevacizumab alone significantly prolonged progression-free 
survival (by 3.8 months in GOG-0218 in the concurrent and maintenance arm and by 5.4 months 
in ICON-7 in patient with high risk for recurrence) relative to standard chemotherapy. Overall 
survival did not differ significantly between patients receiving standard chemotherapy plus 
placebo maintenance and those receiving concurrent plus maintenance bevacizumab in any of 
these trials – in GOG-0218 median OS 39.3 vs 39.7 and 38.7 months vs ICON-7 58.6 vs. 
58.0 months respectively (47-49).
OCEANS (50) was a randomized phase III trial testing the combination of carboplatin and 
gemcitabine with or without the addition of bevacizumab given concurrently and then as 
maintenance until progression in recurrent platinum-sensitive EOC. PFS for the bevacizumab 
arm was 12.4 months (vs. 8.4 months in the placebo group; p < .001). By the final analysis, 
however, there was no difference in overall survival (OS; 33.6 vs. 32.9 months). Of note, nearly 
all of the women in both arms went on to receive additional therapy, including bevacizumab.
In the AURELIA trial (51), bevacizumab was combined with the investigator’s choice of single-
agent chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan), in 
platinum-resistant EOC. The addition of bevacizumab improved PFS (6.7 vs. 3.4 months) and 
response rate, but there was no significant difference in OS (16.6 vs. 13.3 months; p < .17). 
Crossover to single-agent bevacizumab was permitted after progression with chemotherapy 
alone. AURELIA was the first phase III trial to show a benefit with combination therapy in the 
platinum-resistant population and is the basis for the drug FDA approval in EOC.
Bevacizumab was recently FDA approved for use in combination with single-agent 
chemotherapy for platinum-resistant disease; however, its optimal role in this cancer remains 
unclear. Although bevacizumab has activity in many patients with EOC, trials have identified 
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neither the optimal setting for treatment nor a predictive biomarker. The lack of a proven OS 
survival benefit does not necessarily speak against the drug’s efficacy and the median survival in 
EOC is longer than in many other solid tumors; therefore, OS data can be confounded by 
subsequent lines of therapy.
A detailed discussion of the preclinical pharmacology, pharmacokinetics, and toxicology of 
bevacizumab can be found in the Package Insert (http://medlibrary.org/lib/rx/meds/avastin-1/ ).
1.6
Cyclophosphamide
Besides the normalization of tumor vasculature to improve CTL homing, alteration of Tregs is 
also crucial in regulating anticancer immune responses. The increased presence of Tregs is 
associated with poor prognosis in ovarian cancer, while the ability to selective eliminate these 
cells has been repeatedly shown to bolster immune responses in preclinical cancer models. Tregs 
not only suppress cognate T cell responses but also blunt the innate arm of immunity, inhibiting 
NK cell proliferation and effector functions through the capacity to down regulate NKG2D level 
on these cells, thus associated with poor prognosis in cancer patients (52).
Cyclophosphamide is widely available, inexpensive and has multiple immune-modifying 
properties. Oral metronomic cyclophosphamide and VEGF blockade have independently been 
reported to selectively reduce the subset of immunosuppressive Tregs in vivo (53, 54). 
Metronomic chemotherapy refers to the close, regular administration of a chemotherapeutic drug 
at relatively low (non-toxic) doses, over prolonged periods, with no extended drug-free break 
periods (53, 55).
Oral administration of metronomic cyclophosphamide in advanced cancer patients induces a 
profound and selective reduction of circulating Tregs, associated with a suppression of their 
inhibitory functions on conventional T cells and NK cells leading to a restoration of peripheral T 
cell proliferation and innate killing activities (56). Cyclophosphamide also interferes with 
homeostatic proliferation of Tregs, increases their susceptibility to apoptosis, and impairs Treg 
functionality by decreasing the expression of suppression markers, such as glucocorticoid-
induced TNF receptor–related protein (GITR) and FoxP3 (56-58).
Furthermore it was also shown that high-avidity tumor specific CD8+ T cells are not deleted in 
the periphery with the use of cyclophosphamide, instead, these high-avidity T cells can be 
recruited and activated to provide a potent antitumor immune response if Tregs are inhibited, 
which further validates the addition of cyclophosphamide to enhance immunotherapy (59).
Therefore, metronomic regimen of cyclophosphamide does not only affect tumor angiogenesis 
but also strongly curtails immunosuppressive regulatory T cells; favoring a better control of 
tumor progression, thus represent a critical immuno-intervention in the oncologist’s 
armamentarium.
1.6.1
Rational for Combining Bevacizumab with Cyclophosphamide in Ovarian Cancer
As already discussed above, bevacizumab mainly has clinical benefit in patients who have 
advanced metastatic disease only or primarily when it is combined with conventional 
chemotherapy. The exact mechanisms for the chemo-enhancing effects of bevacizumab are still 
unknown, but this has been investigated along with other antiangiogenic drugs that could be 
combined with traditional chemotherapy or immunomodulating agents to improve clinical 
response (60).
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Treatment combinations of metronomic chemotherapy and an antiangiogenic drug have moved 
into phase II clinical trial testing with particularly encouraging results thus far reported in 
metastatic breast and recurrent ovarian cancer. Oral chemotherapy drugs such as 
cyclophosphamide and methotrexate are the main chemotherapeutics used for such trials.
There are already several studies in ovarian cancer which showed that the combination of IV 
bevacizumab (15 mg/kg every 3 weeks) and low dose metronomic oral cyclophosphamide 
(50 mg) is an effective, well-tolerated chemotherapy regimen in heavily pretreated patients with 
recurrent ovarian carcinoma and this combination significantly improved PFS and OS in 
responders (61, 62). Response rates were more favorable to the rates reported for similar patients 
receiving other commonly used second-line chemotherapeutic agents or just bevacizumab or 
cyclophosphamide alone, showing an objective response rate between 40.5-53.5% with 
approximately 10% of patients in each series demonstrating a complete response (61, 63-65). 
The reported severe adverse events in these studies were around 1-1.5%, the regimen was overall 
very well tolerated with only about 10% of patients encountering a side effect that required 
discontinuing treatment (46, 61, 63, 65). Also the median PFS reported in these studies in 
patients with recurrent ovarian cancer ranged from 3.9 months to 5.0 months (61, 63-65).
Therefore the combination of bevacizumab and low dose metronomic oral cyclophosphamide is 
active in recurrent ovarian cancer with improved clinical outcomes; hence the combination of 
these drugs is warranted.
1.7
Translational Science Background
Correlative translational studies for biomarkers will be performed depending on clinical response 
and initial mRNA analysis using NanoString from blood samples and tumor tissue biopsies. The 
list of potential biomarkers tested in genomics, immunohistochemistry, flow cytometry, 
serology, microbiome analysis and Luminex assay will be determined by the Principal 
Investigator (PI) after the initial analysis of clinical response and NanoString results. 
1.7.1
PD-L1 Expression (Integrated Biomarker)
Patients with tumors expressing of PD-L1 have shown improved clinical benefit from therapies 
targeting the PD-1/PD-L1 pathway (42, 66). However, the utility of PD-L1 expression as a 
predictive biomarker has been debated as it is highly dynamic and can be up-regulated in 
response to immune activating factors. In this trial, pre- and post-treatment tumor formalin-fixed, 
paraffin-embedded (FFPE) tissue will be evaluated by immunohistochemistry (IHC) for 
expression of PD-L1 as a predictive biomarker in this patient population.
1.7.2
Analysis of Tumor Infiltrating Immune cells and Targetable Immune Activating 
and Immune Inhibitory Genes (Exploratory Biomarker)
Presence of immune cells in tumor microenvironment has been shown to be predictive of 
response to immunotherapies. Assessment of the immune subsets in the tumors will help to 
establish predictive markers on the basis of pre-treatment phenotype as well to determine 
whether clinical efficacy correlates with the degree of infiltration of specific immune cell 
subsets. As such, pre- and post-treatment FFPE will be evaluated for the presence of TILs and 
immune markers determined by the PI. Examples of such immune checkpoint markers include4-
1BB, OX40, GITR, CD40, ICOS and PD-L1, IDO, B7-H3, B7-H4, LAG3, TIM-3, PD-1, CTLA-
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4, VISTA, and BTLA. Thus, depending on NanoString results and tissue availability, these 
markers potentially will be tested on pre and post-treatment biopsy samples (67).
1.7.3
Neo-antigen Landscape (Exploratory Biomarker)
A recent study by Snyder at al. used next-generation whole exome sequencing to characterize 
neo-antigen landscape in patients with malignant melanoma and defined particular neo-epitope 
signatures that were highly predictive of clinical benefit from anti-CTLA-4 therapy in patients 
with malignant melanoma (68). To determine whether specific tumor genetic determinants, 
including neo-epitope signatures influence the response to either treatment, depending on tissue 
availability and clinical response, DNA isolated from tumor samples may be processed for whole 
exome analysis to assess for specific driver mutations and for potential neo-antigens.
1.7.4
T Cell Receptor (TCR) Repertoires (Exploratory Biomarker)
Since cancer-testis (CT) antigens may not be present in all patients, but the analysis of overall 
changes in TCR repertoires during therapy may help to determine whether certain dominant T 
cell clones emerge or persist in response to therapy. Recently, Cha et al, reported that 
maintenance of specific T cell clonotypes in blood of patients with advanced melanoma treated 
with ipilimumab was associated with improved survival (69). Similar TCR repertoire studies 
were performed in tumors at MSKCC in the setting of a clinical trial in patients with early stage 
breast cancer treated with neoadjuvant cryoablation of breast lesion and ipilimumab, where 
combination therapy demonstrated most significant increase in intra-tumoral T cell clones(70). 
Thus, depending on tissue availability and clinical response, in this trial DNA may be used for 
TCR repertoire analysis and deep sequencing of TCR CDR3 regions.
1.7.5
Tumor-Associated Antigen (TAA) Serologic Responses (Exploratory Biomarker)
Expression of CT antigens in a large percentage of gynecologic malignancies has been reported 
in multiple studies. Monitoring for early responses to CT antigens and TAA such as NY-ESO1, 
MAGE 4, SOX2, and p53 may help identify the patients that are more likely to derive benefit 
from therapy. As such, pre- and post-treatment serum may be used for assessment of TAA 
serologic responses.
1.7.6
Cytokine and Chemokine Landscape (Exploratory Biomarker)
Cytokines and chemokines augment or dampen immune response by activating/exhausting 
certain subset of immune cells and by governing the migration of immune and cancer cells. 
Depending on clinical response and NanoString results – Luminex assay will be used to monitor 
the changes in the cytokine and chemokine landscape during the treatment.
1.7.7
Tumor Associated Lymphocytes in Ascites (Exploratory Biomarker)
Patients who have ascites at any time point during the clinical trial will be offered to undergo 
paracentesis for symptom relief. Ascites from these patients will be collected and later analyzed 
for presence of immune cells and inflammatory markers.
1.7.8
Human microbiome collection (Exploratory Biomarker)
The human microbiome plays an essential role in digestion and nutrient absorption, epithelial 
homeostasis, angiogenesis, and in the proper function of nervous and immune systems (71, 72). 
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Disruption of the microbiome could lead to chronic inflammation, altered immune responses and 
carcinogenesis (73, 74). Most recent research shows that there is a complex reciprocal 
modulation between gut microbiota and the human brain, which involves interaction of the 
central nervous system, sympathetic and parasympathetic branches of the autonomic nervous 
system, the enteric nervous system, and elements of the neuroendocrine and neuroimmune 
systems. For example, some microbiota synthesize neurotransmitters directly (e.g., gamma-
amino butyric acid) while many modulate the synthesis of neurotransmitters, such as serotonin, 
dopamine and norepinephrine, and brain-derived neurotropic factor (75). Microbiotic 
abnormalities have been linked to reductions in neurotransmitter levels, cognitive deﬁcits, 
anxiety, depression, chronic pain and fatigue (76, 77).
The composition of the microbiota also regulates the levels of tryptophan in the systemic 
circulation as well levels and nature of tryptophan catabolites (TRYCATs). These catabolites 
influence epithelial barrier integrity and the presence of an inflammatory or tolerogenic 
environment in the intestine and beyond (78). The composition of the microbiota also determines 
the levels and ratios of short chain fatty acids, such as butyrate and propionate, which are key 
energy source for colonocytes (79). Dysbiosis (altered microbiome) can lead to reduced levels of 
butyrate, and therefore may have adverse effects on epithelial barrier integrity, increase bacterial 
translocation into the systemic circulation, effects energy homeostasis, and the T helper 
17/regulatory/T cell balance. (75, 79).
Increasing evidence suggests that different gut, skin, and vaginal microbiota profiles may be 
related to the etiology of certain gynecological cancers, such as cervical cancer, uterine cancer, 
and ovarian cancer (80). Patients’ severity of side effects and response to certain cancer 
treatments can also be impacted by gut microbiome composition (73). In a recent study by 
Vetizou et al. it was shown that anticancer immunotherapy by CTLA-4 blockade relies on the 
gut microbiota and the authors showed the key role for Bacteroidales in the immunostimulatory 
effects of CTLA-4 blockade both in mice and patients (81). In another recent landmark paper by 
Sivan et al. (82) was shown that Bifidobacterium as associated with the antitumor effects and 
oral administration of Bifidobacterium alone improved tumor control to the same degree as PD-
L1-specific antibody therapy, and combination treatment nearly abolished tumor outgrowth. 
Thus, the authors suggested that manipulating the microbiota may modulate cancer 
immunotherapy (82).
Skin reactions are the most common immune-related side effects of checkpoint inhibitor therapy 
affecting approximately one third of patients on PD-1 inhibitor therapy (83). Currently, no tools 
are available to identify individuals at highest risk of cutaneous side effects prior to therapy, 
although changes in the skin microbiome have been shown in several immune mediated skin 
diseases, such as atopic dermatitis, psoriasis and vitiligo (84, 85). There is no published data on 
microbiome composition in patients with ovarian cancer, particularly in patients with recurrent 
ovarian cancer receiving treatment with a check point inhibitor. Thus, in parallel with the other 
above mentioned translational studies, we will collect pre-, on- and post-treatment skin, vaginal 
and fecal samples from patients participating in this clinical trial to characterize how the 
microbiomes of these parts of the body relate to disease severity and treatment response. We will 
study associations of the cutaneous microbiome and the presentation of skin eruptions during the 
intervention. Moreover, we will correlate efficacy of therapy with the presence of specific 
cutaneous side effects and the microbiome composition in ovarian cancer patients. If there are 
sufficient tumor samples from the core biopsies, we will test the microbiome composition in the 
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tumor microenvironment as well. We will also ask our patients to complete surveys to assess 
their emotional well-being, social functioning, and energy/fatigue level as well as a basic survey 
on their nutrition and lifestyle in order to gather a more comprehensive data on the interaction of 
microbiome and central nervous and immune systems.
1.8
Risks and/or Benefits
1.8.1
Pembrolizumab
The most common adverse reactions (reported in ≥ 20% of patients) to pembrolizumab 
(KEYTRUDA®) include fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, 
arthralgia 
and, 
diarrhea. 
Refer 
to 
package 
insert 
for 
additional 
information 
(http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125514lbl.pdf ).
Pembrolizumab is generally well tolerated and demonstrates a favorable safety profile in 
comparison to chemotherapy. Pembrolizumab is an immunomodulatory agent, and based on this 
mechanism of action, immune mediated adverse events are of primary concern. Important 
identified risks for pembrolizumab are of an immune mediate nature, including: pneumonitis, 
colitis, thyroid disorders (hypothyroidism/ hyperthyroidism), hepatitis, hypophysitis, Type I 
diabetes mellitus, uveitis, and nephritis.
After a recent review of data, events newly characterized as identified risks also include 
pancreatitis, myositis, and severe skin reaction; these are included in the reference safety 
information (refer to IB).
The majority of immune-mediated adverse events were mild to moderate in severity, were 
manageable with appropriate care, and rarely required discontinuation of therapy. Further details 
around frequency, reporting, and management of immune-related adverse events (irAEs) are 
described in the Investigator’s Brochure. In addition to the previously noted identified risks, 
infusion-related reactions are a risk but are not considered immune mediated see Section 10.2).
1.8.2
Bevacizumab
As VEGF plays an important role in normal physiologic processes – such as stabilization of 
damaged endothelia and wound healing – thus the inhibition of VEGF carries a unique toxicity 
profile (86). Bevacizumab in general is well tolerated in all patients. The most common 
toxicities associated with bevacizumab includes mucosal bleeding,  hypertension (HTN), 
proteinuria and wound healing complications, however these adverse events are generally 
manageable (87). New-onset HTN and exacerbation of existing HTN are the most commonly 
reported adverse events attributable to bevacizumab. In randomized trials, the incidence of grade 
3/4 HTN in bevacizumab-treated patients ranged from 3.0% to 14.8% compared with 0% to 
2.0% for controls (88).
Bevacizumab related proteinuria is typically mild in severity and non-dose-limiting, but it can 
rarely escalate to nephrotic syndrome. The incidence of grade 3/4 proteinuria in bevacizumab-
receiving arms  in meta-analysis of 1850 patients treated in seven randomized trials reported 
statistically significant relative risks of proteinuria equal to 1.4 with low-dose bevacizumab and 
2.2 at higher doses (88).
The delay of wound healing, wound dehiscence, fistula, and abscess has been reported in patients 
receiving bevacizumab. Because of the long half-life of bevacizumab ( 20 days), the risk of 
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wound-healing complications persist even after its discontinuation (86). A pooled analysis of two 
randomized metastatic colorectal cancer trials found no difference in the rate of wound-healing 
complications in bevacizumab-treated patients and controls, when bevacizumab was given at 
least 28 days following major surgery; however patients who underwent major surgery while 
receiving bevacizumab had a wound-healing complication rate of 13% compared to 3.4% in 
controls (89).
GOG-0218 and ICON7 did not show increased wound-healing complications in women with 
ovarian cancer, although most participants were not surgical candidates (45, 90). GOG-0218 
protocol also delayed the administration of bevacizumab or placebo until the second cycle of 
chemotherapy, regardless of the timing of primary debulking surgery. In the Bevacizumab 
Regimens' Investigation of Treatment Effects (BRiTE) registry, 622 patients had surgery after 
starting bevacizumab therapy; 23 (3.7%) wound-healing complications were reported, occurring 
more often in patients undergoing major abdominal surgeries < 60 days following the last 
bevacizumab dose (89, 91). According to the BRiTE registry (91) and another study by 
Scappaticci (89), the optimal interval between the last bevacizumab dose administered and 
subsequent major surgery is generally considered to be 60 days.
The previously reported rare life threatening complication related to bevacizumab treatment 
in non-gynecologic tumors included hemorrhagic complications such as gastrointestinal (GI) 
perforations (2.4%) and arterial and venous thromboembolic events (ATE) (3%) (Genentech 
BioOncology, 2006). Of these, GI perforations have been observed in ovarian cancer in 
5.4% of the patients (87). Identification of clinical risk factors for bevacizumab-related GI 
perforations minimizes the incidence of this adverse event as the majority of events occurred in 
patients with at least one of the following characteristics: acute diverticulitis, intra-abdominal 
abscess, GI obstruction, tumor at the GI perforation site, carcinomatosis, or prior radiation 
therapy (86).
Venous thromboembolism (VTE) has been reported in many bevacizumab trials, VTE 
incidence rates in bevacizumab-treated patients that were not statistically different from those 
seen in controls. The incidence of VTE in phase II ovarian studies was relatively low (2% to 3%) 
(45).
The rates of both arterial thromboembolism and hemorrhage are increased in patients 
receiving bevacizumab therapy. Under normal conditions, VEGF mediates the repair of 
endothelial surfaces that have sustained damage secondary to cardiovascular disease and other 
microangiopathies (92). This results in exposed subendothelial tissues that initiate the clotting 
cascade and subsequent clot formation. The underlying prothrombotic state characteristic of 
cancer patients might exacerbate this process. Though somewhat counterintuitive, the 
mechanism leading to hemorrhage might also result from a lack of endothelial repair in areas 
where subendothelial tissues are violated by pathophysiologic processes that may or may not be 
related to the malignancy.
Hemorrhage: The incidence of hemorrhage is increased with bevacizumab therapy. Epistaxis is 
common, occurring in 20-40% of patients, but it is generally mild and rarely requires medical 
intervention. Life-threatening and fatal hemorrhagic events have been observed in bevacizumab 
studies and included pulmonary hemorrhage, CNS bleeding and gastrointestinal (GI) bleeding. In 
a phase 2 study in non-small cell lung cancer, 6 cases of life-threatening hemoptysis or 
hematemesis were reported among 66 patients treated with bevacizumab and chemotherapy; 4 of 
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these events were fatal In the pivotal phase 3 trial in advanced colorectal cancer, the rate of GI 
hemorrhage (all grades) was 24% in the IFL/bevacizumab arm compared to 6% in the IFL arm; 
grade 3-4 hemorrhage was 3.1% for IFL/bevacizumab and 2.5% for IFL. Serious GI hemorrhage 
has also been observed in clinical trials with bevacizumab in patients with pancreatic cancer or 
varices treated with bevacizumab.
The incidence of arterial thromboembolic (ATE) events – such as transient ischemic attacks, 
cerebral infarction, unstable angina, troponin elevation, and acute myocardial infarction – has 
been reported to be slightly higher in bevacizumab-treated patients compared to controls (4.4% 
vs 1.9%) (93, 94). Risk factors for ATE identified in this analysis included age ≥ 65 years, male 
sex, and history of ATE. Ovarian cancer studies reported similarly low incidences of ATE (0% 
to 3%) (86, 87, 94).
All patients on bevacizumab should be considered at risk for ATEs, and extra caution should be 
exercised when prescribing bevacizumab to those > 65 years old with a history of ATE or 
conditions which predispose them to ATE. There is no modification, aside from discontinuation 
of therapy, known to be more effective than standard medical treatment for bevacizumab-
associated ATE events. As with all bevacizumab-related adverse events, the continuation of 
bevacizumab in specific situations in which bevacizumab benefit was either greater than the 
severity of toxicity or underlying predisposing factors were reversible (e.g., cardiac 
revascularization) might be considered, though overall prognosis might preclude such risks.
Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare neurological disorder 
that has been reported in association with HTN, eclampsia, and various states of 
immunosuppression due to organ transplant, chemotherapy – including bevacizumab, or 
autoimmune disorders. RPLS can present with headache, seizure, lethargy, confusion, blindness, 
and other visual and neurologic disturbances, which can occur at any interval following 
bevacizumab administration. The mechanistic link between bevacizumab and RPLS is unknown, 
but RPLS not associated with bevacizumab involves loss of cerebral vascular autoregulation, 
disruption of the cerebral tissue/capillary interface, and vasogenic edema. There is no specific 
treatment for RPLS outside of confirming the diagnosis, providing supportive care, which 
includes aggressive management of HTN, and discontinuing bevacizumab therapy.
In summary, bevacizumab is the first biologic therapy targeted at tumor pathophysiology to show 
significant activity in ovarian cancer with acceptable added toxicity. The adverse events 
associated with bevacizumab, however, are specific to its biologic effects and are potentially 
serious, even fatal.
1.8.3
Cyclophosphamide
Common adverse reactions to cyclophosphamide include neutropenia, febrile neutropenia, fever, 
alopecia, nausea, vomiting and, diarrhea. Refer to package insert for additional information 
(http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/040745Orig1s003lbl.pdf ).
2
RATIONALE
2.1
Rationale for Dose Selection/Regimen/Modification for Pembrolizumab
An open-label Phase I trial (KEYNOTE 001) is completed, evaluating the safety and clinical 
activity of single agent pembrolizumab. The dose escalation portion of this trial evaluated three 
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dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects 
with advanced solid tumors. All three dose levels were well tolerated and no dose-limiting 
toxicities were observed. This first in human study of pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg 
and 10 mg/kg Q2W). No MTD has been identified to date. 
Recent data from other clinical studies within the pembrolizumab program has shown that a 
lower dose of pembrolizumab and a less frequent schedule may be sufficient for target 
engagement and clinical activity.
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic 
data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 days). This 
early PK and pharmacodynamic data provides scientific rationale for testing a Q3W dosing 
schedule.
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters 
of pembrolizumab were found to be dependent on body weight. The relationship between 
clearance and body weight, with an allometric exponent of 0.59, is within the range observed for 
other antibodies and would support both body weight normalized dosing or a fixed dose across 
all body weights. Pembrolizumab has been found to have a wide therapeutic range based on the 
melanoma indication. The differences in exposure for a 200 mg fixed dose regimen relative to a 
2 mg/kg Q3W body weight based regimen are anticipated to remain well within the established 
exposure margins of 0.5 – 5.0 for pembrolizumab in the melanoma indication. The exposure 
margins are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. 
the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The 
population PK evaluation revealed that there was no significant impact of tumor burden on 
exposure. In addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication settings.
The above data indicate that the proposed fixed dose regimen for pembrolizumab of 200mg 
Q3W in the current study is similar to the 10 mg/kg Q2W dose regimen, with regard to efficacy 
and tolerability (refer to Investigator’s Brochure, section 5.4.1.3: Overall Adverse Events: P102, 
A Phase Ib Study of Pembrolizumab in Patients with Advanced Solid Tumors).
2.2
Rationale for Endpoints
According to the design schema the estimated sample size is 40 patients overall. Noting that the 
median PFS of platinum-resistant ovarian cancer patients treated with standard chemotherapy  is 
3.5 months, we would consider a PFS of 7 months or greater to be of interest in this population. 
We expect that no more than 30% of patients treated with standard chemotherapy would achieve 
7 months of PFS. Therefore, we will test the null hypothesis that the PFS response to): 
Pembrolizumab 200 mg  IV + bevacizumab 15 mg/kg every 3 weeks IV + cyclophosphamide 50 
mg po every day combination therapy is equal to 30% versus the one-sided hypothesis that it is 
greater than 30%. Please see section 8.0 for more detailed information on statistical analysis.
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3
OBJECTIVES
3.1
Primary Objectives
•
To evaluate improvement in progression-free survival for patients treated with anti-PD1 
pembrolizumab in combination with IV bevacizumab and oral metronomic 
cyclophosphamide as compared to a historical control.
3.2
Secondary Objectives
•
To obtain pilot data on clinical response rates using both RECIST1.1 criteria (Response 
Evaluation Criteria in Solid Tumors) and immune related response criteria (irRECIST).
•
To obtain data on changes in tumor microenvironment prior to and subsequent to therapy 
and, to screen for potential biomarkers to predict clinical benefit.
•
To determine the safety and tolerability of the treatment combination in the study 
population.
•
To evaluate overall survival in patients treated with anti-PD1 pembrolizumab in 
combination with IV bevacizumab and oral metronomic cyclophosphamide.
•
To assess the impact of the combination of anti-PD1 pembrolizumab, IV bevacizumab 
and oral metronomic cyclophosphamide on anti-tumor immune responses in ovarian 
cancer.
4
METHODOLOGY
4.1
Study Design
This is an open label Phase II study of anti-PD1 antibody pembrolizumab, in combination with 
IV bevacizumab and oral metronomic cyclophosphamide in patients with recurrent platinum 
sensitive, resistant or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer. 
The study will include an initial safety lead-in cohort of 5 patients. The estimated total sample 
size is n=40. The study schema is depicted in Figure 1.
Figure 1
Trial Diagram
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As shown in Figure 1, each cycle consists of 3 weeks. Pembrolizumab with bevacizumab will be 
administered every 3 weeks IV, while cyclophosphamide will be given continuously orally every 
day. 
Dosing regimen: Pembrolizumab 200 mg IV + bevacizumab 15 mg/kg every 3 weeks IV + 
cyclophosphamide 50 mg po every day up to 12 months (maximum of 17 cycles) or until disease 
progression, or until development of unacceptable toxicity, whichever occurs sooner.
Safety Lead-in Cohort: There will be an initial safety lead-in cohort of 5 patients. The 
safety/tolerability of the combination will be examined after each patient completes at least 
3 cycles (i.e., the first 9 weeks of therapy). If 2 or less patients have experienced a drug related 
toxicity requiring drug/treatment delay or suspension (as defined in Sections 6.4, 6.5, and 6.7.3), 
then an additional 35 patients will be enrolled to complete the Phase II study. Otherwise, the 
study will be suspended and the research team will meet to discuss possible safety concerns and 
will decide what actions to take with respect to study continuation.
Assessing response to treatment: Tumor response will be assessed after the 3rd and 6th cycles then 
after every 6 cycles by investigator-assessed clinical exam and immune-related response criteria 
(irRECIST) by independent, central, blinded radiographic review. Conventional RECIST 1.1 will 
also be documented during the trial, however RECIST 1.1 will not be used to determine disease 
progression, as it has been shown in prior clinical trials using Pembrolizumab in large number of 
patients, that conventional RECIST might underestimate the benefit of pembrolizumab in 
approximately 15% of patients; thus using irRECIST could permit treatment beyond initial 
progression per RECIST v1.1 and prevent premature cessation of treatment (95-97).
If, after 12 months of treatment the patient remains without any evidence of disease progression 
(has stable disease, partial or complete response), they will be offered to continue with the 
treatment until disease progression or until treatment is tolerated without severe (grade 3 or 4) 
toxicity that would require drug discontinuation.
Note: If the patient has good clinical response and chooses to remain on the treatment beyond 12 
months, we will continue to collect the same clinical data as we were during the first 12 months, 
as these laboratory tests and imaging studies are standard of care when patients are receiving 
chemotherapy for ovarian cancer.
4.2
Study Endpoints
4.2.1
Primary Endpoints
•
The hazard of having a disease progression or dying (PFS endpoint) by treatment.
4.2.2
Secondary Endpoints
•
The frequency and duration of objective tumor response within 6 months of study entry 
as assessed by immune-related response criteria (irRECIST).
•
The duration of overall survival (OS).
•
The frequency and severity of adverse events, as assessed by CTCAE.
4.2.3
Replacement of Participants
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Any participant, who discontinues the study prior to completion of at least 4 cycles of therapy 
(prior to CT scan after cycle 3 to assess for clinical response) for reasons other than treatment 
related toxicity, will be excluded from the analyses and replaced.
4.3
Target Accrual and Study Duration
The study will enroll approximately 40 evaluable patients in total (includes a safety lead-in 
cohort of n=5). Accrual is expected to take 18 months.
Study treatment is for 12 months (or a maximum of 17 cycles), with a follow-up period of up to 
3 years from initiation of study treatment; for a total study duration of approximately 5 years.
5
PARTICIPANT SELECTION
All participants will sign an informed consent prior to study related tests. All participants will 
meet the inclusion and exclusion criteria summarized in Section 5.1 and Section 5.2.
5.1
Inclusion Criteria
To be included in this study, participants must meet the following criteria:
1. Age ≥ 18 years of age on day of signing informed consent.
2. Have an ECOG Performance Status of 0 or 1 (refer to Appendix A).
3. Have measurable disease per RECIST 1.1 or irRECIST criteria present.
4. Participant may have serous, endometrioid, clear cell, mucinous or undifferentiated type 
of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.
o
Histologic confirmation of the original primary tumor is required via the 
pathology report.
5. Participant can be either platinum-sensitive (platinum free interval (PFI) ≥ 6 months prior 
to recent recurrence) or platinum-resistant (PFI < 6 months prior to recent recurrence). If 
the participant has a platinum sensitive disease, she may only enroll in this clinical trial if 
there is a contraindication for her to receive further treatment with platinum-based 
chemotherapy (such as serious persistent toxicity or severe hypersensitivity to platinum 
agents or she declines standard of care).
6. Participant must be willing to undergo core or excisional biopsy of a tumor lesion within 
4 weeks (28 days) prior to initiation of treatment on Day 1and, after 3 cycles of study 
treatment. Participants for whom newly-obtained samples cannot be provided (e.g. 
inaccessible or subject safety concern) may submit an archived specimen only upon 
agreement from the Principal Investigator.
7. Have the following clinical laboratory values:
o
Absolute neutrophil count (ANC): ≥ 1,500 /mcL
o
Platelets: ≥ 100,000 / mcL
o
Hemoglobin: ≥ 9 g/dL or 5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment)
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o
Serum creatinine: ≤1.5 X upper limit of normal (ULN) OR measured or 
calculated creatinine clearance ≥ 60 mL/min for participant with creatinine levels 
> 1.5 X institutional ULN (refer to Appendix B). GFR can also be used in place 
of creatinine or CrCl.
o
Urine Protein Creatine Ratio (UPCR) < 1 prior to enrollment (refer to Appendix 
C).
o
Serum total bilirubin: ≤ 1.5 X ULN OR direct bilirubin ≤ ULN for participants 
with total bilirubin levels > 1.5 ULN
o
AST (SGOT) and ALT (SGPT): ≤ 2.5 X ULN OR ≤ 5 X ULN for participants 
with liver metastases
o
Albumin: > 2.5 mg/dL
o
International Normalized Ratio (INR) or Prothrombin Time (PT): ≤1.5  unless 
participant is receiving anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
o
Activated Partial Thromboplastin Time (aPTT): ≤1.5 X ULN unless participant is 
receiving anticoagulant therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
8. Participants of childbearing potential must have a negative urine or serum pregnancy 
within 72 hours prior to receiving the first dose of study medication. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.
9. Participants of childbearing potential must be willing to use 2 methods of birth control or 
be surgically sterile, or abstain from heterosexual activity for the course of the study 
through 120 days after the last dose of study medication (participants of childbearing 
potential are those who have not been surgically sterilized or have not been free from 
menses for > 1 year). Should a woman become pregnant or suspect she is pregnant while 
she is participating in this study, she should inform her treating physician immediately.
10. Participant has recovered from toxicities of prior chemotherapy or other therapy (to grade 
2 or less).
11. Participant may have received prior investigational therapy (including immune therapy).
12. Participant may have received prior hormonal therapy.
13. Participant may have received bevacizumab (or other antiangiogenic agent) and/or 
cyclophosphamide in the past.
14. Participant has had at least 4 weeks of postoperative recovery from surgery prior to 
enrollment to ensure complete wound healing. Participants with bowel resections at 
surgery should begin protocol at least 42 days after surgery.
15. Ability to swallow and retain oral medication.
16. Participant or legal representative must understand the investigational nature of this study 
and sign an Independent Ethics Committee/Institutional Review Board approved written 
informed consent form prior to receiving any study related procedure.
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5.2
Exclusion Criteria
Participants will be excluded from this study for the following:
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks of the first dose of treatment.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment or, is taking any other medication that might affect immune function.
3. Has a known history of active TB (Bacillus Tuberculosis).
4. Hypersensitivity to bevacizumab, cyclophosphamide, pembrolizumab or any of its 
excipients.
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier.
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to a previously administered agent.
o
Note: Participants with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study
o
Note: If participant received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy and, has to be at least 28 days after the surgery 
7. Has a known additional malignancy that is progressing or requires active treatment: 
exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or cervical cancer in situ that has 
undergone potentially curative therapy.
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks prior 
to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment. This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.
9. Has active autoimmune disease that has required systemic treatment in the past 6 months 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment.
10. Has known history of, or any evidence of active, non-infectious pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the participant’s participation 
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for the full duration of the trial, or is not in the best interest of the patient to participate, in 
the opinion of the treating investigator.
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
14. Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the 
trial, starting with the pre-screening or screening visit through 120 days after the last dose 
of trial treatment.
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
18. Has received a live vaccine within 30 days of planned start of study therapy.
o
Note: Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-
Mist®) are live attenuated vaccines, and are not allowed.
19. Active or history of inflammatory bowel disease (colitis, Crohn's), diverticulitis, irritable 
bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions 
associated with diarrhea. Active or history of systemic lupus erythematosus or Wegener's 
granulomatosis.
20. Participant has clinical symptoms or signs of partial or complete gastrointestinal 
obstruction or, requires parenteral hydration and/or nutrition.
21. Participant requires, or is likely to require, more than a two - week course of 
corticosteroids for intercurrent illness. Participant must complete the course of 
corticosteroids 2 weeks before screening to meet eligibility.
22. Participant has a serious, non- healing wound, ulcer, or bone fracture.
23. Participant has a clinically significant cardiovascular disease including:
o
Uncontrolled hypertension, defined as systolic > 150 mmHg or diastolic 
> 90 mmHg
o
Myocardial infarction or unstable angina within 6 months prior to enrollment
o
New York Heart Association (NYHA) Grade II or greater congestive heart 
failure (refer to Appendix F)
o
Participant has a grade II or greater peripheral vascular disease
o
Participant has a clinically significant peripheral artery disease (e.g. those with 
claudication, within 6 months)
24. Participant has organ allografts.
25. Participant is receiving medication(s) that might affect immune function.
26. Unwilling or unable to follow protocol requirements.
5.3
Inclusion of Women and Minorities
Women of all races and ethnic groups are eligible for this study.
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6
TREATMENT PLAN
6.1
Dosing and Administration
Duration of treatment is 12 months (with a maximum of 17 cycles) or until disease progression 
or development of unacceptable toxicity, whichever occurs sooner, or any severe toxicity that 
requires drug discontinuation.
If after 12 months of treatment, a patient remains without any evidence of disease progression 
(has stable disease, partial or complete response), they will be offered to continue with the 
treatment until disease progression or until treatment is tolerated without severe (grade 3 or 4) 
toxicity that requires drug discontinuation.
Each cycle consists of 3 weeks: Pembrolizumab with bevacizumab will be administered every 3 
weeks IV, while cyclophosphamide will be given continuously orally every day. Pembrolizumab 
will be administered first, followed by bevacizumab.
Initially, a safety lead-in cohort of n=5 patients will be enrolled under the proposed study 
treatment regimen (as outlined in Table 1) and the safety/tolerability of the combination will be 
examined after each patient completes at least 3 cycles. At that time, the study team will decide 
what action to take, e.g., continue the study as is, make changes to the study with regard to 
treatment or dose modifications, or discontinue the study.
If 2 or less patients have experienced a drug related toxicity requiring drug/treatment delay or 
suspension (as defined in Sections 6.4, 6.5, and 6.7.3), then an additional 35 patients will be 
enrolled to complete the Phase II study. Otherwise, the study will be suspended and the research 
team will meet to discuss possible safety concerns and will decide what actions to take with 
respect to study continuation.
The rationale for selection of doses to be used in this trial is provided in Section 2.1.
Reported adverse events (AEs) and potential risks are described in Section 1.8. Appropriate dose 
modifications are described in Section 6.4
The treatment regimen to be used in this trial is outlined below (Table 1):
Table 1
Study Treatment Regimen
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each 3 week 
cycle
Experimental
Bevacizumab
15 mg/kg
Q3W
IV infusion
Day 1 of each 3 week 
cycle
Standard
Cyclophosphamide
50 mg 
Q.D.
p.o.
Day 1 to day 21 
continuously
Standard
In case of significant toxicity, evaluation will be performed to determine which drug could have 
been responsible for the adverse reaction and also to exclude other possible causes.
If the adverse reaction is attributed to pembrolizumab, drug will be either withheld or 
permanently discontinued per Section 6.4
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If the adverse reaction is attributed to bevacizumab or cyclophosphamide, drug will be either 
withheld or permanently discontinued per Section 6.5
Note: There are no dose reductions for pembrolizumab, bevacizumab or, cyclophosphamide.
6.1.1
Dosing of Pembrolizumab
Pembrolizumab 200 mg will be administered prior to bevacizumab, as a 30 minute IV infusion 
every 3 weeks. Sites should make every effort to target infusion timing to be as close to 30 
minutes as possible. However, given the variability of infusion pumps from site to site, a window 
of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
Refer to the Pharmacy Manual: Pembrolizumab (MK-3475) for specific instructions for the 
preparation of the pembrolizumab infusion fluid and administration of infusion solution.
6.1.2
Dosing of Bevacizumab
Bevacizumab will be administered at 15 mg/kg IV every 3 weeks (following pembrolizumab 
infusion), infused over 30 min (first time infusion over 90 min, second time infusion over 
60 min, then every subsequent infusion for 30 min). Bevacizumab dosing will be based on the 
participant’s actual body weight for each treatment cycle.
6.1.3
Dosing of Cyclophosphamide
50 mg orally: daily during each 21 day cycle.
Patient will be instructed to swallow cyclophosphamide capsules whole, without cutting, 
chewing or crushing. Patient should take the capsule in the morning, it can be taken with or 
without food, and patient is recommended to drink 2-3 quarts of fluid/day. 
There will be no dose reductions for cyclophosphamide.
6.2
Timing of Dose Administration
Trial treatment will be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed in Table 4 (Schedule of Procedures and Observations). Trial 
treatment may be administered up to 3 days before or after the scheduled Day 1 of each cycle 
due to administrative reasons.
All trial treatments will be administered on an outpatient basis.
6.3
Prohibited Concomitant Therapeutic Modalities
Prior to documented disease progression, the following therapeutic modalities are prohibited:
1. Anti-neoplastic therapy not otherwise specified in the current protocol, including 
cytotoxic, biologic, hormonal, or radiation therapy, regardless of indication (treatment of 
measurable disease or consolidation therapy).
6.4
Dose-Limiting Toxicity and Dose Delays for Pembrolizumab
There will be no dose reductions for pembrolizumab.
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
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related toxicities and severe or life-threatening AEs (to include as events only if toxicities are 
considered related, probably related, or possibly related to the drug) as per Table 2 below. 
Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse 
Events Version 4.0 (CTCAE v4.0).
A dose limiting toxicity (DLT) will be defined as any ≥ grade 3 clinically significant toxicity, 
which is deemed to be probably or possibly treatment related and, occurs within the first 9 weeks 
of therapy (9 weeks = 3 cycles).
See Section 6.7.1 and Event of Clinical Interest Guidance Document for supportive care 
guidelines, including use of corticosteroids.
Table 2
Pembrolizumab: Dose Modification Guidelines for Drug-Related Adverse 
Events
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 
weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day 
within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Grade 2
Withhold 
Pneumonitis 
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
•
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
•
Monitor participants for 
signs and symptoms of 
pneumonitis
•
Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate 
corticosteroid treatment
•
Add prophylactic 
antibiotics for 
opportunistic infections
Grade 2 or 3
Withhold
Diarrhea / Colitis 
Grade 4
Permanently 
discontinue
•
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
•
Monitor participants for 
signs and symptoms of 
enterocolitis (ie, 
diarrhea, abdominal 
pain, blood or mucus in 
stool with or without 
fever) and of bowel 
perforation 
(ie, peritoneal signs and 
ileus).
•
Participants with ≥ 
Grade 2 diarrhea 
suspecting colitis should 
consider GI consultation 
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and performing 
endoscopy to rule out 
colitis. 
•
Participants with 
diarrhea/colitis should 
be advised to drink 
liberal quantities of 
clear fluids.  If 
sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted 
via IV infusion.
Grade 2
Withhold
•
Administer corticosteroids 
(initial dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 3 or 4 
Permanently 
discontinue
•
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
•
Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 
enzyme value returned 
to baseline or is stable
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold
•
Initiate insulin replacement 
therapy for participants with 
T1DM 
•
Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 
•
Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes.
Grade 2
Withhold
Hypophysitis
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
•
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated.  
•
Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency) 
Grade 2
Continue 
Hyperthyroidism 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
•
Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate 
•
Monitor for signs and 
symptoms of thyroid 
disorders. 
Hypothyroidism
Grade 2-4
Continue 
•
Initiate thyroid replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) per standard 
of care
•
Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 2
Withhold 
Nephritis and 
Renal 
dysfunction
Grade 3 or 4 
Permanently 
discontinue
•
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper.
•
Monitor changes of 
renal function
Grade 1 or 2
Withhold
Myocarditis
Grade 3 or 4
Permanently 
discontinue
•
Based on severity of AE 
administer corticosteroids
•
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes
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Intolerable/ 
persistent Grade 2
Withhold
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis
All other 
immune-related 
AEs
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
•
Based on type and severity 
of AE administer 
corticosteroids 
•
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or 
achieved metabolic control (in case of T1DM).  
6.5
Dose Delays for Bevacizumab
There will be no dose reduction for bevacizumab. Treatment should be interrupted or 
discontinued for certain adverse events, as described below:
•
Hypertension
Patients receiving bevacizumab should be monitored prior to each dose with measurement of 
blood pressure. Medication classes used for management of patients with Grade 2 or 3 
hypertension receiving bevacizumab included angiotensin-converting enzyme inhibitors, beta 
blockers, diuretics, and calcium channel blockers, but preferably should be a beta blocking 
agent, if no contraindications. The use of anxiolytics in conjunction with specific anti-
hypertensive agents is not prohibited. The goal for blood pressure control should be 
consistent with general medical practice guidelines (i.e. < 150/90 mmHg in general and < 
130/80 mmHg for patients with diabetes). 
o
For asymptomatic grade 2 or grade 3 hypertension (systolic > 150 mm Hg or 
diastolic > 90 without any concern for life-threatening consequences) treating 
physician may administer antihypertensive (and/or anxiolytic) agent in the office 
and proceed with treatment if blood pressure lowers to <150/90 - per physicians’ 
discretion. Patient will be asked to monitor BPs regularly at home and follow up 
with primary care physician within a week.  
o
For symptomatic grade 2 or grade 3 hypertension or for grade 4 hypertension 
(BPs that are concerning for life-threatening consequences), hold bevacizumab 
treatment 
(and 
pembrolizumab, 
but 
patient 
can 
continue 
with 
oral 
cyclophosphamide) up to 1 week, ( see below), administer antihypertensive 
therapy  as clinically needed and arrange appropriate follow up/admission for 
blood pressure control. 
o
During the period of combination chemotherapy with bevacizumab, if 
hypertension becomes controlled (under 150/90 during the majority of the time) 
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and symptomatic hypertension has resolved by one week after holding treatment, 
continue all therapy.
o
During the period of combination chemotherapy with bevacizumab, if 
hypertension remains persistently uncontrolled on one or several antihypertensive 
agents taken appropriately or remains symptomatic one week after holding 
treatment, the next treatment cycle should contain pembrolizumab and 
cyclophosphamide only, if applicable, as otherwise indicated in the protocol, with 
bevacizumab omitted.
o
If uncontrolled or symptomatic hypertension has not resolved by three weeks after 
holding treatment with bevacizumab (despite patient taking antihypertensive 
agents appropriately) , treatment with bevacizumab should be discontinued for the 
remainder of the study, but patient may continue with pembrolizumab and oral 
cyclophosphamide
•
Proteinuria
Patients receiving bevacizumab should be monitored by urine analysis for urine protein: 
creatinine (UPC) ratio prior to every other dose of bevacizumab. If,
o
UPC ratio ≤ 3.5: Continue bevacizumab
o
UPC ratio > 3.5: Hold bevacizumab until UPC ratio recovers to < 3.5. If therapy 
is held for > 2 months due to proteinuria, discontinue bevacizumab
o
Grade 4 or nephrotic syndrome: Discontinue bevacizumab
•
Hemorrhage
Bevacizumab will be discontinued in patients with CTCAE Grade 3 hemorrhage and 
receiving full-dose anticoagulation. For all other patients with CTCAE Grade 3 hemorrhage, 
bevacizumab should be held until ALL of the following criteria are met:
o
bleeding has resolved
o
blood hemoglobin level is stable
o
there is no bleeding diathesis that would increase the risk of therapy
o
there is no anatomical or pathologic condition that can increase the risk of 
hemorrhage recurrence
Patients who experience delay of resolution according to the above criteria for >3 weeks, 
recurrence of Grade 3 hemorrhage, or any CTCAE Grade 4 hemorrhage will be taken off 
bevacizumab therapy.
•
Thrombosis
Arterial Thrombosis: Bevacizumab will be discontinued for ≥ CTCAE Grade 3 arterial 
thrombotic events (including cerebrovascular ischemia, transient ischemic attack, cardiac 
ischemia/infarction, peripheral or visceral arterial ischemia) or CTCAE Grade 2 arterial 
thrombotic events new or worsened since beginning bevacizumab therapy.
Venous Thrombosis: Treatment with bevacizumab will be held for CTCAE Grade 3 or 
asymptomatic CTCAE Grade 4 (including pulmonary embolism) venous thrombosis. For 
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patients on therapeutic anticoagulation, PT INR or PTT (whichever appropriate) should be 
monitored closely during bevacizumab therapy.
o
The participant must have an in-range INR (usually between 2 and 3) on a stable 
dose of warfarin (or other anticoagulant) or on stable dose of heparin prior to 
restarting treatment.
o
The participant must not have pathological conditions that carry high risk of 
bleeding (e.g. tumor involving major vessels).
o
The subject must not have had hemorrhagic events while on study.
o
The patient is benefiting from treatment (no evidence of disease progression). 
Patients with symptomatic Grade 4 thromboembolic events after study enrollment 
but prior to course 2 should be managed according to the above guidelines above.
However, patients with symptomatic CTCAE Grade 4 after receiving any bevacizumab, or 
recurrent/worsening venous thromboembolic events after resumption of bevacizumab 
treatment will be taken off bevacizumab therapy.
•
Coagulopathy
Bevacizumab should be held if the coagulation parameters are higher than the intended 
therapeutic range or for coagulopathy as follows:
o
For CTCAE Grade 3 or 4 coagulopathy: hold treatment, until PT/PTT resolve to 
Grade 1.
o
For patients with PT/INR > therapeutic range while on therapeutic warfarin, 
treatment with bevacizumab/placebo will be held until PT/INR is within the 
therapeutic range.
Patients experiencing treatment delay > three weeks because of failure to meet the above 
criteria will be taken off bevacizumab therapy.
•
Wound Disruption/Bowel Perforation, Fistula, or GI Leak
Treatment with bevacizumab will be modified in the event of wound disruption requiring 
medical or surgical intervention, bowel perforation or fistula (including tracheal-esophageal 
fistula) as follows:
o
In the event of superficial wound separations healing by secondary intention with 
no evidence of fascial dehiscence or infection, therapy with bevacizumab may be 
initiated with weekly wound examinations until complete closure. After initiation 
of bevacizumab, bevacizumab will be discontinued for any new event, regardless 
of Grade.
•
Intestinal Obstruction
o
Bevacizumab will be held for occurrence of CTCAE Grade 3 toxicity, until 
resolution to ≤CTCAE Grade 1 and will be permanently discontinued for 
occurrence of CTCAE Grade 4 toxicity.
Since the development of intestinal obstruction could be a result of cancer progression, the 
investigator should take steps to evaluate such patients for the possibility of disease 
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progression, using clinical, laboratory and radiographic information as clinically indicated; in 
the event of disease progression, all protocol-directed therapy would be discontinued.
•
Treatment Guidelines for Reversible Posterior Leukoencephalopathy Syndrome 
(RPLS)
o
Bevacizumab should be held in patients with symptoms/signs suggestive of 
RPLS, pending work-up and management, including control of blood pressure. 
Bevacizumab should be discontinued upon diagnosis of RPLS.
Note: Resumption of bevacizumab may be considered in patients who have documented 
benefit from the agent, provided that RPLS was mild and has completely resolved clinically 
and radiographically within 2-4 weeks; decision to resume bevacizumab in these patients 
must be discussed with the Principal Investigator and approved by Merck.
6.6
General Concomitant Medications/ Vaccinations
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The investigator should discuss any questions regarding this with 
the Merck Clinical team. The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the subject's primary physician.
6.6.1
Acceptable Concomitant Medications
All treatments that the principal investigator considers necessary for a participant’s welfare may 
be administered at the discretion of the investigator in keeping with the community standards of 
medical care. 
All concomitant medications ongoing within 28 days before the first dose of trial treatment as 
well as any that will be discontinued within 1 week prior to the first dose of study drug will be 
recorded on the CRF. This is to include all prescription, over-the-counter (OTC), herbal 
supplements, and IV medications and fluids. Assessment of concomitant medications occurs at 
the beginning of every treatment cycle during the trial period. Any changes that occur during the 
trial period (e.g., drug dosage, frequency, route, date) will be included on the CRF.
Concomitant medications administered after 30 days after the last dose of trial treatment will be 
recorded for SAEs and ECIs as defined in Section 10.3Section 10.2, respectively.
Participants may be pretreated for nausea and vomiting with appropriate anti-emetics.
6.6.2
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the Baseline period and 
Treatment Phase of the study:
•
Antineoplastic systemic chemotherapy or biological therapy 
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
•
Investigational agents other than pembrolizumab
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•
Radiation therapy 
o
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion.  
•
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.
•
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. The use of physiologic 
doses of corticosteroids may be approved after consultation with Merck.
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Participants may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria (Section 5.2) describes other medications which are prohibited in this 
trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
6.7
Supportive Care Guidelines
6.7.1
Pembrolizumab Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined below and in greater detail in the ECI 
Guidance Document. Where appropriate, these guidelines include the use of oral or intravenous 
treatment with corticosteroids as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids. Note that several courses of steroid tapering may 
be necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are intended 
to be applied when the investigator determines the events to be related to pembrolizumab.
Note: If after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI Document reporting guidance but does not need to follow the 
treatment guidance (as outlined in the ECI Guidance Document).
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. Suggested conditional procedures, as appropriate, 
can be found in the ECI Guidance Document.
•
Pneumonitis
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks.
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o
For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration.
•
Diarrhea/Colitis
Participants should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).
o
All participants who experience diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids. If sufficient oral fluid intake is not feasible, 
fluid and electrolytes should be substituted via IV infusion. For Grade 2 or 
higher diarrhea, consider GI consultation and endoscopy to confirm or rule 
out colitis.
o
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer 
oral corticosteroids.
o
For Grade 3 or 4 diarrhea/ colitis that persists > 1 week, treat with 
intravenous steroids followed by high dose oral steroids.
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.
•
Type 1 Diabetes Mellitus or ≥ Grade 3 Hyperglycemia
For Type 1 diabetes mellitus (TIDM), if new onset, including diabetic ketoacidosis 
(DKA) or, Grade 3-Grade 4 hyperglycemia if associated with ketosis (ketonuria) or 
metabolic acidosis (DKA):
o
Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria
o
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.
•
Hypophysitis
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.
•
Hyperthyroidism or Hypothyroidism
Thyroid disorders can occur at any time during treatment: Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):
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
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism 

Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.
•
Hematologic
o
For Grade 2 events, treat with corticosteroids, if indicated.
o
For Grade 3-4 events, treat with systemic or oral corticosteroids, as appropriate.
•
Hepatic
o
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).
o
Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous glucocorticosteroids for 24 to 48 
hours.
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.
In addition, the event must be reported as a Drug Induced Liver Injury (DILI) ECI, if the 
patient meets the laboratory criteria for potential DILI defined as:
o
An elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab 
value that is greater than or equal to three times (3X) the upper limit of normal 
(ULN) and
o
An elevated total bilirubin lab value that is greater than or equal to two times (2X) 
ULN and, at the same time, an alkaline phosphatase (ALP) lab value that is less 
than 2X ULN,
o
As a result of within-protocol-specific testing or, unscheduled testing.
•
Neurologic
o
For Grade 2 events, consider treatment with corticosteroids, as appropriate.
o
For Grade 3-4 events, treat with systemic corticosteroids. If condition worsens, 
consider IVIG or other immunosuppressive therapies, as per local guidelines.
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.
•
Ocular
o
For Grade 2 events, treat with topical steroids, such as 1% prednisolone acetate 
suspension and iridocyclitics.
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o
For Grade 3-4 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, a steroid taper should be started and continued over no 
less than 4 weeks.
•
Renal Failure or Nephritis
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.
•
Skin
o
For Grade 2 events, symptomatic treatment with topical glucocorticosteroids or 
urea-containing creams, in combination with oral anti-pruritics.
o
For Grade 3-4 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, a steroid taper should be started and continued over no 
less than 4 weeks.
NOTE: Refer to the ECI Guidance Document (Section 3.9.1: Immediate Evaluation for 
Potential Skin ECIs) for detailed evaluation and reporting requirements.
•
Other Events of Clinical Interest (ECIs)
The following AEs, regardless of grade, are considered ECIs and should be reported to 
Merck (see Section 10.3.3):
o
Myocarditis
o
Pericarditis
o
Pancreatitis
o
Any additional Grade 3 or higher event which the investigator considers to be 
immune-related.

For Grade 2 events, or Grade 1 events that do not improve with 
symptomatic treatment: Systemic corticosteroids may be indicated.

For Grade 3-4 events, treat with systemic corticosteroids. When 
symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.
•
Infusion Reactions
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion. Table 3 shows treatment 
guidelines for participants who experience an infusion reaction associated with 
administration of pembrolizumab.
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Table 3
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for < =24 
hr.
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
•
IV fluids
•
Antihistamines
•
NSAIDS
•
Acetaminophen
•
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 50% 
of the original infusion rate (e.g., from 100 mL/hr 
to 50 mL/hr). Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further trial treatment 
administration.
Subject may be premedicated 1.5 hr 
(± 30 minutes) prior to infusion of 
pembrolizumab with:
•
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine).
•
Acetaminophen 
500-1000 mg po (or 
equivalent dose of 
antipyretic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates).
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
•
IV fluids
•
Antihistamines 
•
NSAIDS
•
Acetaminophen
•
Narcotics
•
Oxygen
•
Pressors
•
Corticosteroids
•
Epinephrine
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from 
further trial treatment administration
No subsequent dosing
Note: Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration.
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6.7.2
Bevacizumab Supportive Care Guidelines
If an infusion-related adverse reaction occurs, the patient should be premedicated for the next 
course; however, the infusion time for bevacizumab may not be decreased for the next infusion. 
If the next infusion is well tolerated with pre-medication, the infusion time for the next dose may 
then be decreased by 30 ± 10 minutes as long as the patient continues to be pre-medicated. If a 
patient experiences an infusion-associated adverse event with the 60-minute infusion, all 
subsequent doses should be given over 90 ± 15 minutes. Similarly, if a patient experiences an 
infusion-associated adverse event with the 30-minute infusion, all subsequent doses should be 
given over 60 ± 10 minutes.
6.7.2.1 Suggested Prophylaxis in Event of Prior Bevacizumab Infusion Reaction
In the event of a prior bevacizumab hypersensitivity reaction, subsequent infusions should be 
delivered over 90 minutes, and the following prophylactic regimen is recommended upon re-
exposure: 
1. H1 blocker (diphenhydramine 25-50 mg IVP or orally one hour prior to injection; or an 
equivalent dose of an alternate H1 blocker, such as loratadine 10 mg or fexofenadine 
60 mg).
2. H2 blocker (famotidine 20 mg IVP or orally one hour prior to injection; or an equivalent 
dose of an alternate H2 blocker).
3. Dexamethasone (10 mg administered PO 12 and 6 hours prior to bevacizumab injection). 
Recommended only for hypersensitivity reaction.
6.7.3
Cyclophosphamide Supportive Care Guidelines
•
Oral cyclophosphamide will be held in patients with Grade 3 or higher hematologic, 
gastrointestinal, hepatic, genitourinary, neurologic, cardiac or pulmonary toxicities until 
patient recovers to at least grade 1 toxicity level. 
•
In case of Grade 3 or higher neurologic, cardiac or pulmonary toxicity that is attributed to 
cyclophosphamide treatment, drug will be discontinued permanently
6.8
Diet/Activity/Other Considerations
6.8.1
Diet
Participants should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
6.8.2
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm. Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are 
considered highly unlikely to conceive. Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
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duration of the study. The two birth control methods can be either: two barrier methods or, a 
barrier method plus a hormonal method to prevent pregnancy. Subjects should start using birth 
control from study Visit 1 throughout the study period up to 120 days after the last dose of study 
therapy. The following are considered adequate barrier methods of contraception: diaphragm, 
condom (by the partner), copper intrauterine device, sponge, or spermicide. Appropriate 
hormonal contraceptives will include any registered and marketed contraceptive agent that 
contains an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents).
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the 
study they must adhere to the contraception requirement (described above) for the duration of the 
study and during the follow-up period. If there is any question that a subject will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study.
6.8.3
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study. The site will contact the subject at least monthly 
and document the subject’s status until the pregnancy has been completed or terminated. The 
outcome of the pregnancy will be reported to the Principal Investigator and to Merck without 
delay and within 24 hours to the Principal Investigator and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to Merck.
6.8.4
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing infant, 
subjects who are breast-feeding are not eligible for enrollment.
6.8.5
Skin Toxicity
Skin reactions are the most common immune-related side effects of checkpoint inhibitor therapy 
affecting approximately one third of patients on PD-1 inhibitor therapy (83). Currently, no tools 
are available to identify individuals at highest risk of cutaneous side effects prior to therapy, 
although changes in the skin microbiome have been shown in several immune mediated skin 
diseases, such as atopic dermatitis, psoriasis and vitiligo (84, 85).
Prior to starting on study treatment (and after Cycle 3 and at end of treatment or disease 
progression), participants will be encouraged to have a skin check performed through the 
Dermatology Department. RPCI Dermatology will schedule appointments at a time that is 
convenient for the participant (without a wait time) and will monitor their skin for potential 
cutaneous side effects and will provide preventive/management skin care.
In addition, if any cutaneous symptoms or side effects are noted, participants will be offered 
immediate follow up with dermatology, particularly if the participant has grade 3-4 skin toxicity.
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6.9
Duration of Treatment
Participants may remain on study and continue to receive treatment (12 months with a maximum 
of 17 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal from 
study, intercurrent illness that prevents further administration of treatment, participant 
demonstrates an inability/refusal to comply with oral medication regime or, participant 
withdraws from study.
If patient has good clinical response after 12 months of treatment without any severe adverse 
event, she may be offered to continue with the treatment after discussing this with her provider 
and the Principal Investigator.
Note: If the patient has good clinical response and chooses to remain on the treatment beyond 12 
months, we will continue to collect the same clinical data as we were during the first 12 months, 
as these laboratory tests and imaging studies are standard of care when patients are receiving 
chemotherapy for ovarian cancer
6.9.1
Assessing for Secondary Cytoreduction and additional tumor biopsies to evaluate 
for response to treatment
Patients who have stable disease or showed progression on this clinical trial may be offered to 
undergo PET CT with biopsy of non-responsive tumor lesions to evaluate for viable tumor tissue 
and for translational studies or could be considered for secondary cytoreduction, if surgerycould 
provide additional survival benefit. The goal of secondary cytoreduction is to achieve complete 
resection, which has been shown to increase survival in this patient population. Tumor tissue 
harvested during secondary cytoreduction will be used for translational studies and also to 
evaluate for response to treatment by assessing for viable/necrotic tissue. Patients who have 
found to have mostly necrotic tumor tissue (thus clear clinical benefit from treatment), will be 
offered to stay on the trial, even if per prior imaging they met criteria for disease progression, as 
the reliability of CT scans determining disease progression in this patient population has not been 
reported. Survival data from these patients will be censored based on true progression (new 
viable tumor tissue growth on CT scan or on biopsy/surgery) and there treatment course will be 
further described in future publications.  
6.10
Treatment Discontinuation
Upon treatment discontinuation all end of treatment evaluations and tests will be conducted. All 
participants who discontinue due to an AE must be followed until the event resolves or stabilizes. 
Appropriate medical care should be provided until signs and symptoms have abated, stabilized, 
or until abnormal laboratory findings have returned to acceptable or pre-study limits. The final 
status of the AE will be reported in the participant’s medical records and the appropriate eCRF.
Reasons for treatment discontinuation should be classified as follows:
•
Death
•
Progressive disease
•
Toxicity; treatment related or unrelated
•
Investigator judgment
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o
The Investigator may discontinue a participant if, in his/her judgment, it is in the 
best interest of the participant to do so.
•
Noncompliance
•
Participant voluntary withdrawal
o
A participant may withdraw from the study at any time, for any reason. If a 
participant discontinues treatment, an attempt should be made to obtain 
information regarding the reason for withdrawal.
•
Participant lost to follow-up
•
Sponsor decision.
•
Intercurrent illness that prevents further administration of treatment.
•
The participant has a confirmed positive serum pregnancy test.
6.11
Compliance
A medication diary (Appendix E) will be provided to monitor participant compliance for oral 
cyclophosphamide.
As most studies show that adherence to long-term oral drug therapies are around 40-50%, we 
will consider a 60% of compliance with oral Cytoxan adequate. We will monitor adherence by 
patient self-report, pill diaries as well as rates of prescription refills. If patient is below the 60% 
compliance (which will be assessed each 3 weeks) – she will be asked to increase compliance 
with the next cycle. If she fails to comply in more than 2 cycles (>6 weeks) without any medical 
reason, she will be replaced at any point in the study.
7
INVESTIGATIONAL PRODUCTS
7.1
Pembrolizumab
Pembrolizumab (KEYTRUDA®) is a humanized monoclonal antibody that blocks the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa 
immunoglobulin with an approximate molecular weight of 149 kDa.
7.1.1
Active Substance and Source
Product Name & Potency
Dosage Form
Pembrolizumab 50 mg
Lyophilized Powder for Injection
Pembrolizumab 100 mg/ 4mL
Solution for Injection
Pembrolizumab lyophilized powder for injection is a sterile, preservative-free, white- to off-
white lyophilized powder in single-use vials. Each vial is reconstituted and diluted for 
intravenous infusion. Each 2 mL of reconstituted solution contains 50 mg of pembrolizumab and 
is formulated in L-histidine (3.1 mg), polysorbate 80 (0.4 mg), and sucrose (140 mg); may 
contain hydrochloric acid/sodium hydroxide to adjust pH to 5.5.
Pembrolizumab solution for injection is a sterile, preservative-free, clear to slightly opalescent, 
colorless to slightly yellow solution that requires dilution for intravenous infusion. Each vial 
contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg 
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of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose 
(70 mg), and Water for Injection, USP.
7.1.2
Drug Shipment
Pembrolizumab will be provided by Merck & Co., Inc. and shipped to the participating site, and 
will be labeled in accordance with regulatory requirements.
The date of receipt and the amount of drug received will be documented. Drug shipment records 
will be retained by the investigational pharmacist or designee.
7.1.3
Preparation
Pembrolizumab Powder for Solution for Infusion, 50 mg/vial, is reconstituted with sterile water 
for injection prior to use.
The lyophilized DP after reconstitution with sterile water for injection and the liquid DP are clear 
to opalescent solutions, essentially free of visible particles. The reconstituted lyophilized product 
and the liquid product are intended for intravenous (IV) administration. The reconstituted DP 
solution or the liquid DP can be further diluted with normal saline or 5% dextrose in the 
concentration range of 1 to 10 mg/mL in IV containers made of polyvinyl chloride (PVC) or 
non-PVC material. Reconstituted vials should be used immediately to prepare the infusion 
solution in the IV bag, and the infusion solution should be administered immediately. Diluted 
pembrolizumab solutions may be stored at room temperature for a cumulative time of up to 4 
hours. This includes room temperature storage of admixture solutions in the IV bags and the 
duration of infusion. In addition, IV bags can be stored at 2° to 8°C for up to a cumulative time 
of 20 hours. This recommendation is based on up to 24 hours of room temperature and up to 24 
hours of refrigerated stability data of diluted pembrolizumab solutions in the IV bags.
Please refer to Pharmacy Manual: Pembrolizumab (MK-3475) for more detailed preparation 
instructions.
7.1.4
Storage and Stability
The Investigator or designate will be responsible for ensuring that the investigational product is 
securely maintained in a locked, limited-access facility, and in accordance with the applicable 
regulatory requirements.
Pembrolizumab for injection (lyophilized powder): Store vials under refrigeration at 2°C to 8°C 
(36°F to 46°F).
Pembrolizumab injection (solution): Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) 
in original carton to protect from light. Do not freeze. Do not shake.
Drug storage temperature will be maintained and recorded, as applicable.
7.1.5
Handling and Disposal
All products dispensed will be recorded on a product accountability record. Records of product 
lot numbers and dates received will be entered on a product accountability form. It is the 
Investigator’s responsibility to ensure that an accurate record of investigational drug issued and 
returned is maintained.
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All unused and/or partially used investigational drug will be destroyed according to standard 
practices after properly accounting for the dispensing. Partially used vials of study drug will not 
be re-used for other participants.
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
7.1.6
Overdose
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater (≥5 times the indicated dose). No specific information is available on the 
treatment of overdose of pembrolizumab.
In the event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
7.2
Bevacizumab
Please refer to package insert. Use of biosimilar per Institute standard is allowed.
7.3
Cyclophosphamide
Please refer to package insert.
8
STUDY PROCEDURES
Eligibility of each participant will be established prior to enrollment.
Informed consent MUST be completed prior to receiving any study related procedures.
The individual trial procedures are described in detail below and summarized in Table 4.
All on-study visit procedures are allowed a window of ± 3 days unless otherwise noted (Note: It 
may be necessary to perform these procedures at unscheduled time points if deemed clinically 
necessary by the investigator).
Unless otherwise defined in the written protocol text, all procedures/assessments will be 
conducted in accordance with RPCI Clinical Research Services Standard Operating Procedures.
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Table 4
Schedule of Procedures and Observations
Trial Period:
Screening Phase
Treatment Cycles1
Post-Treatment
To be repeated beyond 8 cycles
Treatment Cycle/Title:
Baseline3
1
2
3
4
5
6
7
8
10
End of 
Treatment2  
OR 
At time of 
Discontinuation
Safety 
Follow-
up4
Follow 
Up 
Visits5
Survival 
Follow-
Up6
Administrative Procedures
Demographics and Medical 
History
X
X
X
X
X
X
X
X
X
X
X
X
Prior and Concomitant 
Medication Review
X7
X8
X8
X8
X8
X8
X8
X8
X8
X8
X8
X8
Trial Treatment 
Administration9
X
X
X
X
X
X
X
X
X
Post-study anticancer 
therapy status10
X
X
Survival Status
X
X
X
Clinical Procedures/Assessments
Review Adverse Events11
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical 
Examination12; including 
vital signs and body weight
X
X
X
X
X
X
X
X
Directed Physical 
Examination including vital 
signs and body weight
X
X
X
X
X
ECOG Performance 
Status13
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: Refer to Appendix D
Pregnancy Test – Urine or 
Serum β-HCG
X14
PT/INR and aPTT
X
X
X
X
Hematology15
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry15
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis15( every other 
X
X
X
X
X
X
X

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Trial Period:
Screening Phase
Treatment Cycles1
End of 
Treatment2  
OR 
At time of 
Discontinuation
Post-Treatment
Treatment Cycle/Title:
Baseline3
1
2
3
4
To be repeated beyond 8 cycles
Safety 
Follow-
up4
Follow 
Up 
Visits5
Survival 
Follow-
Up6
5
6
7
8
10
cycle)
Urine sample for Urine 
Protein Creatinine Ratio 16
X
X
X
X
X
X
T3, FT4 and TSH 17
X
X
X
X
X
Efficacy Measurements
Imaging: CT (chest, 
abdomen, and pelvis)18
X
X
X
X
X
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood
Newly Obtained (or 
Archival) Tissue 
Collection19
X
X
X
Correlative Studies Blood 
Collection20
X21
X
X
X
X29
X
Ascites Collection 22
Dermatology visit (will be 
recommended to all 
patients at RPCI) 23
X
X
X
Human microbiome 
collection (stool, vaginal 
and skin samples) 24
X25
X26
X28
X27
Microbiome Initial 
Assessment Questionnaire 
X
Microbiome Collection 
Questionnaire
X
X
X28
X
Quality of Life 
Questionnaires: EORTC 
QLQ-C30, QLQ-OV28, 
MFSI-SF 
X
X
X
X29
X

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Trial Period:
Screening Phase
Treatment Cycles1
End of 
Treatment2  
OR 
At time of 
Discontinuation
Post-Treatment
Treatment Cycle/Title:
Baseline3
1
2
3
4
To be repeated beyond 8 cycles
Safety 
Follow-
up4
Follow 
Up 
Visits5
Survival 
Follow-
Up6
5
6
7
8
10
1
1.
Each cycle is 3 weeks: pembrolizumab + bevacizumab will be administered on Day 1 of each 3 week cycle and, cyclophosphamide will 
be taken (po) daily. Treatment will be for 12 months (with a maximum of 17 cycles) or until disease progression or development of 
unacceptable toxicity (whichever occurs sooner) or, any severe toxicity (e.g. Grade 3 - Grade 4 toxicity requiring drug discontinuation). 
Note:  After Cycle I Day 1, all on-study visit procedures are allowed a window of ± 3 days unless otherwise noted.
2.
 When a subject discontinues/withdraws prior to trial completion, all applicable activities scheduled for the final trial visit should be 
performed at the time of discontinuation 
3.
Performed within 28 days prior to first dose of study medication.
4.
Safety Follow-Up Visit should be conducted approximately 30 days (± 3 days) after the last dose of trial treatment, or until resolution of 
any drug-related toxicity or before the initiation of a new anti-cancer treatment, whichever comes first.
5.
Participants who discontinue trial treatment for a reason other than disease progression will move into the Follow-Up Phase: 
assessments every 3 months, for 1 year, following end of treatment then, every 6 months (Section 8.7.2).
6.
Once a participant experiences confirmed disease progression or starts a new anti-cancer therapy: Telephone contact every 12 weeks 
(± 1 week: up to 3 years from initiation of treatment) to assess for survival status until death, withdrawal of consent, or the end of study, 
whichever occurs first (Section 8.7.3).
7.
List any medications that are ongoing, or that will be discontinued, within 1 week prior to first dose of study drug.
8.
List any ongoing medications with dose changes, as applicable.
9.
Trial treatment is administered on Day 1 of each cycle after all procedures/assessments have been completed. Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle (following Cycle 1) due to administrative reasons.
10. Review all new anti-neoplastic therapy initiated after the last dose of trial treatment (Section 8.1.5)
11. All AEs of unknown etiology associated with pembrolizumab, bevacizumab and cyclophosphamide exposure should be evaluated to 
determine if it is possibly an ECI of a potentially immunologic etiology (termed immune-related adverse events, or irAEs). Please refer 
to Section 10.2, as well as the separate Event of Clinical Interest Guidance Document regarding the identification, evaluation and 
management of potential irAEs.
12. .On study treatment days (prior to administration of study treatment), the Full Physical Examination will include basic neurological 
examination, vital signs and, body weight: height collected at baseline only. For cycles that do not require a full physical exam per the 
Trial Flow Chart, the investigator or qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration. 
13. At baseline, prior to the administration of each dose of trial treatment and discontinuation of trial treatment: (Appendix A)
14. Within 72 hours prior to first study treatment. If the urine test is positive, or cannot be confirmed as negative, a serum pregnancy test will 
be required.
15. Refer to Appendix D.

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Trial Period:
Screening Phase
Treatment Cycles1
End of 
Treatment2  
OR 
At time of 
Discontinuation
Post-Treatment
Treatment Cycle/Title:
Baseline3
1
2
3
4
To be repeated beyond 8 cycles
Safety 
Follow-
up4
Follow 
Up 
Visits5
Survival 
Follow-
Up6
5
6
7
8
10
16. Baseline, Cycle 1 Day 1 and, Day 1 of every 2nd cycle. Note: For the purpose of this study, participant must have a Urine Protein 
Creatine Ratio (UPCR) < 1 prior to enrollment and < 3.5 for any subsequent cycles. Refer to Appendix C
17. Every 3 cycles
18. To be obtained within 30 days of trial start, then after the 3rd and 6th cycles. If patient remains on the regimen longer than that, CT will be 
performed after every 6th cycle, or sooner if there is clinical suspicion for disease progression. Refer to Section 8.4.1
19. Baseline, 2-3 weeks after Cycle 3, end of treatment (optional). See Section 8.9.1 and Section 8.9.2 for processing and handling.
20. Peripheral blood samples will be collected at baseline (within 2 weeks prior to start of study treatment), Cycle 2 – Day 1, Cycle 4 – Day 
1, Cycle 7 –Day 1 and at the end of study treatment or at time of discontinuation (within two weeks after the last cycle is completed or, at 
the time of progression; or for any other reason that requires study termination, whichever occurs sooner. Note for samples collected 
while participant is receiving study treatment: Blood is to be collected prior to pembrolizumab administration – it is not required to hold 
cyclophosphamide dosing until after sample collection. Refer to Section 8.8.1 (Blood Collection Sampling and Processing)
21. Note : Within 2 weeks prior to start of study treatment
22. If a patient has ascites at any time during the study period and is willing to undergo paracentesis, or wishes to undergo paracentesis for 
symptom relief. This is optional for the patient. Refer to Section 8.8.3for collection, processing and, handling
23. Dermatology visit will be recommended to all patients at RPCI prior to starting treatment, after 3 cycles and, at time of progression to 
monitor cutaneous side effects.  In addition to this, if any cutaneous symptoms or side effects are noted, they will be offered immediate 
follow up with dermatology, particularly if patient has grade 3-4 skin toxicity (see Section 6.8.5). 
24. Stool collection within 24 hours of next study visit. If not possible, then at the time of visit via digital rectal exam. If not able to collect 
via either method, then within next 7 days via home collection per patient. Telephone contact to remind patient about stool collection and 
to review instructions for vaginal and skin microbiome collection 3-5 days prior to study visit by the clinical research coordinator. 
25. Cycle 1-Day 1 prior to starting chemotherapy is preferred (or within 7 days prior to start of treatment)
26. Day 1-Cycle 4 prior to starting chemotherapy is preferred (or within 7 days prior to starting Cycle 4)
27. Samples collected during the last physical examination at the time of study termination (stool sample collection within 7 days of visit)
28. On those patients, who have already completed 10 cycles, the one additional correlative blood, microbiome and questionnaires will be 
collected at the time of their next cycle. At the discretion of the investigator, selected patients may be asked to bring an additional stool 
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8.1
Administrative Procedures
8.1.1
Informed Consent
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial: Informed consent MUST be completed prior to receiving 
any study related procedures.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified 
designee to ensure that the subject qualifies for the trial: The eligibility of each 
participant will be established prior to study enrollment.
8.1.3
Medical History
8.1.3.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding 
disease status.
8.1.3.2 Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries.
8.1.4
Prior and Concomitant Medications Review
8.1.4.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the 
participant within 28 days before starting the trial.
Treatment for the disease for which the subject has enrolled in this study will be recorded 
separately and not listed as a prior medication.
8.1.4.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the 
participant during the trial. All medications related to reportable SAEs and ECIs should 
be recorded as defined in Section 10.1.
8.1.5
Post-Study Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-neoplastic therapy 
initiated after the last dose of trial treatment.
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If a participant initiates a new anti-cancer therapy within 30 days after the last dose of 
trial treatment, the 30 day Safety Follow-up visit must occur before the first dose of the 
new therapy. 
Once new anti-cancer therapy has been initiated the subject will move into survival 
follow-up.
8.1.6
Survival Follow-Up
Once a participant experiences confirmed disease progression or starts a new anti-cancer 
therapy, the participant moves into the survival follow-up phase and should be contacted 
by telephone every 12 weeks (up to 3 years from initiation of treatment) to assess for 
survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
8.2
Clinical Procedures/Assessments
8.2.1
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential 
new or worsening AEs as specified in the Schedule of Procedures and Observations and, 
more frequently if clinically indicated. Adverse experiences will be graded and recorded 
throughout the study and during the follow-up period according to NCI CTCAE 
Version 4 (see Section 10.1.2). Toxicities will be characterized in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatment.
All AEs of unknown etiology associated with pembrolizumab, bevacizumab and 
cyclophosphamide exposure should be evaluated to determine if it is possibly an ECI of a 
potentially immunologic etiology (termed immune-related adverse events, or irAEs). 
Please refer to Section 10.2, as well as the separate Event of Clinical Interest Guidance 
Document regarding the identification, evaluation and management of potential irAEs.
8.2.2
Full Physical Examination
The investigator or qualified designee will perform a complete physical exam (including 
basic neurological, vital signs and body weight) during the baseline screening period (if 
clinically indicated, a neuro exam will be performed). Height will be collected at baseline 
only. Clinically significant abnormal findings should be recorded as medical history.
8.2.3
Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the 
investigator or qualified designee will perform a directed physical exam (to include basic 
neurological, vital signs and body weight) as clinically indicated prior to trial treatment 
administration.
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8.2.4
Vital Signs
The investigator or qualified designee will take vital signs (temperature, heart rate, 
respiratory rate, blood pressure) at baseline, prior to the administration of each dose of 
trial treatment and at treatment discontinuation.
8.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (Appendix A) at baseline 
screening, prior to the administration of each dose of trial treatment and discontinuation 
of trial treatment..
8.3
Laboratory Procedures/Assessments
Details regarding the timing of specific laboratory procedures/assessments to be 
performed in this trial are provided in Table 4. The laboratory tests for hematology, 
chemistry, urinalysis, and others are specified in Appendix D.
8.4
Efficacy Measurements
8.4.1
Tumor Imaging and Assessment of Disease
Radiographic tumor measurements should be obtained via contrast CT of the chest, 
abdomen and pelvis. Immune related response criteria (irRECIST) (96) will be used to 
assess disease at baseline and subsequent assessments.
CT needs to be obtained within 30 days of trial start, then after the 3rd and 6th cycles. If 
patient remains in the regimen longer than that, CT will be performed after every 6th 
cycles or sooner if there is clinical suspicion for disease progression.
In addition to irRECIST, RECIST 1.1 (98) measurements will also be used for disease 
assessment.
8.5
Tissue Collection, Correlative Blood Sampling and Microbiome Samples
Mandatory research tumor tissue core biopsies are obtained at two time points: prior to 
initiating study treatment and after 3 cycles of study treatment (refer to Section 8.8.2 for 
processing and handling). If patient remains on the treatment much longer, at the time of 
progression she will be offered to undergo another CT guided biopsy for research 
purposes, however this is not mandatory.
Mandatory research blood samples are obtained at five time points: Baseline (within 2 
weeks prior to initiating study treatment), Cycle 2 - Day 1, Cycle 4 – Day 1, Cycle 7 –
Day 1, Cycle 10 –Day 1  and at the end of study treatment or at time of discontinuation 
(within 2 weeks after the last treatment cycle is completed) or, at the time of disease 
progression or for any other reason that requires study treatment termination, whichever 
occurs sooner (refer to Section 8.8.1 for processing and handling).
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Mandatory stool, vaginal, skin microbiome collection as well as correlative study questionnaires 
prior to cycle#1 (within 7 days of starting treatment, preferably on D1 of cycle 1 prior to staring 
chemotherapy), after 3 cycles (within 7 days of starting cycle 4, preferably on D1 of cycle 4 prior 
to starting chemotherapy and at Cycle 10 – Day 1), at the end of treatment (during the last 
physical exam at the time of study termination, stool sample collection within 7 days of this 
visit) (Refer to Section 8.10).
On those patients, who have already completed 10 cycles, the one additional correlative blood, 
microbiome and questionnaires will be collected at the time of their next cycle. 
8.6
End of Treatment/Withdrawal/Discontinuation
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 8.2: Assessing and 
Recording Adverse Events.
8.7
Post-Treatment Visits
8.7.1
Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes 
first.
All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Subjects with an AE 
of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning 
of a new anti-neoplastic therapy, whichever occurs first. 
SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded. 
8.7.2
Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed every 3 months by radiologic imaging to 
monitor disease status. After 1 year, the imaging time point will occur every 6 months (up to 3 
years from initiation of treatment).
Every effort should be made to collect information regarding disease status until the start of new 
anti-neoplastic therapy, disease progression or, death.
8.7.3
Survival Follow-Up
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted by telephone every 12 
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weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
8.8
Collection and Handling of Specimens
8.8.1
Blood Sample Collection and Processing for Correlative Studies
Peripheral blood samples will be collected prior to starting treatment (within 2 weeks) and, prior 
to study treatment administration after the 1st cycle (Day 1-Cycle 2), the 3rd cycle (Day 1-Cycle 
4) and the 6th cycle (Day 1-Cycle 7) and at 2 weeks after ending study treatment (e.g., at 12 
months or, at the time of progression; or any other reason that requires study termination, 
whichever occurs sooner).
Blood samples will be collected via venipuncture for Correlative Studies Analysis (see 
Section 8.11): 
Samples will be collected using two, 10 mL green-top tubes and one, 10 mL red-top tube, two 
lavender-top tubes and one PAXgene RNA tube for each time point listed below:
•
Baseline (within 2 weeks prior to start of treatment)
•
Cycle 2 – Day 1 
•
Cycle 4 - Day 1
•
Cycle 7 – Day 1
•
Cycle 10 –Day 1
•
End of Treatment or at time of discontinuation (within 2 weeks after the last treatment 
cycle is completed) or, at the time of disease progression or for any other reason that 
requires study treatment termination, whichever occurs sooner.
•
On those patients, who have already completed 10 cycles, the one additional correlative 
blood sample will be collected at the time of their next cycle. 
Note for samples collected while participant is receiving study treatment: Blood is to be 
collected prior to pembrolizumab administration – it is not required to hold cyclophosphamide 
dosing until after sample collection.
All of the above blood samples will be sent at ambient temperature for processing, and/or to be 
stored frozen, to the Center for Immunotherapy at Roswell Park Cancer Institute for further 
studies:
Roswell Park Cancer Institute
Immune Analysis Facility Shared Resource
Cancer Cell Center, 4th Floor, Room 416
Elm and Carlton Streets
Buffalo, NY 14263
Telephone #: (716) 845-8459
Junko.Matsuzaki@RoswellPark.org 
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Note: All laboratories housing research samples need to maintain current, study-specific 
Temperature 
Logs 
and 
Sample 
Tracking 
and 
Shipping 
Logs. 
The 
Principal 
Investigator/Laboratory Manager must ensure that the stated lab(s) have a process in place to 
document the receipt/processing/storage/shipping of study-related samples/specimens. This is 
required for both observational and interventional clinical studies collecting clinical samples.
8.8.2
Tumor Tissue Collection
Mandatory research tumor tissue core biopsies are obtained at two time points: prior to initiating 
study treatment and after 3 cycles of study treatment. If patient remains on the treatment much 
longer at the time of progression she will be offered to undergo another CT guided biopsy for 
research purposes, however this is not mandatory.
Pre-treatment tumor biopsy needs to be obtained within 4 weeks (28 days) prior to treatment 
start. (Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or 
subject safety concern) may submit an archived specimen only upon agreement from the 
Principal Investigator).
On-treatment CT guided tumor biopsies will be done after 3 cycles of treatment (between week 
#8- #10), even if patient has no signs of disease progression and wishes to remain on the 
regimen. If patient completes 12 months of treatment and has measurable lesion but wishes to 
continue with treatment, repeat CT guided biopsy will be offered. 
Ovarian adenocarcinoma tissue biopsy (before and after treatment) will be collected by 
needle core biopsy A minimum of 7 cores will be obtained (preferably l cm or more in 
length).
8.8.3
Ascites
If a patient has ascites at any time during the study period and is willing to undergo paracentesis, 
or wishes to undergo paracentesis for symptom relief, it is recommended to obtain a minimum of 
200 cc (and up to 500 cc) by paracentesis in order to yield an adequate amount of cells for 
analysis.
Lower or higher volumes are acceptable. Note: The higher the volume of ascites fluid submitted, 
the better the yield of Tumor Ascites Lymphocytes (TALs).
Ascites fluid will be shipped on wet ice, the same day as collection, to:
Roswell Park Cancer Institute
Immune Analysis Facility Shared Resource
Cancer Cell Center, 4th Floor, Room 403
Elm and Carlton Streets
Buffalo, NY 14263
Telephone #: (716) 845-4199
Anthony.Miliotto@RoswellPark.org 
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The laboratory at the IAF at RPCI will process the ascites and bank for batch analysis. Samples 
will be processed at RPCI to obtain cell-free ascites (supernatant following centrifugation). The 
cell pellet will be utilized for isolation of TALs.
Note: All laboratories housing research samples need to maintain current, study-specific 
Temperature 
Logs 
and 
Sample 
Tracking 
and 
Shipping 
Logs. 
The 
Principal 
Investigator/Laboratory Manager must ensure that the stated lab(s) have a process in place to 
document the receipt/processing/storage/shipping of study-related samples/specimens. This is 
required for both observational and interventional clinical studies collecting clinical samples.
8.9
Pathology
8.9.1
Pre- and On-Treatment Biopsies
Ovarian adenocarcinoma tissue biopsy before and after treatment will be collected by needle 
core biopsy [participants for whom newly-obtained biopsy samples cannot be provided (e.g. 
inaccessible or subject safety concern) may submit an archived specimen only upon agreement 
from the Principal Investigator. Seven cores will be obtained, preferably l cm or more in 
length. Adequate specimen must be collected and divided into 5 different aliquots. These 
specimens in order of priority include tissue collected and:
1) 2 cores: Fixed in formalin for 8 to 24 hours and processed as a paraffin embedded 
block (FFPE block) for subsequent immunohistochemistry correlative studies
2) 1 core: Placed in RPMI with 5% FBS on wet ice (flow cytometry specimen) for 
immediate processing to isolate infiltrating immune cells; tissue will be used for 
subsequent flow cytometry sorting of tumor and subpopulations of hematopoietic 
cells
3) 3 cores (each cores will be stored separately): Snap frozen in cryovials in liquid 
nitrogen (RNA specimen) for subsequent RNA isolation
4) 1 core (separately): Snap-frozen in cryovials in liquid nitrogen (DNA specimen) for 
subsequent DNA analysis
For needle core biopsies the following is the minimum amount of tissue for each of the 
above listed specimens and each specimen is listed in the order of priority if less than a full 
complement of 7 cores can be procured:
1) FFPE block - 2 needle cores not less than an 18 gauge needle and not less than 1 cm in 
length
2) Flow cytometry specimen - 1 needle core not less than an 18 gauge needle and not less 
than 1 cm in length
3) RNA specimen - minimum of 3 needle cores not less than an 18 gauge needle and not 
less than 1 cm in length
4) DNA specimen. minimum of 1 needle core biopsy not less than an 18 gauge needle 
and not less than 1 cm in length for DNA analysis
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* Core biopsy tissue samples are to be labeled with a study-specific ID number, clinical study 
number, protocol time point and, protocol day. 
Tissue in RPMI with 5% FBS will be sent same day to Junko Matsuzaki laboratory for 
additional processing and analysis. Snap frozen tissue may be batched in CSPO (S-636, GBSB) 
and will be sent to Dr. Zsiros’ lab upon request:
Center for Immunotherapy at Roswell Park Cancer Institute for further studies:
Roswell Park Cancer Institute
Immune Analysis Facility Shared Resource
Cancer Cell Center, 4th Floor, Room 416
Elm and Carlton Streets
Buffalo, NY 14263
Telephone #: (716) 845-8459
Junko.Matsuzaki@RoswellPark.org 
Core biopsy tissue that is fixed in formalin will be delivered to: RPCI Paraffin Core Facility, 
GBSB S-601, Telephone number: 845-3006. The finished blocks will be batched in CSPO (S-
636, GBSB) and will be sent to Dr. Zsiros’ lab upon request.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
8.9.2
Pre-Treatment Formalin-Fixed Paraffin-Embedded (FFPE) Biopsy Samples
For patients whom a new biopsy is contraindicated, the following sections of tissue from the 
most recent (must be within 28 days prior to start of study treatment) neoplastic tissue biopsy 
that exists in the Paraffin Archive in the Department of Pathology (or outside institution) will be 
collected:
1. Eight unstained sections cut at 4 microns on plus glass slides.
2. One H&E stained section
Slides will be forwarded from CSPO to Dr. Zsiros’ laboratory in the Center for Immunotherapy 
(see above for full contact information) upon request.
8.10
Human Microbiome collection
8.10.1 Assessing quality of life and emotional well-being and lifestyle using the EORTC 
QLQ-C30, QLQ-OV28, MFSI-SF and Microbiome questionnaires 
EORTC QLQ-C30 (Appendix G) has been developed to assess the quality of life of cancer 
patients. It is supplemented by disease-specific modules such as breast, lung, head & neck and, 
ovarian (QLQ-OV28: Appendix H). The Multidimensional Fatigue Symptom Inventory-Short 
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Form (MFSI-SF: Appendix I) gathers information on emotional well-being, social functioning, 
energy/fatigue and physical functioning. All of these questionnaires have been well validated in 
large number of studies and have been widely used in cancer patients. 
The Microbiome Initial Assessment Questionnaire (Appendix K
) 
and 
the 
Microbiome 
Collection Questionnaire (Appendix J) were specifically designed for patients enrolling in this 
study in order to broaden the information gathered on nutrition and basic lifestyle habits that 
have been shown to have an impact on human microbiome composition.
At every collection visit the clinical research coordinator will administer the following 
questionnaires to assess the patient’s quality of life, stress/fatigue level as well as basic lifestyle 
information:
1. EORTC QLQ-C30 and EORTC QLQ-OV28
2. Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF)
3. Microbiome Collection Questionnaire
The Microbiome Initial Assessment Questionnaire will be completed only once, prior to 
cycle #1.
EORTC QLQ-C30, EORTC QLQ-OV28 and Multidimensional Fatigue Symptom Inventory-
Short Form (MFSI-SF) will be collected on Cycle 7 Day – 1, Cycle 10 Day 1 and at the end of 
study as well to assess quality of life during the study.  
The Microbiome Collection 
Questionnaire will be collected each time there is microbiome sampling (see Section 8.10.2)
Paper questionnaires will be collected by the clinical research coordinator on the day of the 
patient’s visit (see below Microbiome collection time points) and will be kept in a secured, 
locked-up study folder in the clinic. Prior to analysis, the PI will request that a database be built 
(either in EXPeRT or REDCAP) and the data from the paper questionnaires collected throughout 
the trial be entered into the database by the CRC for analysis.
8.10.2  Microbiome collection time points
All collections (skin, vaginal sampling and stool collection) will be performed at the following 
time points:
1. Prior to cycle#1 (within 7 days of starting treatment, preferably on D1 of cycle 1 prior to 
staring chemotherapy)
2. After 3 cycles (within 7 days of starting cycle 4, preferably on D1 of cycle 4 prior to 
starting chemotherapy)
3. After 9 cycles, (within 7 days of starting cycle 10, preferably on D1 of cycle 10 prior to 
starting chemotherapy)
4. At the end of treatment (during the last physical exam at the time of study termination, 
stool sample collection within 7 days of this visit)\
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On those patients, who have already completed 10 cycles, the one additional microbiome sample 
will be collected at the time of their next cycle.
Prior to each time point the clinical research coordinator   will call the patient on the phone (3-5 
days prior) to remind her to follow the written instructions given to her prior to collection and to 
answer any questions the patient may have. 
All microbiome samples will be labeled with the participant’s MR number, participant’s initials, 
participant’s study number, clinical study number, protocol time point, and protocol day. Unless 
otherwise indicated all samples will be sent to DBBR for de-identification, storage and future 
DNA extraction.
Roswell Park Cancer Institute
DBBR Laboratory
GBSB Bldg. 7th Floor, Rm. 726 via Tube station # 86
Attn: Study Number – I 270715 (RQ-006865)
Elm & Carlton Streets
Buffalo, NY 14263
Tel: 716-845-1036
Fax: 716-845-1350
warren.davis@roswellpark.org 
8.10.3 Skin microbiome collection
Prior to each collection patients will be instructed by the clinical research coordinator. The 
participant will also receive written instructions (Appendix L) to follow the guidelines for 
optimal collection. Prior to each collection visit patients will be asked:
•
to abstain from using antibiotic containing soaps and washes for 1 week
•
to abstain from topical antibiotics for 1 week – unless patient was specifically instructed 
to use antibiotics
•
not to swim in pool, use hot tubs or tan for 3 days prior to sample collection
•
to abstain from using moisturizers and cosmetics or other topical products and washing 
sampled skin areas for 24 hours
8.10.3.1 Skin microbiome collection sites
Skin samples for microbiome analysis will be collected from the following sites:
•
bilateral volar forearms
•
bilateral inguinal crease
•
bilateral upper back 
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8.10.3.2 Skin microbiome collection technique and specimen handling:
A standard kit put together by DBBR for skin microbiome collection will be sent and stored at 
the gynecologic clinic by the clinical research coordinator.
Swab-scrape-swab technique will be used, as described by Oh et al (99). If a skin eruption is 
present, an area closest to the planned collection site that is unaffected by the cutaneous eruption 
will be sampled.
Skin microbiome collection will be done prior to cycle #1, cycle #4, cycle #10 and at the time of 
study termination by clinician and/or research nurse, as described above. Labeled tubes will be 
sent to DBBR for de-identification, storage and future DNA extraction and genetic analysis 
depending on patients’ clinical response.
8.10.3.3 Skin checkups and monitoring for cutaneous side effects
Given the high frequency of dermatologic side effects with immune check point inhibitors, we 
will encourage all patients to undergo a dermatological examination before the initiation of the 
study and after cycle #3 and at the end of the study. Any skin lesion will be documented and 
followed up for changes by a dermatologist. In addition to this, if any cutaneous symptoms or 
side effects are noted, the patient will be offered immediate follow up with dermatology, 
particularly if patient has grade 3-4 skin toxicity.
8.10.4 Vaginal sample collection technique and specimen handling
Prior to collecting the vaginal samples patients will be given written instructions (Appendix M) 
during her prior visit to not to use any vaginal lubricants/cream/medications or perform vaginal 
douching 3 days prior to her visit.
A standard kit put together by DBBR for vaginal microbiome collection will be used. Vaginal 
samples will be collected during sterile speculum exam with no lubrication use (water is 
permitted) posterior fornix and lateral fornices with a swab swirled around. Two separate 
collections will be performed. One collection will be obtained for Gram staining and one for 
bacterial genomic DNA extraction. The first vaginal collection of vaginal fluid will be used for 
genomic DNA extraction following Roswell Park Cancer Institute’s internal protocol on vaginal 
microbiome collection . It will be sent to DBBR immediately for de-identification, storage and 
future DNA extraction. The second collection will be a standard vaginal culture and will be sent 
to the lab for Gram-stain as vaginal culture.
8.10.5 Fecal microbiome collection
The stool specimen will be self-collected by participants. Patients will be provided with a fecal 
sample collection kit. Patients will be provided with written instructions (Appendix N), and 
study staff will explain how to use the kits to collect fecal samples in the privacy of their own 
homes prior to scheduled clinic visits. We will instruct the participants to collect stool specimens 
within 24 h before each sampling visit and bring them to the visits. If patient is not able to 
provide us the sample with home collection or enough sample for analysis, we will perform stool 
sample collection during the routine rectovaginal exam at that time of their study visit. If not 
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successful with stool sample collection sample with either of these methods (home collection or 
during office visit), we will ask the patient to collect the sample within the following 7 days and 
coordinate the sample handing with the clinical research coordinator (sample to be either brought 
to the clinic or mailed to the clinic in a kit provided).
Collected stool samples will be sent to DBBR for de-identification, storage and future DNA 
extraction.
Stored stool samples in DBBR will be sent out to commercial entities without PHI for stool 
metabolite analysis per PI’s decision.
Stool samples can be used for fecal microbiota transfer to animals under approved IACUC 
protocols.
8.11
Planned Correlative Studies
NOTE: This section contains a comprehensive list of proposed correlative studies, however 
depending on the clinical response of patients, available tumor tissue and budget, the PI will 
select the most appropriate translational studies to obtain the most comprehensive analysis on the 
collected specimens (See comment in Section 1.7).
8.11.1 Assessment of dynamic changes in tumor microenvironment prior to and 
subsequent to therapy
Pre-treatment and on-treatment tumor CT guided biopsy tissue will be processed for RNA 
isolation and evaluated for gene RNASeq. PI may use any prior/and or future banked tissue, 
blood, ascites and microbiome specimen on all enrolled patient for translational research 
purposes.
Transcriptional findings will be validated by immunohistochemistry/ immunofluorescence for 
expression of PD-L1 as a predictive biomarker and presence of various infiltrating immune cell 
subsets, including CD8 cells, CD4+ effector cells (FoxP3-), CD4+ regulatory T cells (FoxP3+), 
and myeloid cells. Immunohistochemistry for PD-L1 expression will be performed by QualTek 
Laboratories, the rest of the staining will be done at Roswell Park Cancer Institute. Depending on 
tissue availability, tumors will be assessed for expression of immune inhibitory receptors and 
proteins (such as indoleamine dioxygenase (IDO), B7-H3, B7-H4, LAG3, TIM3, PD-1, CTLA-4, 
VISTA, and BTLA), and immune-activating receptors (such as 4-1BB (CD137), OX40, GITR, 
CD40, and ICOS). DNA extracted from tumors will be sent for deep sequencing of T cell 
receptor V beta chain to determine repertoire composition.
Refer to Table 5 for planned sample analysis methods for changes in the tumor 
microenvironment pre- and post-treatment.
Table 5
Analysis of Tumor Microenvironment
Biomarker
Approach
Parameters*
Immune cell subsets
RNASeq+/- IHC**
CD3, CD4, CD8, FOXP3, CD56, 
CD14, CD33, CD19, CD11c, 
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Targetable immune activating 
genes
RNASeq+/- IHC*
4-1BB, OX40, GITR, CD40, and 
ICOS
Targetable immune inhibitory 
genes
RNASeq+/- IHC*
PD-L1, IDO, B7-H3, B7-H4, LAG3, 
TIM-3, PD-1, CTLA-4, VISTA, and 
BTLA
Neo-antigen Landscape
Whole-exome sequencing of DNA
Mutation load, driver mutations, 
neo-antigens
Cancer-testis antigens
RNASeq+/- IHC*
e.g. NY-ESO-1, MAGE A4, etc. 
T cell receptor repertoire
Adaptive Biotechnologies 
Immunoseq
T cell density, TCR clonality, clonal 
overlap.
*Additional parameters will be added from the panel, depending on the results from the initial few patients
**Validation by IHC will depend on tissue availability
The following will be shipped  to Tyler Curiel at University of Texas, San Antonio:
•
De-identified IHC slides for PDL1 and PDL2 staining
•
Qualtek data
•
Nanostring digital spatial imaging data on tumor microenvironment
•
RNA and whole exome sequencing data
All data and slides will be sent in a blinded fashion and are not to include any PHI. Only the data 
on clinical efficacy will be shared with his team.
Tyler Curiel
Cancer Therapy and Research Center
7979 Wurzbach Rd # 600,
San Antonio, TX 78229 
curielt@uthscsa.edu 
8.11.2 Exploration of peripheral blood biomarkers as early predictors of clinical benefit
Pre-treatment and on-treatment/post-treatment samples will be analyzed by NanoString platform 
and by flow cytometry to study the effects of treatment on various peripheral blood immune cell 
subsets. PBMC isolated from whole blood will be processed for multicolor flow cytometry 
analyses looking at different cell subsets such as CD4+, CD8+, NK, NKT, and regulatory T cells 
(CD25+FoxP3+), markers of T cell activation (CD25, CD62L, HLA-DR, CD150, ki67, granzyme 
B, ICOS, CD137, OX40, GITR), inhibition/exhaustion (PD-1, LAG3, TIM3, CD160), and 
percentages of myeloid-derived suppressor cells (MDSCs) (HLA-DR, CD33, CD14, CD15, 
CD3, CD19, CD56, CD16). DNA extracted from PBMC would be sent for deep sequencing of T 
cell receptor V beta chain to determine repertoire composition. 
Serum cytokines and chemokines will be measured to evaluate for evidence of Th1/Th2/Th17 or 
other type of immune response (ELISA).
Refer to Table 6 for planned analyses of tentative peripheral blood biomarkers.
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Table 6
Analysis of Peripheral Blood Biomarkers
Biomarker
Approach
Parameters*
Transcriptional profile*
RNASeq
Markers related to immune 
activation and inhibition, as 
discussed in text
T cell activation
Flow cytometry
CD25, CD62L, HLA-DR, CD150, 
ki67, granzyme B, ICOS, CD137, 
OX40, GITR
T cell exhaustion
Flow cytometry
PD-1, LAG3, TIM3, CD160
MDSC
Flow cytometry
HLA-DR, CD33, CD14, CD15, 
CD3, CD19, CD56, CD16
T cell receptor repertoire
Adaptive Biotechnologies 
Immunoseq
T cell density, TCR clonality, clonal 
overlap.
Inflammatory Cytokines
Flow Cytometry:
HCYTMAG-60K-PX41 | 
MILLIPLEX MAP Human 
Cytokine/Chemokine Magnetic 
Bead Panel
sCD40L, EGF, Eotaxin/CCL11, 
FGF-2, Flt-3 ligand, Fractalkine, G-
CSF, GM-CSF, GRO, IFN-α2, IFN-
γ, IL-1α, IL-1β, IL-1ra, IL-2, IL-3, 
IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, 
IL-10, IL-12 (p40), IL-12 (p70), IL-
13, IL-15, IL-17, IP-10, MCP-1, 
MCP-3, MDC (CCL22), MIP-1α, 
MIP-1β, PDGF-AA, PDGF-AB/BB, 
RANTES, TGF-α, TNF-α, TNF-β, 
VEGF
*Due to potential differences in PBMC processing amongst different sites (if additional sites are used), 
transcriptional profiling of freshly frozen buffy coats will be used to get a broad standardized assessment of the 
immune changes in the peripheral blood.
8.11.3 Exploration of genetic predictors of response
To determine whether specific tumor genetic determinants influence the response to treatment, 
DNA isolated from archived tumor samples may be processed for whole exome analysis to 
assess for specific driver mutations and for potential neoantigens using appropriate 
bioinformatics algorithms developed at MSKCC.
Refer to Table 7 for tentative planned genomic analyses.
Table 7
Analysis of Genetic Predictors
Biomarker
Approach
Parameters
Genetic drivers
Whole exome sequencing
Presence of mutations/alterations in 
a panel of known oncogenes/tumor 
suppressors
Neoantigen signature
Whole exome sequencing
Presence of immunogenic epitopes 
based on prediction algorithms
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8.11.4 Exploration of human microbiome as a predictor of clinical response and its 
association with potential side effects
Depending on clinical results and patient’s side effects, bacterial DNA will be extracted from 
fecal, skin and vaginal samples using standard DNA extraction methods per Roswell Park 
Cancer Institute microbiome protocol. Collected clinical questionnaires will be used to interpret 
the final analyzed microbiome data. The microbial community will be assessed using 16S rRNA 
profiling of the V4 variable region via MiSeq next generation sequencing in the RPCI Genomics 
Shared Resource. Prior to sequencing, DNA with be amplified with PCR and barcoded primers 
so that amplicons can be pooled for analysis. Following sequencing, sequences will be screened 
and assigned to samples using the barcodes, and all failed sequence reads, low-quality sequence 
ends and tags will be removed and sequences will be depleted of any non-bacterial ribosome 
sequences and chimeras using the Black Box Chimera Check software B2C2 (described and 
available at http://www.researchandtesting.com/B2C2.html  
for free). Sequences will be 
imported into ARB and aligned to a 16S rRNA curated database of sequences representative of 
the gut, skin and vaginal microbiomes from curated databases.
Cleaned sequences will be aligned in MOTHUR. Sequences will be imported into ARB and 
phylogenetic relationships of the aligned 16S rRNA gene sequences will be inferred using 
maximum likelihood from a reference tree generated using RAXML in ARB (version 100, 
www.arb-silva.de) and placer. Phylogenetic trees will be constructed from approximately 10,000 
16S rRNA sequences using the weighted UniFrac metric that can detect differences in how many 
organisms from each lineage are present, as well as detecting differences in which organisms are 
present. A distance matrix based on the UniFrac metric will be exported and used in multivariate 
analysis to explain the variation in the microbial communities. As an alternative analysis, we will 
also test other distance-based metrics to optimize characterization the microbial communities’ 
qPCR of 16S rRNA genes using standard techniques and established primers will be used to 
estimate the copy number for different microbial groups. The lowest quantifiable 16S rRNA 
gene copy number estimate for bacterial groups is as follows: Eubacteria: 700; 
Lactobacteriaceae: 400; Enterobacteriaceae: 250; Bacteroidaceae: 450; Clostridium Cluster 
XIVa: 1000 copies. Assuming that the bacterial biomass of the gut is 1011 cells/g and that there 
is at minimum one 16S rRNA gene copy per cell, the detection limit is very low.
Sequences will be clustered into operational taxonomic units (OTU) at 97% similarity based on 
the average neighbor-joining algorithm and classified using a naïve Bayesian classifier 
implementation in MOTHUR. After classification, sequences will be assigned to phylum and 
genus-level phylotypes, after which alpha (diversity within an individual) and beta (diversity 
between individuals) diversity will be calculated. Alpha diversity will be measured with the 
inverse Simpson index and beta diversity as the Theta YC distance metric from UniFrac.
•
In microbial communities, 16S rRNA genes are usually not normally distributed. 
Therefore, bacterial communities will be analyzed using NMS, an approach that has been 
widely used in ecological community data analysis and is based on a distance metric 
between samples (i.e., Euclidean, Jenson-Shannon Divergence, or UniFrac). NMS 
analysis is an iterative, non-parametric ordination technique that searches for the best 
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position of the different microbial populations, measured as 16S rRNA genes, in multi-
dimensions that minimizes the stress of the multiple dimensional configurations of 
samples. A Monte Carlo test will be used to assess whether the final solution that 
minimizes stress is significantly different from the solution produced by random chance. 
NMS provides composite scores of 16S rRNA genes that can be used in regression 
analysis. In the context of the current study design, this means that each person has a 
microbial community fingerprint signature. This approach is defined as a composite 
measure of microbial community composition.
8.11.5 Assessment of Biospecimens and Clinical data
Biospecimens, clinical efficacy, basic clinical information, and toxicity data could be shared with 
other academic institutions and commercial entities without PHI with whom Roswell Park 
Cancer Institute has an MTA in place with in order to enhance biomarker/translational research.
9
EFFICACY EVALUATIONS
Tumor response will be assessed after the 3rd and 6th cycles then after every 6 cycles by immune-
related response criteria (irRECIST) (96, 100) by independent, central, blinded radiographic 
review. Conventional RECIST 1.1 (98) will also be documented during the trial, however 
RECIST 1.1 will not be used to determine disease progression, as it has been shown in prior 
clinical trials using Pembrolizumab in large number of patients, that conventional RECIST might 
underestimate the benefit of pembrolizumab in approximately 15% of patients; thus using 
irRECIST could permit treatment beyond initial progression per RECIST v1.1 and prevent 
premature cessation of treatment (95-97). 
The irRECIST will be used for tumor response assessment at time of continuing review and will 
be used for IRB reporting and formal analysis.
9.1
Baseline
9.1.1
Measurable Lesion Definitions and Target Lesion Selection
•
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, will be identified as target lesions and recorded and 
measured at baseline
•
Measurable lesions must be accurately measured in at least one dimension with a 
minimum size of:
o
10 mm in the longest diameter by CT or MRI scan (or no less than double the 
slice thickness) for non- nodal lesions and ≥ 15 mm in short axis for nodal lesions.
o
10 mm caliber measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).
o
20 mm by chest X-ray
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•
A sum of the longest diameter (short axis for lymph nodes) of all target lesions will be 
calculated and reported as the baseline sum diameters. This will be used as reference to 
further characterize the objective tumor response of the measurable dimension of the 
disease.
9.1.2
Non-measurable Lesion Definitions
•
Non-target lesions will include:
o
Measurable lesions not selected as target lesions
o
All sites of non-measurable disease, such as neoplastic masses that are too small 
to measure because their longest uninterrupted diameter is < 10 mm (or < two 
times the axial slice thickness), i.e., the longest perpendicular diameter is ≥ 10 and 
< 15 mm.
o
Other types of lesions that are confidently felt to represent neoplastic tissue, but 
are difficult to measure in a reproducible manner. These include bone metastases, 
leptomeningeal metastases, malignant ascites, pleural or pericardial effusions, 
ascites, inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, 
ill-defined abdominal masses, skin lesions, etc.
•
All lesions or sites of disease not recorded as target lesions (e.g., small lesions and non-
measurable lesions) should be identified as non-target lesions and indicated as present in 
the source documents at baseline. There is no limit to the number of non-target lesions 
that can be recorded at baseline. The general location will also be documented on the 
images, drawing a regularly-shaped Region of Interest. 
•
Measurements of the non-target lesions will not be performed, but the presence or 
absence of each should be noted throughout follow-up and evaluation.
9.1.3
Target and Non-Target Lymph Node Lesion Definitions
•
To be considered pathologically enlarged and measurable, a lymph node must be 
≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be 
measured and followed.
9.1.4
Non-Target Lesion Selection
•
All lesions or sites of disease not recorded as target lesions should be recorded as non-
target lesions at baseline. There is no limit to the number on non-target lesions that can be 
recorded at baseline.
9.1.5
Bone Lesions
•
Bone scan, 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.
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•
Regardless of the imaging modality blastic bone lesions will not be selected as target 
lesions. Lytic or mixed lytic-blastic lesions with a measurable soft tissue component 
≥ 10 mm can be selected as target lesions.
9.1.6
Cystic and Necrotic Lesions as Target Lesions
•
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts.
•
Lesions that are partially cystic or necrotic can be selected as target lesions.
•
The longest diameter of such a lesion will be added to the Total Measured Tumor 
Burden (TMTB) of all target lesions at baseline. 
If other lesions with a non-liquid/non-necrotic component are present, those should be preferred.
9.1.7
Lesions with Prior Local Treatment
•
During target lesion selection the radiologist will consider information on the anatomical 
sites of previous intervention (e.g. previous irradiation, RF-ablation, TACE, surgery, 
etc.).
•
Lesions undergoing prior intervention will not be selected as target lesions unless there 
has been a demonstration of progress in the lesion.
9.1.8
No Disease at Baseline
•
If a patient has no measurable and no non-measurable disease at baseline the radiologist 
will assign ‘No Disease’ (irND) as the overall tumor assessment for any available follow-
up time-points unless new measurable lesions are identified and contribute to the TMTB.
9.2
Follow-Up
9.2.1
Recording of Target and New Measurable Lesion Measurements
•
The longest diameters of non-nodal target and new non-nodal measurable lesions, and 
short axes of nodal target and new nodal measurable lesions will be recorded. Together 
they determine the Total Measured Tumor Burden (TMTB) at follow-up.
9.2.2
Definition of New Measurable Lesions
•
In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions total, 
per time-point), new lesions must meet criteria as defined for baseline target lesion 
selection and meet the same minimum size requirements of 10 mm in long diameter and 
minimum 15 mm in short axis for new measurable lymph nodes. New measurable lesions 
shall be prioritized according to size, and the largest lesions shall be selected as new 
measured lesions.
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9.2.3
Non-Target Lesion Assessment
•
The RECIST 1.1 definitions (98) for the assessment of non-target lesions apply (i.e., 
measurements of the non-target lesions will not be performed, but the presence or 
absence of each should be noted throughout follow-up and evaluation).
•
The response of non-target lesions primarily contributes to the overall response 
assessments of irCR and irNon-CR/Non-PD (irNN).
•
Non-target lesions do not affect irPR and irSD assessments. 
•
Only a massive and unequivocal worsening of non-target lesions alone, even without 
progress in the TMTB is indicative of irPD.
9.2.4
New Non-Measurable Lesions Definition and Assessment
•
All new lesions not selected as new measurable lesions are considered new non-
measurable lesions and are followed qualitatively. 
•
Only a massive and unequivocal progression of new non-measurable lesions leads to an 
overall assessment of irPD for the time-point.
•
Persisting new non- measurable lesions prevent irCR.
9.2.5
irRECIST Overall Tumor Assessments
The irRECIST overall tumor assessment is based on the TMTB (total measured tumor burden) of 
measured target and new lesions, non-target lesion assessment and new non-measurable lesions.
•
irCR: Complete disappearance of all measurable and non-measurable lesions. Lymph 
nodes must decrease to < 10 mm in short axis.
•
irPR: Decrease of ≥ 30% in TMTB relative to baseline, non-target lesions are irNN, and 
no unequivocal progression of new non-measurable lesions.
•
irSD: Failure to meet criteria for irCR or irPR in the absence of irPD.
•
irNN: No target disease was identified at baseline and at follow-up the patient fails to 
meet criteria for irCR or irPD.
•
irPD: Minimum 20% increase and minimum 5 mm absolute increase in TMTB compared 
to nadir, or irPD for non-target or new non-measurable lesions. Confirmation of 
progression is recommended minimum 6 weeks after the first irPD assessment.
•
irNE: Used in exceptional cases where insufficient data exists.
•
irND: In adjuvant setting when no disease is detected.
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New Lesions: the presence of new lesion(s) does not define progression. The measurements of 
the new lesion(s) are included in the sum of the measurements (the sum of the measurements = 
the sum of the longest diameters of all target lesions and new lesions, if any).
9.2.6
Confirmation Measurement
A confirmatory assessment is required no less than 6 weeks after an irPR or irCR is deemed by 
irRECIST (96)
9.3
Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation. All baseline evaluations 
should be performed as closely as possible to the beginning of treatment and never more than 
4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. . The preferred imaging modality for this clinical 
trial is conventional CT scan using IV contrast.
•
Clinical Lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
•
Chest x-ray: Chest x-ray is not accurate in assessment of lesion size in the lung and 
should not be used as a method of measurement. Conventional chest CT is the preferred 
imaging modality to evaluate response to treatment.
•
Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body 
scans) however, conventional CT scan is the preferred modality to determine response 
to treatment.
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the irRECIST or RECIST 1.1 guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be 
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used and the image acquisition protocol should be followed as closely as possible to prior scans. 
Body scans should be performed with breath-hold scanning techniques, if possible.
•
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances.
•
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint.
•
Tumor Markers: Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.
•
Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
10
SAFETY EVALUATION
10.1
Adverse Events
10.1.1 Definition
An adverse event or adverse experience (AE) is any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related. Therefore, an AE can 
be ANY unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product (attribution of ‘unrelated’, 
‘unlikely’, ‘possible’, ‘probable’, or ‘definite’).
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
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Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death.
10.1.1.1 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF 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 clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
10.1.1.2 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF.
However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF.
10.1.1.3 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 x the upper limit of normal associated with 
cholecystitis), only the diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event 
CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated serum potassium level of 7 mEq/L should be recorded as 
“hyperkalemia.”
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
10.1.1.4 Preexisting Medical Conditions (Baseline Conditions)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
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an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
10.1.1.5 Overdose
Refer to Section 7.1.6 for a definition of pembrolizumab overdose.
•
If an adverse event(s) is associated with (“results from”) the overdose of 
pembrolizumab, the adverse event(s) is reported as a serious adverse event, even if 
no other seriousness criteria are met.
•
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology 
“accidental or intentional overdose without adverse effect.”
10.1.2 Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 4 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP
Version 4 of the CTCAE is identified and located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
AEs not covered by specific terminology listed should be reported with common medical 
terminology, and documented according to the grading scales provided in the CTCAE Version 4.
Any adverse event which changes CTCAE grade over the course of a given episode will have 
each change of grade recorded on the adverse event case report forms/worksheets.
The relationship of event to study drug will be documented by the Investigator as follows:
•
Unrelated: The event is clearly related to other factors such as the participant’s clinical 
state, other therapeutic interventions or concomitant drugs administered to the participant.
•
Unlikely: The event is doubtfully related to investigational agent(s). The event was most 
likely related to other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs.
•
Possible: The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the participant’s 
clinical state, other therapeutic interventions or concomitant drugs.
•
Probable: The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot 
be reasonably explained by other factors such as the participant’s clinical state, 
therapeutic interventions or concomitant drugs.
•
Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the participant’s condition, therapeutic interventions or 
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concomitant drugs; AND occurs immediately following study drug administration, 
improves upon stopping the drug, or reappears on re-exposure.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. An 
investigator, who is a qualified physician, will evaluate all adverse events using the following 
guidelines:
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V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include 
an adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a 
preexisting condition which has not worsened does not constitute a serious adverse event.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer; (that is not a condition of the study) or
Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is 
not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event 
when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Merck product to be discontinued?
Relationship to 
test drug 
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the 
AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. 
The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the 
adverse event based upon the available information. 
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment 
(pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Merck product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Merck 
product
(continued) 
De-challenge
Was the Merck product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive de-challenge. If no, this is a negative de-challenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Merck product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug 
trial); or (3) Merck product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. 
CLINICAL MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship).
Yes, there is a reasonable 
possibility of Merck product 
relationship.
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck 
product is reasonable.  The AE is more likely explained by the Merck product than by another cause.
No, there is not a reasonable 
possibility Merck product 
relationship
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not 
reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.)

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10.1.3 Reporting Adverse Events
Table 8
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
Routine AEs occurring from the time the consent form is signed until 30 days after the last 
intervention, or until the event has resolved, the study participant is lost to follow-up, the start of 
a new treatment, or until the study investigator assesses the event(s) as stable or irreversible, will 
be reported. New information will be reported after it is received.
10.2
Events of Clinical Interest (ECIs)
Refer to the separate guidance document entitled “Event of Clinical Interest Guidance 
Document” for detailed instruction regarding identification, evaluation and management of ECIs 
and immune-related adverse events (irAEs).
Participants should be assessed for possible ECIs prior to each dose. Lab results should be 
evaluated and participants should be asked for signs and symptoms suggestive of an immune-
related event. Participants who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes. If lab results or symptoms indicate a possible 
immune-related ECI, then additional testing should be performed to rule out other etiologic 
causes. If no other cause is found, then it is assumed to be immune-related.
Any Grade 3 or higher event that the investigator considers to be immune-related should be 
reported as an ECI regardless of whether the specific event term is in Table 9 and reported to 
Merck within 24 hours from the time the Investigator/physician is aware of such an occurrence. 
Adverse events that are both an SAE and an ECI should be reported one time as an SAE only. 
ECIs will not be indicated in the data base, but will be tracked by the clinical research 
coordinator in an AE log to facilitate reporting to Merck (refer to Event of Clinical Interest 
Guidance Document, v.5, page 8).
Table 9
Events of Clinical Interest
Pneumonitis (reported as ECI if ≥ Grade 2)
Acute interstitial pneumonitis
Interstitial lung disease
Pneumonitis
Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE)
Intestinal Obstruction
Colitis
Colitis microscopic
Enterocolitis
Enterocolitis hemorrhagic
Gastrointestinal perforation
Necrotizing colitis
Diarrhea
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Endocrine (reported as ECI if ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of systemic steroids to treat 
the AE)
Adrenal Insufficiency
Hyperthyroidism
Hypophysitis
Hypopituitarism
Hypothyroidism
Thyroid disorder
Thyroiditis
Hyperglycemia, if ≥Grade 3 and associated with ketosis or metabolic acidosis (DKA)
Endocrine (reported as ECI)
Type 1 diabetes mellitus (if new onset)
Hematologic (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat 
the AE)
Autoimmune hemolytic anemia
Aplastic anemia
Thrombotic Thrombocytopenic Purpura 
(TTP)
Idiopathic (or immune) 
Thrombocytopenia Purpura (ITP)
Disseminated Intravascular Coagulation 
(DIC)
Hemolytic Uremic Syndrome (HUS)
Any Grade 4 anemia regardless of underlying mechanism
Hepatic (reported as ECI if ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat the 
AE)
Hepatitis
Autoimmune hepatitis
Transaminase elevations (ALT and/or 
AST)
Infusion Reactions (reported as ECI for any grade)
Allergic reaction
Anaphylaxis
Cytokine release syndrome
Serum sickness
Infusion reactions
Infusion-like reactions
Neurologic (reported as ECI for any grade)
Autoimmune neuropathy
Guillain-Barre syndrome
Demyelinating polyneuropathy
Myasthenic syndrome
Ocular (report as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE)
Uveitis
Iritis
Renal (reported as ECI if ≥ Grade 2)
Nephritis
Nephritis autoimmune
Renal Failure
Renal failure acute
Creatinine elevations (report as ECI if ≥Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE)
Skin (reported as ECI for any grade)
Dermatitis exfoliative
Erythema multiforme
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Skin (reported as ECI if ≥ Grade 3)
Pruritus
Rash
Rash generalized
Rash maculopapular
Any rash considered clinically significant in the physician’s judgment
Other (reported as ECI for any grade)
Myocarditis
Pancreatitis
Pericarditis
Any other Grade 3 event which is considered immune-related by the physician
Events of clinical interest for this study include:
•
An overdose of pembrolizumab that is not associated with clinical symptoms or abnormal 
laboratory results.
•
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
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upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
o
*Note: These criteria are based upon available regulatory guidance documents. 
The purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require an additional evaluation for an underlying etiology. Guidance for 
assessment and follow up of these criteria can be found in the Event of Clinical 
Interest Guidance Document.
10.3
Serious Adverse Events
10.3.1 Definition
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor results in ANY of the following:
•
Death.
•
A life-threatening adverse event (experience). Any AE that places a participant or 
participants, in the view of the Investigator or sponsor, at immediate risk of death from 
the reaction as it occurred. It does NOT include an AE that, had it occurred in a more 
severe form, might have caused death.
•
Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).
•
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.
•
A congenital anomaly or birth defect.
•
Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the 
outcomes listed above.
•
Is associated with an overdose
•
Is a new cancer (that is not a condition of the study)
Additionally, any serious adverse event considered by an investigator who is a qualified 
physician to be related to the investigational drug, that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph, also 
must be reported immediately to the Sponsor.
10.3.2 Reporting Serious Adverse Events
All new SAEs occurring from the date the participant signs the study consent until 90 days after 
the last intervention or a new treatment is started, whichever comes first, will be reported. The 
RPCI SAE Source Form is to be completed with all available information, including a brief 
narrative describing the SAE and any other relevant information. 
SAEs occurring after the 90 day follow-up period that the investigator determines to be possibly, 
probably or definitely related to the study intervention should be reported.
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SAEs identified as an Unanticipated Problem by the Investigator must be reported. Please refer 
to Section 10.6 for details on reporting Unanticipated Problems.
10.3.3 Reporting Events of Clinical Interest (ECIs)
ECIs (both non-serious and serious adverse events) identified in the Event of Clinical Interest 
Guidance Document from the date of first dose of pembrolizumab through 90 days 
following cessation of treatment, or 30 days after the initiation of a new anticancer therapy, 
whichever is earlier, need to be reported within 24 hours to the Principal Investigator and 
within 2 working days to Merck Global Safety, regardless of attribution to study treatment, 
consistent with standard SAE reporting guidelines.
Attn: Worldwide Product Safety
FAX 215 993-1220
10.3.4 Reporting of Overdose
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Principal Investigator and within 2 working days hours to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220).
10.3.5 Reporting of Pregnancy and Lactation
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a participant 
(spontaneously reported to them), including the pregnancy of a male participant's female partner 
that occurs during the trial or within 120 days of completing the trial completing the trial, or 30 
days following cessation of treatment if the participant initiates new anticancer therapy, 
whichever is earlier. All participants and female partners of male participants who become 
pregnant must be followed to the completion/termination of the pregnancy. Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, 
fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Such events must be reported within 24 hours to the Principal Investigator and within 2 
working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220).
10.4
Follow-Up for Serious Adverse Events
All related SAEs should be followed to their resolution, until the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as 
stable or irreversible. New information will be reported when it is received.
10.5
Follow-Up for Events of Clinical Interest
All related ECIs should be followed to resolution. The Adverse Experience eCRF should be 
updated with information regarding duration and clinical course of the event. Information 
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obtained from the consulting specialist, including diagnosis, should be recorded in the 
appropriate AE fields. Free-text fields should be used to record narrative information:
•
Clinical course of the event
•
Course of treatment
•
Evidence supporting recovery
•
Follow-up to the clinical course
Any treatments administered for the event should also be entered in the Concomitant Medication 
eCRF.
10.6
Unanticipated Problems
10.6.1 Definition
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:
•
Unexpected (in terms of nature, severity, or frequency) given:
a) The research procedures that are described in the study-related documents, including 
study deviations, as well as issues related to compromise of participant privacy or 
confidentiality of data.
b) The characteristics of the participant population being studied.
•
Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research).
•
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized and if in relation to an AE is also deemed Serious per Section 10.3.
10.6.2 Reporting Unanticipated Problems
Unanticipated problem reporting will begin at the time of participant consent. The Unanticipated 
Problem Form will be submitted to the CRS Compliance Office within 1 business day of 
becoming aware of the Unanticipated Problem. After review, CRS Compliance will submit the 
UP to the IRB.
When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to CRS Compliance with an updated Unanticipated Problem Form. The site 
Investigator or designated research personnel will report all unanticipated problems, whether 
related or unrelated to the investigational agent(s) to the IRB in accordance with their local 
institutional guidelines.
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10.7
FDA Reporting
When RPCI is the IND holder the following describes the FDA reporting requirements by 
timeline for AEs and new safety findings that meet the criteria outlined below:
Within 7 Calendar Days
Any adverse event that meets ALL the following criteria:
•
Related or possibly related to the use of the study drug;
•
Unexpected; and
•
Fatal or life-threatening.
Within 15 Calendar Days
Any adverse event that meets ALL the following criteria:
•
Related or possibly related to the use of the study drug;
•
Unexpected; and
•
Serious but not fatal or life-threatening;
Or, meets ANY of the following criteria:
•
A previous adverse event that is not initially deemed reportable but is later found to fit 
the criteria for reporting (report within 15 days from when event was deemed reportable).
•
Any findings from other studies, including epidemiological studies, pooled analysis of 
multiple studies, or other clinical studies conducted with the study drug that suggest a 
significant risk in humans exposed to the drug.
•
Any findings from animal or in vitro testing that suggest a significant risk for human 
participants including reports of mutagenicity, teratogenicity, or carcinogenicity or 
reports of significant organ toxicity at or near the expected human exposure.
•
Any clinically important increase in the rate of occurrence of a serious, related or 
possibly related adverse event over that listed in the protocol or investigator brochure.
Sponsors are also required to identify in IND safety reports, all previous reports concerning 
similar adverse events and to analyze the significance of the current event in the light of the 
previous reports.
Reporting Process
The principal investigator or designee will complete and submit a FDA Form 3500A MedWatch 
for any event that meets the above criteria. Forms will be submitted to the CRS Compliance 
Office via email to CRSCompliance@RoswellPark.org.
11 DATA AND SAFETY MONITORING
The RPCI Data and Safety Monitoring Board will assess the progress of the study, the safety 
data, and critical efficacy endpoints. The DSMB will review the study annually and will make 
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recommendations that include but not limited to; (a) continuation of the study, (b) modifications 
to the design (c) or termination of the study.
12 STATISTICAL METHODOLOGY
The primary objective of this study is:
•
To evaluate improvement in progression-free survival for patients treated with anti-PD1 
pembrolizumab in combination with IV bevacizumab and oral metronomic 
cyclophosphamide as compared to a historical control. Data will be collected to be used 
for final analysis (Clinical Data Appendix).
The secondary objectives of this study are:
•
To obtain pilot data on clinical response rates using both RECIST1.1 criteria (Response 
Evaluation Criteria in Solid Tumors) and immune related response criteria (irRECIST).
•
To obtain data on changes in tumor microenvironment prior to and subsequent to therapy 
and, to screen for potential biomarkers to predict clinical benefit.
•
To determine the safety and tolerability of the treatment combination in the study 
population.
•
To evaluate overall survival in patients treated with anti-PD1 pembrolizumab in 
combination with IV bevacizumab and oral metronomic cyclophosphamide.
•
To assess the impact of the combination of anti-PD1 pembrolizumab, IV bevacizumab 
and oral metronomic cyclophosphamide on anti-tumor immune responses in ovarian 
cancer.
12.1
Sample Size Determination
The primary objective of the Phase II study is to evaluate the progression-free survival (PFS) for 
patients treated with pembrolizumab in combination with IV bevacizumab and oral metronomic 
cyclophosphamide in women with recurrent/persistent platinum –sensitive, -resistant, or -
refractory ovarian, primary peritoneal, or fallopian tube cancers. The median PFS of platinum 
resistant ovarian cancer patients treated with standard chemotherapy is approximately 3.5 
months. In a recent study, platinum-resistant ovarian cancer patients treated with a combination 
of IV bevacizumab and oral metronomic cyclophosphamide (61) a median PFS and overall 
survival (OS) of 4.5 and 10.7 months, respectively. In another study, patients with recurrent 
ovarian treated with bevacizumab plus low-dose metronomic oral cyclophosphamide (62) had a 
median response duration of 3.9 months. Therefore we would consider a PFS of 7 months or 
greater to be of interest in this population.
Based on this we expect that no more than 30% of patients treated with standard chemotherapy 
would achieve 7 months of PFS. Therefore, we will test the null hypothesis that the 7-month PFS 
rate (π) in patients treated with pembrolizumab 200 mg IV + bevacizumab 15 mg/kg every 3 
weeks IV + cyclophosphamide 50 mg po every day combination therapy is less than or equal to 
30% versus the one-sided hypothesis that it is greater than 30%. That is:
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  	

  	

Where  is the 7-month PFS rate.

Consider a sample size of n=40 patients (including 5 patients from the safety cohort), with up to 
1 year of follow-up, and a maximum drop-out rate of 10%. If the true 7-month PFS rate is 50% 
(a median PFS of 7 months) for the proposed treatment combination, then a one-sided Wald-type 
test has approximately an 86.1% chance of resulting in significance. A nominal significance 
level of 10% is considered, this would be the probability of erroneously finding a truly 
ineffective treatment as worthy of further research.
The study will thus enroll 40 evaluable patients in total, with 5 in the safety cohort and an 
additional 35 to complete the Phase II study. The accrual is expected to take 18 months.
12.2
Demographics and Baseline Characteristics
Descriptive statistics (as appropriate: n, percent, mean, median, min and max) will be used to 
summarize demographic and baseline characteristics.
12.3
Phase II Analysis
12.3.1 Safety Lead-in Cohort
A safety lead-in cohort of n1=5 patients will enrolled and the safety/tolerability of the 
combination will be examined after each patient completes at least 3 cycles. If 2 or less patients 
have experienced a drug related toxicity requiring drug/treatment delay or suspension (as defined 
in Sections 6.4, 6.5, and 6.7.3), then an additional n2=35 patients are enrolled to complete the 
Phase II study. Otherwise, the study will be suspended and the research team (to include RPCI 
Phase I committee, Study PI and study statistician) will meet to discuss possible safety concerns 
and will decide what actions to take with respect to study continuation.
If the true SAE rate of the proposed treatment combination is 0.30, then there is an 83% chance 
of continuing study enrollment. Additional scenarios are given below:
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True Treatment Toxicity Rate
0.1
0.2
0.3
0.4
0.5
Chance of Continuation
0.99
0.94
0.83
0.68
0.50
12.3.2 Primary Objective
The primary endpoint is progression free survival (PFS). The PFS will be treated as bivariate 
time-to-event data, where an event indicator variable (0=censored, 1=event) is paired with a 
continuous time variable. Patients who are progression-free and still on treatment at last follow-
up or those who drop-out of the study, for any reason, will be considered censored events; while 
patients who experience disease progression or death from disease will be considered PFS 
events. The PFS time will be measured as the time from the start of the study treatment until PFS 
event, last follow-up or drop-out.
The primary analysis will consider the following hypotheses about the 7 month PFS rate (
) in 

women with recurrent/persistent platinum –sensitive, -resistant, or -refractory ovarian, primary 
peritoneal, or fallopian tube cancers treated with pembrolizumab in combination with IV 
bevacizumab and oral metronomic cyclophosphamide:
  	

  	

These hypotheses will be assessed using the set of patients whom completed at least 1 cycle 
treatment or those who stopped the first cycle due to disease progression or toxicity. The PFS 
will be summarized using standard Kaplan-Meier methods, from which an estimate of the 7-
month survival rate and corresponding standard error will be obtained using the methods 
proposed by Breslow and Day (101). A Wald type test, utilizing these estimates, will be used to 
evaluate the given hypotheses. These methods have been applied to survival outcomes in similar 
settings (102). All analysis will be conducted in SAS v9.4 (Cary, NC) at a significance level of 
0.10.
12.3.3 Secondary Objectives
The frequency of toxicities, AE’s and SAE’s, will be tabulated by grade (as appropriate) across 
all dose levels and cycles. The toxicity, AE and SAE, rates will be estimated using 90% 
confidence intervals, which will be obtained using Jeffreys prior method. All participants who 
receive any study treatment will be considered evaluable for these outcomes.
The overall and progression free survival will be summarized using standard Kaplan-Meier 
methods, with estimates of median survival and given survival rates will be obtained with 90% 
confidence intervals.
Objective tumor response will be tabulated for all patients that completed at least three cycles of 
the proposed treatment combination. The response rate will be estimated using 90% confidence 
intervals, obtained using Jeffreys prior method.
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The plasma and tumor biomarkers will be reported using the appropriate descriptive statistics. 
Associations between these markers and PFS will be evaluated using Cox regression models; 
while associations with tumor response will be evaluated using logistic regression models.
12.4
Interim Analysis and Criteria for Early Termination of the Study
No additional explicit interim analyses or early termination criteria are planned for the Phase II 
study. However, the toxicity and safety outcomes will be reviewed regularly through the DSMB.
13 ETHICAL AND REGULATORY STANDARDS
13.1
Ethical Principles
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC). Each participant (or legal guardian) shall read, understand, 
and sign an instrument of informed consent prior to performance of any study-specific 
procedure. It is the responsibility of the investigator to ensure that the participant is made aware 
of the investigational nature of the treatment and that informed consent is given.
The Investigator is responsible for the retention of the participant log and participant records; 
although personal information may be reviewed by authorized persons, that information will be 
treated as strictly confidential and will not be made publicly available. The investigator is also 
responsible for obtaining participant authorization to access medical records and other applicable 
study specific information according to Health Insurance Portability and Accountability Act 
regulations (where applicable).
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the participant is treated. The clinical trial should be 
conducted in accordance with the ethical principles embodied in the Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research, consistent with 
good clinical practice and the applicable regulatory requirements and according to the guidelines 
in this protocol, including attached appendices.
13.2
Informed Consent
The Investigator (or IRB specified designee) is responsible for obtaining written consent from 
each participant or the participant's legally authorized representative in accordance with GCP 
guidelines using the approved informed consent form, before any study specific procedures 
(including screening procedures) are performed. The informed consent form acknowledges all 
information that must be given to the participant according to applicable GCP guidelines, 
including the purpose and nature of the study, the expected efficacy and possible side effects of 
the treatment(s), and specifying that refusal to participate will not influence further options for 
therapy. Any additional information that is applicable to the study must also be included. 
Additional national or institutionally mandated requirements for informed consent must also be 
adhered to. The participant should also be made aware that by signing the consent form, 
processing of sensitive clinical trial data and transfer to other countries for further processing is 
allowed.
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The Investigator shall provide a copy of the signed consent form to the participant and the signed 
original shall be maintained in the Investigator File. A copy of the signed consent form must be 
filed in the participant file. At any stage, the participant may withdraw from the study and such a 
decision will not affect any further treatment options.
14
STUDY RESPONSIBILITIES
14.1
Data Collection
Data entry into the database is to be completed in a timely fashion after the participant’s clinic 
visit. If an AE is considered serious it is captured on both the Adverse Event page and the 
Serious Adverse Event Source Form, which is handled in an expedited fashion.
Data management activities will be performed using eClinical. eClinical is a suite of software 
tools that enables the collection, cleaning and viewing of clinical trial data. CRS data 
management will design the study-specific database and facilitate its development by the 
eClinical Information Technology team. Once the database design is approved by the 
Investigator, Statistician, and Clinical Research Coordinator, the database will be put into 
production and data entry can begin. Data can be entered and changed only by those with the 
rights to do so into the eCRFs (via the EXPeRT Module). eClinical is compliant with all relevant 
technical aspects of relevant GCP guidelines.
•
The system can generate accurate copies of stored data and audit trail information in 
human readable form.
•
System access is limited to authorized individuals through the controlled assignment of 
unique ID and password combinations.
•
The system is designed to periodically force users to change their passwords and verifies 
that user ID and password combinations remain unique.
•
The system automatically generates a permanent time-stamped audit trail of all user 
interactions.
When data entry is complete, data management will review the data and will query any missing, 
incomplete, or invalid data points for resolution by the Clinical Research Coordinator and 
Investigator. Once all queries have been resolved, the data can be released to the statistician for 
analysis.
14.2
Maintenance of Study Documents
Essential documents will be retained per RPCI’s policy for 6 years from the study termination 
date. These documents could be retained for a longer period, however, if required by the 
applicable local regulatory requirements or by an agreement with RPCI.
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15 ADMINISTRATIVE RULES
15.1
Revisions to the Protocol
RPCI may make such changes to the protocol as it deems necessary for safety reasons or as may 
be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to the 
IRB/ERC for written approval before implementation.
15.2
Termination of the Study
It is agreed that, for reasonable cause, either the RPCI Investigators or Merck, may terminate this 
study, provided a written notice is submitted within the time period provided for in the Clinical 
Trial Agreement. In addition, RPCI may terminate the study at any time upon immediate notice 
if it believes termination is necessary for the safety of participants enrolled in the study.
Merck’s Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below:
•
Quality or quantity of data recording is inaccurate or incomplete
•
Poor adherence to protocol and regulatory requirements
•
Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
•
Plans to modify or discontinue the development of the study drug
In the event of Merck’s decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made.
15.3
Confidentiality
Any data, specimens, forms, reports, video recordings, and other records that leave the site will 
be identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
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16 APPENDICES
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Appendix A
ECOG Performance Status Scores
Description
Status
Fully active, able to carry on all pre-disease performance without restriction.
0
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work.
1
Ambulatory and capable of all self-care but unable to carry out any work activities.
2
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
4
Dead
5
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Appendix B
Calculation for Creatinine Clearance
Cockroft-Gault Equation*
Men: CrCl = [(140-YR) x IBW] / (SCr x 72)
Women: CrCl = 0.85 x [(140-YR) x IBW] / (SCr x 72)
Where:
CrCl is creatine clearance (mL/min)
IBW is ideal body weight (kg)
SCr is serum creatinine (mg/dL)
YR is age (years)
*Cockcroft D, W, Gault M, H, Prediction of Creatinine Clearance from Serum Creatinine. 
Nephron. 1976; 16 (1):31-41)
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Appendix C
Procedure for Obtaining a Urine Protein Creatinine Ratio (UPCR)
1. Obtain at least 4 ml of a random urine sample in a sterile container(does not have to be a 
24-hour urine)
2. Determine protein concentration (mg/dL)
3. Determine creatinine concentration (mg/dL)
4. Divide #2 by #3 above:
 
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!" 

 
!" 
The UPC directly correlates with the amount of protein excreted in the urine per 24 hr (i.e., a 
UPC of 1 should be equivalent to 1 g protein in a 24 hr urine collection).
For the purpose of this study, participant must have a Urine Protein Creatine Ratio 
(UPCR) < 1 prior to enrollment and ≤ 3.5 for any subsequent cycles.
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Appendix D
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin (β-hCG)†
Hemoglobin
Alkaline phosphatase
Glucose  
PT (INR)
Platelet count
Alanine aminotransferase 
(ALT)
Protein
aPTT
WBC (total and 
differential)
Aspartate aminotransferase 
(AST)
Specific gravity
Total triiodothyronine (T3)
Red Blood Cell Count
Lactate dehydrogenase 
(LDH)
Microscopic exam (If 
abnormal)
Free thyroxine (T4)
Absolute Neutrophil 
Count
Carbon Dioxide
(CO2 or bicarbonate)‡
results are noted
Thyroid stimulating hormone 
(TSH)
Absolute Lymphocyte 
Count
Uric Acid
Urine pregnancy test †
Calcium
UPCR
Blood for correlative studies
Chloride
Glucose  
Phosphorus
Potassium
Sodium
Magnesium
Total Bilirubin
Direct Bilirubin (If total 
bilirubin is elevated above 
the upper limit of normal)
Total protein
Blood Urea Nitrogen
Creatinine
If patient has a random blood glucose value ≥ 200 mg/dL: a fasting blood sugar level and Hemoglobin A1C will be 
obtained within 48 hours and, treatment will be held until the patient is clinically and metabolically stable – this will 
be determined by the treating physician.
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a 
serum pregnancy test will be required.
‡ If considered standard of care in your region.
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Appendix E
Medication Diary
Study No.: ______________
Subject’s Name: ______________________________
Drug Name: _____________
Cycle #: ______
Medical Record No.: _________________________
Study Medication Calendar for Cyclophosphamide
You should swallow your medication whole: without cutting, chewing, or crushing. The capsule should be taken in 
the morning (with or without food) and, it is recommended to drink 2-3 quarts of fluid per day. Wash your hands 
immediately if you touch a broken tablet
Please complete this calendar on a daily basis immediately after you take your capsule. Fill in the date for each day 
and write the total number of capsules you take each day. Take 1 capsule each day, in the morning (with or without 
food). 
Start Date: _________________
Cycle Day
Day 1
Day 2
Day 3 
Day 4
Day 5
Day 6
Day 7
Date
Number of 
capsules 
taken
Cycle Day
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Date
Number of 
capsules 
taken
Cycle Day
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Date
Number of 
capsules 
taken
Cycle Day
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Date
Number of 
capsules 
taken
Cycle Day
Day 29
Day 30
Day 31
Date
Number of 
capsules 
taken
Please remember to bring this calendar with you to your next clinic appointment.
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_______________________________________________________________________________________________
Coordinator’s Use Only
#$ 
%&'($$)*+
%&'($$),-!&$! . /
00000#$  

  . /
Subject’s Signature: __________________________________________
Date: ____________
CRC’s Signature: ____________________________________________
Date: ____________
Investigator’s Signature: ______________________________________
Date: ____________
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Appendix F
NYHA Functional Classification System
New York Heart Association (NYHA)
Congestive Heart Failure (CHF)
Functional Classification Systema
Class
Functional Description
NYHA Class I
Cardiac disease, but no symptoms and no 
limitation in ordinary physical activity (e.g., 
shortness of breath when walking, climbing 
stairs, etc.).
NYHA Class II
Mild symptoms (mild shortness of breath 
and/or angina) and slight limitation during 
ordinary activity.
NYHA Class III
Marked limitations in activity due to 
symptoms, even during less-than-ordinary 
activity [e.g., walking short distance (20-100 
m)]. Comfortable only at rest.
NYHA Class IV
Severe limitations. Experiences symptoms 
even while at rest. Mostly bedbound patients.
a The Criteria Committee of the New York Heart Association. (1994). Nomenclature and Criteria for Diagnosis 
of Diseases of the Heart and Great Vessels. (9th ed.). Boston: Little, Brown & Co. pp. 253–256.
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Appendix G
EORTC QLQ-C30 
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Appendix H
EORTC OLQ-OV28
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Appendix I
Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF)
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Appendix J
Microbiome Collection Questionnaire
                                             
Patient’s name:
 MRN:
Date:
Cycle Number:
MICROBIOME COLLECTION QUESTIONNAIRE
1. Have you had any fevers or infections in the past 2 weeks?
o
No
o
Yes, please specify:______________________________
2. Have you taken antibiotics or antifungal agents in the past 4 weeks?
o
No
o
Yes, please tell us which medication(s):___________________________
o
Why were you given antibiotics? __________________________________
o
For how long did you take it? ______________________________________
3. How many times a week do you eat red meat? 
o
I don’t eat red meat
o
1-3 times a week
o
More than 3 times a week
4. How many times a week you eat cruciferous vegetables such as cabbage, broccoli, kale, 
and cauliflower?
o
I don’t eat cruciferous vegetables
o
1-3 times a week
o
More than 3 times a week
5. Do you eat yoghurt? 
o
I don’t eat yoghurt
o
1-3 times a week (please specify which kind)________________________________
o
More than 3 times a week (please specify which kind)______________________
6. Do you take probiotics?
o
No
o
Yes, please indicate how often_________________________________________________
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Patient’s name:
 MRN:
Date:
Cycle Number:
7. Do you have any food allergies?
o
No
o
Yes, please list any food allergies:_____________________________________________
o
Foods you avoid for religious, personal, or cultural reasons:__________________________________
o
Foods your Doctor told you to avoid:________________________________________
8. If you are CURRENTLY on a special diet, please indicate below:
o
Not on a special diet
o
Weight loss
o
Weight gain
o
Vegetarian
o
Diet for diabetes
o
Diet for heart disease
o
Diet for kidney disease
o
Other:____________________
9. Are you currently taking prescribed or over-the-counter medications to lose weight or 
maintain your current weight? 
o
No 
o
Yes, I am on these weight loss medications:_________________________________
10.Are you taking laxatives to have a bowel movement on a regular basis?
o
No
o
Yes, please describe which kind and how often:_____________________
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Patient’s name:
 MRN:
Date:
Cycle Number:
11.How would you describe your bowel movements in the past 2 weeks:
o
Regular bowel movements every 1-2 days with no change
o
Frequent issues with diarrhea, please describe_____________________________
o
Frequent issues with constipation, please describe_________________________
12.Do you participate in regular physical activity? 
o
No
o
Yes, please describe what exercise you like to do? _______________________
o
How long? __________________________  
o
How many times a week? _________________________
13.Do you smoke?
o
No
o
Yes (please indicate how many cigarettes a day)___________________
14.Did you swim in a chlorinated pool or use a hot tub in the past 2 weeks?
o
No
o
Yes, please indicate how many times a week_______________
15.Did you use a tanning bed/sun lamp in the past 2 weeks?
o
No
o
Yes, please indicate how many times and when was the last 
time_______________________________________
16. Do you use vaginal douching? 
o
No
o
Yes, please indicate how many times a week and which kind: 
______________________________________
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o
Patient’s name:
o
 MRN:
o
Date:
o
Cycle Number:
17.Have you used lubrication or any vaginal product/medication in the past 2 weeks?
o
No
o
Yes, please specify_______________________________
18.Have you had any abnormal vaginal discharge or bleeding in the past 2 weeks?
o
No
o
Yes, please specify:_________________________
19.Are you currently sexually active?
o
No
o
Yes
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Appendix K
Microbiome Initial Assessment Questionnaire
o
Patient’s name:
o
MRN:
o
Date:
o
Cycle Number:
MICROBIOME INITIAL ASSESSMENT QUESTIONNAIRE
1. What is your race? (one or more categories may be selected)
o
American Indian or Alaska Native
o
Black or African American 
o
White
o
Asian, please specify: ___________
o
Native Hawaiian/Other specific Islander: ____________
o
Other Race, please specify:_______________
2. Are you of Hispanic or Spanish origin?
o
No
o
Yes
3. Were you breastfed as an infant?
o
No
o
Yes
o
I don’t know
4. Were you delivered via vaginal delivery or C-section?
o
Vaginal delivery
o
C-section
o
I don’t know
5. Have you had an appendectomy?
o
No
o
Yes
o
I don’t know
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o
Patient’s name:  
o
 MRN:
o
Date:
o
Cycle Number:
6. Have you ever had any bowel surgery/removal of a portion of your bowel or stomach?
o
No
o
Yes, please specify__________________________
o
I don’t know
7. Were you ever diagnosed with an autoimmune disease?
o
No
o
Yes, please specify_________________________
8. How often do you use a tanning bed/sun lamp?
o
Never
o
1-3 times a year
o
4-10 times a year
o
More than 10 times a year
9. Do you regularly swim or use a hot tub?
o
No
o
Yes, please indicate how many times a week_______________
10.If your untanned skin was exposed to the summer sun for the first time for 45 minutes, 
would you:
o
Always burn, tan minimally
o
Burn moderately, tan gradually
o
Burn minimally, tan well
o
Rarely/never burn
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Appendix L
Collection Instructions: Skin
SKIN SAMPLE COLLECTION INSTRUCTIONS
During your next office visit we will collect swabs from the surface of your forearms, inguinal 
creases and upper back to study the bacteria on your skin. The collection will not cause any 
discomfort and will involve small gentle scraping on the surface of the collection sites and then 
using a swab to touch the area. 
In order to get accurate samples, we ask you to follow the instructions below:
•
Please do NOT use antibiotic-containing soaps and washes for 1 week. Most soaps/body 
wash products do not contain antibiotics, thus you should be fine using regular 
soap/body wash products.
•
Please do NOT put any topical antibiotics on your skin for 7 days, unless you have a skin 
infection and were specifically instructed to do so by your doctor.
•
Please do NOT swim in chlorinated pools, use hot tubs, or tan for 3 days prior to sample 
collection.
•
Please abstain from using moisturizers and cosmetics or other topical products and, from 
washing sampled skin areas (forearms, inguinal creases, upper back) for 24 hours before 
your next visit.
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Appendix M Collection Instructions: Vaginal
VAGINAL SAMPLE COLLECTION INSTRUCTIONS
At the time of your next visit we will collect 2 vaginal swabs for research purposes during the 
routine pelvic exam. The sample collection will not cause any additional discomfort and will be 
similar to getting a Pap smear.
In order to get accurate samples, we ask you to follow the instructions below:
•
Please do NOT use any vaginal lubricants/cream/medications for 3 days prior to your 
visit.
•
Please do NOT use vaginal douching for 3 days prior to your visit.
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Appendix N
Collection Instructions: Stool
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APPENDIX O - CLINICAL DATA NEEDED FOR FINAL ANALYSIS
1. Did the patient have primary debulking surgery?   Yes □    No □  
1a. If yes, did the patient have optimal tumor debulking (<1 cm residual disease)  Yes □    No □  
1b. If no, did the patient receive neoadjuvant chemotherapy?  Yes □    No □  
i. If yes, patient received neoadjuvant chemotherapy, did she have interval 
cytoreduction?  Yes □    No □  
ii. If the patient had interval cytoreduction after neoadjuvant chemotherapy, did she 
have optimal tumor debulking (<1 cm residual disease) Yes □    No □  
2. Did the patient have any secondary debulking at any time of tumor recurrence?  Yes □    No □  
2a. If yes, did the patient have optimal tumor debulking (<1 cm residual disease)  Yes □    No □  
Prior Chemotherapy
3. How many prior lines of chemotherapies the patient has received?  _________
4. Is the patient platinum resistant?  Yes □    No □  
5. Prior Avastin (Bevacizumab) exposure?  Yes □    No □  
5a. If yes, for how many cycles?   _________
6. Prior oral single agent Cytoxan exposure?  Yes □    No □  
6a. If yes, for how many cycles?   _________
7. Prior exposure to combination of oral Cytoxan and Avastin (Bevacizumab)?  Yes □    No □  
7a. If yes, for how many cycles?  _________
7b. If yes, what response did she have (CR, PR, DP)? 
8. Any prior exposure to immunotherapy?  Yes □    No □  
8a. If yes, what kind of immunotherapy?  ___________
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Medical history
9. Any history of high blood pressure?  Yes □    No □  
10. Any history of kidney disease?  Yes □    No □  
11. Any history of autoimmune disease?  Yes □    No □  
12. Any history of radiation?  Yes □    No □  
13. Does the patient have BRCA1 or 2 mutation?  Yes □    No □  
14. Any exposure of PARP-inhibitors?  Yes □    No □  
Follow up / Off Study
15. Any subsequent exposure to Avastin (Bevacizumab)?  Yes □    No □  
15a. If yes, for how many cycles?  ___________
15b. If yes, any major side effects from Avastin (Bevacizumab)?  Yes □    No □   ___________
16. How many additional lines of chemotherapy?  __________
17. Any subsequent exposure to immunotherapy?  Yes □    No □  
17a. If yes, what kind of immunotherapy?  __________________.____   
18. Any new cancer diagnosis?  Yes □    No □    _____________   
19. Any new diagnosis of autoimmune disease?  Yes □    No □   ______________._____   
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17
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