Conditions: Cervical Cancer
Keywords: Recurrent Cervical Cancer Persistent Cervical Cancer Metastatic Cervical Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 17
Healthy volunteers: no

Brief summary:
The investigators propose to evaluate the efficacy of the combination of standard chemotherapy with bevacizumab with Pembrolizumab in women with recurrent, persistent, or metastatic cervical cancer.

Detailed description:

Arms:
arm 1: On day 1 of each 21 day cycle, participants will be administered Pembrolizumab 200mg (IV); Chemotherapy including Paclitaxel 175mg/m2 or 135 mg/m2 (IV), and Cisplatin 50mg/m2 (IV) or Carboplatin area under the curve (AUC) 5; and Bevacizumab 15mg/kg (IV).

Interventions: intervention 1: Pembrolizumab intervention 2: Paclitaxel intervention 3: Cisplatin intervention 4: Carboplatin intervention 5: Bevacizumab
Intervention descriptions: intervention 1: IV intervention 2: Administered intravenously (IV) on day 1 intervention 3: Administered intravenously (IV) on day 1 intervention 4: Administered intravenously (IV) on day 1 intervention 5: Administered intravenously (IV) on day 1

Protocol document:
Prot_SAP_000.pdf: 
Page 1 of 85
eProst # 20170846
Phase II Single Arm Study of Combination Pembrolizumab, 
Chemotherapy and Bevacizumab in Patients with 
Recurrent, Persistent, or Metastatic Cervical Cancer
VERSION #
6.1
VERSION DATE
28/October/2022
PRINCIPAL INVESTIGATOR (PI):
Marilyn Huang, MD, MS
Division of Gynecologic Oncology
Confidentiality Statement:  The information contained in this document, especially 
unpublished data, is confidential property.  The information in this document may not be 
disclosed to others unless federal or state law or regulations require such disclosure.  Subject to 
the foregoing, this information may be disclosed only to those persons involved in the study who 
have a need to know with the obligation not to further disseminate this information.
   NCT03367871
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 2 of 85
CONTACT INFORMATION
Principal Investigator
Marilyn Huang, MD, MS
University of Miami (UM) / Sylvester Comprehensive 
Cancer Center (SCCC)
Miami, FL 33136
Telephone: 305-243-2233
Statistician
Isildinha M. Reis, PhD
Clinical Trial Management
Gynecologic Oncology Manager, Research Support
Clinical Research Services
University of Miami (UM) / Sylvester Comprehensive 
Cancer Center (SCCC)
Miami, FL 33136
Regulatory Sponsor
University of Miami (UM) / Sylvester Comprehensive 
Cancer Center (SCCC)
Miami, FL 33136
Funding Source
Merck Sharp & Dohme Corp.
Investigational Agent
Pembrolizumab – supplied by Merck; commercial supply
Other Agents
Paclitaxel – commercial supply
Cisplatin – commercial supply
Carboplatin – commercial supply
Bevacizumab – commercial supply
IND Status
Exempt
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version #: 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 3 of 85
INVESTIGATOR AGREEMENT
I confirm that I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practices, and the applicable federal, state, and local 
laws, rules, and regulations relating to the conduct of the protocol.
I have read and understand the information in the Investigators’ Brochure (and/or other such 
pertinent safety information) regarding the risks and potential benefits.
I agree to inform all those who assist/collaborate with me in the conduct of this study of their 
responsibilities and obligations.
Once the protocol has been reviewed and approved by the Institutional Review Board (IRB) I 
understand that any change(s) made during the course of the study must also (first) be approved 
by the IRB prior to implementation, except when such modification is made to remove any 
immediate hazard(s) to the subject(s).
I certify that I, and the study staff responsible, have received the requisite training to conduct this 
research protocol.
I agree to maintain adequate and accurate records in accordance with the University of Miami 
policies, federal, state and local laws and regulations.
I agree to maintain the confidentiality of all information received and/or developed in connection 
with this protocol.
eProst Number: 20170846
Protocol Version Number: 6.1
Protocol Version Date:
28/October/2022
Signature of Investigator:
Date:
Name of Investigator (printed):
Institution: University of 
Miami (UM) / Sylvester 
Comprehensive Cancer 
Center (SCCC)
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 4 of 85
TABLE OF CONTENTS
INVESTIGATOR AGREEMENT ..................................................................................................3
TABLE OF CONTENTS ................................................................................................................4
ABBREVIATIONS & DEFINITIONS ...........................................................................................8
PROTOCOL SYNOPSIS ................................................................................................................9
1.0 BACKGROUND AND RATIONALE....................................................................................14
1.1 Cervical Cancer....................................................................................................................14
1.2 Cancer Immune Surveillance...............................................................................................14
1.3 Anti-PD-1/PD-L1 Therapies (Pembrolizumab)...................................................................14
1.4 Rationale for Use of Pembrolizumab...................................................................................15
1.5 Rationale for Pembrolizumab Dose/Regimen Selection......................................................16
1.6 Rationale for Correlative Studies.........................................................................................16
2.0 OBJECTIVES AND ENDPOINTS.........................................................................................18
2.1 Primary Objective ................................................................................................................18
2.2 Secondary Objectives...........................................................................................................18
2.3 Exploratory Objectives ........................................................................................................18
2.4 Primary Endpoint .................................................................................................................18
2.5 Secondary Endpoints............................................................................................................18
2.6 Exploratory Endpoints .........................................................................................................18
3.0 SUBJECT RECRUITMENT & SCREENING .......................................................................20
3.1 Patient Selection...................................................................................................................20
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 5 of 85
3.2
Strategies for Recruitment and Retention .......................................................................22
4.0 STUDY DESIGN ....................................................................................................................24
5.0 TREATMENT PLAN..............................................................................................................25
5.1 Chemotherapy Discontinuation at the PI’s Discretion.........................................................25
5.2 Pembrolizumab ....................................................................................................................25
5.3 Paclitaxel..............................................................................................................................25
5.4 Cisplatin (or Carboplatin) ....................................................................................................25
5.5 Bevacizumab........................................................................................................................25
5.6 Concurrent Medications (as Applicable) .............................................................................26
5.7  Acceptable Medications......................................................................................................27
5.8 Prohibited Medications ........................................................................................................27
5.9 Duration of Treatment..........................................................................................................27
5.10 Duration of Follow-Up.......................................................................................................27
6.0 TREATMENT/DOSE MODIFICATIONS.............................................................................29
6.1 Assessment for Causality.....................................................................................................29
6.2 General Procedure for Supportive Care...............................................................................29
6.3 Dose Interruptions and Supportive Care Guidelines for AEs associated with 
Pembrolizumab ..........................................................................................................................29
6.4 Paclitaxel (Taxol®), Cisplatin (Carboplatin), and Bevacizumab ........................................37
7.0 TREATMENT DISCONTINUATION................................................................................40
8.0 SCHEDULE OF CLINICAL & LABORATORY EVALUATIONS.....................................41
8.1 Pre-Treatment Evaluations (Screening)...............................................................................41
8.2 Evaluations on Treatment ....................................................................................................42
8.3 All Cycles*, Day 1 (±3 days)...............................................................................................42
8.4 Safety Evaluation Visit ........................................................................................................43
8.5 Follow-up Evaluations .........................................................................................................43
8.6 Calendar of Clinical and Laboratory Evaluations................................................................44
9.0 SCHEDULE OF CORRELATIVE EVALUATIONS ............................................................46
9.1 Pre-Treatment Specimen Collection ....................................................................................46
9.2 All Cycles, Day 1.................................................................................................................46
9.3 Off Treatment Specimen Collection ....................................................................................46
10.0 AGENTS (DRUG FORMULATION AND PROCUREMENT)..........................................47
10.1 Pembrolizumab ..................................................................................................................47
11.0 MEASUREMENT OF EFFECT ...........................................................................................48
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 6 of 85
11.1 RECIST Guidelines ...........................................................................................................48
11.2 Antitumor Effect – Solid Tumors ......................................................................................48
12.0 ADVERSE EVENTS.............................................................................................................55
12.1 Purpose...............................................................................................................................55
12.2 Adverse Event....................................................................................................................55
12.3 Serious Adverse Events (see also Appendix A).................................................................56
12.4 Adverse Event Collection Period.......................................................................................56
12.5 Adverse Event Reporting Requirements............................................................................57
12.6 Expedited Adverse Event Reporting Requirements...........................................................57
12.7 Events of Clinical Interest..................................................................................................58
13.0 STATISTICAL CONSIDERATIONS ..................................................................................59
13.1 Planned Statistical Analysis...............................................................................................59
13.2 Sample Size Justification ...................................................................................................59
13.3 Stopping Rules ...................................................................................................................60
14.0 DATA REPORTING, MONITORING, AND AUDITING..................................................62
14.1
Data and Safety Monitoring............................................................................................62
14.2
Study Auditing and Monitoring ......................................................................................62
15.0 INVESTIGATOR RESPONSIBILITIES..............................................................................62
15.1 Investigator Responsibility/Performance...........................................................................62
15.2 Confidentiality ...................................................................................................................62
15.3 Informed Consent and Permission to Use Protected Health Information..........................62
15.4 Source Documentation and Investigator Files ...................................................................63
15.5 Recording and Processing of Data.....................................................................................63
15.6 Non-Protocol Research ......................................................................................................63
15.7 Ethics..................................................................................................................................63
REFERENCES ..............................................................................................................................64
APPENDIX A:  EXPEDITED ADVERSE EVENT (AE) REPORTING REQUIREMENTS.....67
APPENDIX B: PERFORMANCE STATUS SCALES ................................................................70
APPENDIX C: NYHA CLASSIFICATION OF HEART DISEASE...........................................71
APPENDIX D: BIOMARKER, CORRELATIVE AND SPECIAL STUDIES ...........................72
APPENDIX E: CYP1A2, CYP2C8, CYP2C19, CYP3A4 SUBSTRATES, INHIBITORS & 
INDUCERS * ................................................................................................................................79
APPENDIX F: PROTOCOL-APPROVED METHODS OF CONTRACEPTION......................82
Table 1:  Treatment Schema.......................................................................................................26
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 7 of 85
Table 2:  Pembrolizumab:  Supportive Care Guidelines for Immune-Mediated Drug-
Related Adverse Events...............................................................................................................33
Table 3:  Dose Reduction Sequence for Paclitaxel at 175 mg/m2 Cisplatin or Carboplatin.37
Table 4:  Dose Reduction Sequence for Paclitaxel at 135 mg/m2 Cisplatin and Carboplatin
.......................................................................................................................................................37
Table 5:  Treatment Modifications and Management of Toxicities for Paclitaxel and 
Cisplatin........................................................................................................................................37
Table 6:  Calendar of Clinical and Laboratory Evaluations ...................................................44
Table 7:  Response Criteria (Target Lesions) ...........................................................................52
Table 8:  Response Criteria (Non-Target Lesions)...................................................................52
Table 9:  Best Overall Response - Measurable Disease............................................................52
Table 10:  Best Overall Response - Non-measurable Disease..................................................53
Table 11.  Stopping Boundaries for Toxicity.............................................................................61
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 8 of 85
ABBREVIATIONS & DEFINITIONS
Term
Abbreviation
Definition
Overall Survival
OS
The length of time from start of treatment until 
death due to any cause.
Progression-Free Survival
PFS
The length of time from the date of first dose of 
study treatment until date of disease progression 
or death due to any cause, whichever comes 
first.
Progressive Disease
PD
Cancer that is growing, spreading, or getting 
worse.
Objective Response Rate
ORR
The percentage of patients whose cancer shrinks 
or disappears after treatment (partial or 
complete response).
Stable Disease
SD
Cancer that is neither decreasing nor increasing 
in extent or severity.
Reference: National Cancer Institute (NCI) Dictionary of Cancer Terms 
http://www.cancer.gov/dictionary 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 9 of 85
PROTOCOL SYNOPSIS
Protocol 
Title
Phase II Single Arm Study of Combination Pembrolizumab, 
Chemotherapy and Bevacizumab in Patients with Recurrent, 
Persistent, or Metastatic Cervical Cancer
Targeted 
Patient 
Population
Women with recurrent, persistent, or metastatic cervical cancer dispositioned 
to receive combination chemotherapy.
Study Design
This is a single arm, two-stage, open-label, phase II study to assess objective 
response to treatment with Pembrolizumab, chemotherapy, and Bevacizumab 
in patients diagnosed with recurrent, persistent, or metastatic cervical cancer. 
Treatment 
Schema
Eligible patients will require tissue for diagnostic confirmation of metastatic 
disease, disease recurrence or persistence.  Patients will be treated with 3 
cycles of combination therapy – 1) Pembrolizumab, 2) Paclitaxel, 3) 
Cisplatin OR Carboplatin, and 4) Bevacizumab – on Day 1 every 21 days. 
Duration of 
Treatment
Trial therapy may stop early due to withdrawal of consent or disease 
progression, and/or if other criteria for discontinuation is met (whichever 
occurs first).  Treatment is considered complete if imaging demonstrates 
complete resolution of disease.  See Section 9.4 for treatment discontinuation 
criteria.
Follow-up 
Required 
Post-
Treatment
All patients will be followed for a Safety Evaluation at approximately 30-
days (+/-7 days) after study discontinuation.  Thereafter, patients will be 
followed for survival only. 
Objectives
Primary Objective
To determine the objective response rate (ORR) (partial or complete 
response) of patients treated with combination Pembrolizumab, 
chemotherapy, and Bevacizumab.
Secondary Objectives

To determine progression-free survival (PFS)

To determine overall survival (OS)

To determine the safety and tolerability of Pembrolizumab in 
combination with chemotherapy and Bevacizumab
Exploratory Objectives

To determine if an immunologic profile will be useful as a predictive 
biomarker of treatment response and PFS

To perform exploratory translational studies on tissue biopsies at the time 
of recurrence, persistence, or metastatic disease compared to post-
treatment samples
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 10 of 85
Expected 
Number of 
Patients
40 total evaluable patients: (Refer to Section 13.0 Statistical Considerations.)
Expected 
Number of 
Centers
University of Miami (UM) / Sylvester Comprehensive Cancer Center 
(SCCC), including its satellite affiliates
Expected 
Duration of 
the Protocol
Estimated time for accrual is approximately 24 months; estimated duration 
of the total protocol is approximately 48 months. 
Inclusion 
Criteria
1. Patients must have histologically-confirmed recurrent, persistent or 
metastatic (primary stage IVB) squamous cell carcinoma, 
adenosquamous carcinoma or adenocarcinoma of the cervix that is not 
amenable to curative treatment with surgery and/or radiation therapy.
2. Patients must have measurable disease as defined by Response 
Evaluation Criteria In Solid Tumors (RECIST) 1.1.  
3. Patients must have recovered from effects of recent surgery, radiotherapy 
or chemoradiotherapy.
4. Patients should be free of active infections requiring antibiotics (with the 
exception of uncomplicated urinary tract infection).
5. Tissue from an archival sample or newly-obtained core or excisional 
biopsy of a tumor lesion confirming diagnosis.
6. Age ≥ 18 years.
7. Life expectancy > 3 months.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 
or 1. See Appendix B: Performance Status Scales for more information.
9. Patients must have normal organ and marrow function as defined below:
SYSTEM
LABORATORY VALUE
Hematological
Absolute neutrophil 
count (ANC)
≥1,500 cells/mcL
Platelets
≥100,000 cells/mcL
Hemoglobin
≥8 g/dL or ≥5.6 mmol/L without transfusion 
or erythropoietin (EPO) dependency
Renal
Serum creatinine OR
Measured or calculateda 
creatinine clearance
(glomerular filtration 
rate [GFR] can also be 
used in place of 
creatinine or creatinine 
clearance [CrCl])
≤1.5 X upper limit of normal (ULN) 
OR
≥60 mL/min for subject with creatinine levels 
> 1.5 X institutional ULN
Hepatic
Serum total bilirubin
≤ 1.5 X ULN 
OR
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 11 of 85
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN
Aspartate 
aminotransferase (AST; 
serum glutamic-
oxaloacetic transaminase 
[SGOT]) and alanine 
transaminase (ALT; 
serum glutamic-pyruvic 
transaminase [SGPT])
≤ 2.5 X ULN  
OR
≤ 5 X ULN for subjects with liver metastases
Albumin
>2.5 mg/dL
Coagulation
International Normalized 
Ratio (INR) or 
Prothrombin Time (PT)
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy
OR
as long as PT or partial thromboplastin time 
(PTT) is within therapeutic range of intended 
use of anticoagulants
Activated Partial 
Thromboplastin Time 
(aPTT)
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy
OR
as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants
a Creatinine clearance should be calculated per institutional standard.
10. Negative urine or serum pregnancy test ≤72 hours (i.e., 3 days) prior to 
receiving the first dose of study medication if not surgically sterilized.  If 
the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.
11. Female subjects of childbearing potential (i.e., have not been surgically 
sterilized or have not been without menses for >1 year) should be willing 
to use 2 methods of birth control at the same time, be surgically sterile, or 
abstain from heterosexual activity for the course of the study and at least 
120 days after the last study dose.  See Appendix F: Protocol-Approved 
Methods of Contraception for further details.
12. Ability to understand and the willingness to sign a written informed 
consent document.
Exclusion 
Criteria
1. Patients with a history of other invasive malignancies, with the exception 
of non-melanoma skin cancer, are ineligible if there is any evidence of 
other malignancy being present within the last 5 years.
2. Patients who have had prior chemotherapy except when used 
concurrently with radiation therapy. 
3. Patients who have received prior radiotherapy to any portion of the 
abdominal cavity or pelvis other than for the treatment of cervical cancer 
within the last 5 years are excluded.  Prior radiation for localized cancer 
of the breast, head and neck, or skin is permitted provided that it was 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 12 of 85
completed more than 3 years prior to registration, and the patient remains 
free of recurrent or metastatic disease.
4. Patients with an ECOG performance status of 2, 3 or 4 (Appendix B).
5. Patients who have received prior therapy with an anti- programmed cell 
death 1 (PD-1), anti-programmed cell death ligand 1 (PD-L1), or anti-
PD-L2 agent.
6. Patients with known active central nervous system (CNS) metastases 
and/or carcinomatous meningitis.  
7. Patients with known history of human immunodeficiency virus (HIV) or 
active bacillus tuberculosis (TB).
8. Known psychiatric or substance abuse disorders that would interfere with 
cooperation with requirements of the study.
9. Has active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e., with use of disease modifying agents, 
corticosteroids or immunosuppressive drugs).  Replacement therapy (i.e., 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for 
adrenal or pituitary insufficiency, etc.) is not considered a form of 
systemic treatment.
10. History of non-infectious pneumonitis that required steroids, evidence of 
interstitial lung disease or active, non-infectious pneumonitis, or history 
of pneumonitis requiring treatment.
11. Is pregnant, breastfeeding or expecting to conceive within the projected 
duration of the study, starting with the pre-screening or screening visit 
through 120 days after the last dose of study treatment.
12. Has a known history of Hepatitis B (defined as Hepatitis B surface 
antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as 
HCV RNA [qualitative] is detected) infection.  Note:  no testing for 
Hepatitis B and Hepatitis C is required unless mandated by local health 
authority.
13. Received live vaccine within 30 days prior to the first dose of study 
treatment.  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.
14. Patient with known hypersensitivity to Pembrolizumab or any of its 
excipients (active ingredients).
15. Patient receiving concurrent additional biologic therapy.
16. Patients who are adults and unable to consent, who are not yet adults, 
pregnant and nursing women, and prisoners are ineligible.
17. Has an active infection requiring systemic therapy.
18. Thromboembolism (either arterial or venous) within 6 weeks of initiation 
of treatment. 
19. Has significant cardiovascular disease, such as New York Heart 
Association (NYHA) cardiac disease classification of Class II or greater 
(See Appendix C: NYHA Classification of Heart Disease for more 
information), myocardial infarction, or cerebrovascular accident within 3 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 13 of 85
months prior to initiation of study treatment, unstable arrhythmias, or 
unstable angina.  Patients with known coronary artery disease, congestive 
heart failure not meeting the above criteria, or left ventricular ejection 
fraction <50% must be on a stable medical regimen that is optimized in 
the opinion of the treating physician in consultation with a cardiologist if 
appropriate.
20. Has undergone major surgical procedure within 28 days prior to first 
Bevacizumab dose or anticipation of the need for a major surgical 
procedure during the course of the study. 
21. Has proteinuria, as demonstrated by urine dipstick or >2.0 g of protein in 
a urine protein-to-creatinine ratio and/or 24 hr urine collection.  All 
patients with ≥2+ protein on dipstick urinalysis at baseline must undergo 
a urine-to-protein ratio and/or 24 hr urine collection and demonstrate 
<2.0 g of protein. 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 14 of 85
1.0 BACKGROUND AND RATIONALE
1.1 Cervical Cancer
Cervical cancer is the third most common gynecologic malignancy with nearly 12,990 new cases 
and 4,120 deaths in the United States (US) in 20161.  Women with recurrent or persistent cervical 
cancer after platinum-based chemoradiation as well as women that present with metastatic (stage 
IVB) cervical cancer have few options with a 5-year overall survival rate of 5-10% 6-7.  This cohort 
accounts for the large majority of cervical cancer deaths.  As a result, there remains an urgent need 
to identify novel agents and/or combination regimens to improve survival in women with 
recurrent, persistent or metastatic cervical cancer.  In 2014, results from Gynecologic Oncology 
Group (GOG) 240, a phase III trial evaluating the effectiveness of Bevacizumab with Paclitaxel 
and either platinum or a non-platinum agent in women with recurrent, persistent or metastatic 
cervical cancer, were published.  The combination therapy yielded a response rate of 48% 
compared to 36% (relative probability of a response, 1.35; 95% confidence interval (CI), 1.08 to 
1.68; p=0.008) and a median progression-free survival (PFS) of 8.2 months compared to 5.9 
months in patients treated with chemotherapy alone (p=0.002).  The authors found the addition of 
Bevacizumab to doublet chemotherapy was associated with a 3.7-month improvement in median 
overall survival (OS).  The results from this trial represent the current standard of care for this 
population8.  Despite this, the OS in this cohort of women remains dismal at approximately 17 
months.  The poor survival outcomes of this patient population represent a large unmet need for 
active treatments for cervical cancer in the US as well as globally, particularly in developing 
countries.  
1.2 Cancer Immune Surveillance
The programmed death-1 (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, is to down modulate unwanted or excessive immune responses, including 
autoimmune reactions12.  PD-1 (encoded by the gene PDCD1) is an Ig superfamily member related 
to CD28 and cytologic T-lymphocyte antigen (CTLA-4), which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD L2)13.  
Cytotoxic T-lymphocyte antigen (CTLA-4) and PD-1 normally function to counteract T-cell 
activation to self-antigens12,14. 
In normal healthy individuals, PD-L1 expression is low (i.e., little, if any) while in a variety of 
cancers, it is richly expressed.  Tumors can exploit this pathway to escape antitumor 
immunosurveillance16-17.  Blocking the PD-1/PD-L1 pathway may reduce the development of 
cervical tumor immune evasion and is an attractive target for therapeutic intervention especially 
in combination with standard lines of treatment18-19. 
1.3 Anti-PD-1/PD-L1 Therapies (Pembrolizumab)
Pembrolizumab 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.  Pembrolizumab can be administered intravenously and is approved in the United 
States for many oncology indications both as monotherapy and in combination therapy. Please 
refer to the Investigator Brochure for study details and results20. 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 15 of 85
1.3.1 Clinical Experience
Early data from a phase IB study of Pembrolizumab in patients with HPV positive and negative 
head and neck cancers have been presented at the American Society of Clinical Oncology (ASCO) 
2014 conference.  The authors screened 104 head and neck cancer patients and found that 78% of 
the 61 patients enrolled had PD-L1 positive tumors.  In this cohort, there were 23 HPV-positive 
and 37 HPV-negative cases.  Interestingly, the ORR was similar in HPV-positive and HPV-
negative patients, but the PFS and OS were longer in HPV-positive patients.  PD-L1 expression 
was positively correlated with ORR (p=0.018) and PFS (p=0.024)21. Further, other pharmaceutical 
companies are actively investigating immunotherapy options including vaccine development in 
HPV associated cervical cancers (AstraZeneca and Advaxis). 
KEYNOTE-028 is a Phase IB, multi-cohort study of Pembrolizumab in advanced solid tumors.  In 
this study, Pembrolizumab demonstrated antitumor activity and durability in a heavily pretreated 
cancer cohort with a manageable safety and toxicity profile.  The study demonstrated durable 
tumor regression (ORR) and prolonged stabilization of disease in advanced cancers.  Responses 
lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up22. 
In study KN158, which was used to support Pembrolizumab approval for treatment of cervical 
cancer in the US, 77 participants with cervical cancer that was previously treated with one or more 
prior lines of chemotherapy with PD-L1 expression CPS ≥1 had an ORR of 14% (CI: 7, 24) on a 
regimen of Pembrolizumab.  Of these patients, 2.6% had a complete response (CR) and 11.7% had 
a partial response (PR).  The response to Pembrolizumab treatment varied based on the findings 
that a median duration of response was never determined, the longest duration of participant 
response reported was over 18 months while the shortest duration was 4.1 months, and 80% of the 
cohort had a response duration beyond 12 months.  The median time to response was 2.2 months, 
the median PFS was 2.1 months, and the 12-month OS was 47%.
1.3.2 Cisplatin/Paclitaxel plus Pembrolizumab
Safety data for the combination of Paclitaxel/Cisplatin and Pembrolizumab is available for 
multiple indications. Please refer to the Investigator Brochure for study details and results20.  
Furthermore, the safety of this agent in combination with a platinum and taxane doublet has been 
previously demonstrated27.   
1.4 Rationale for Use of Pembrolizumab
Human papilloma virus (HPV) has long been shown to play an active role in the development of 
cervical cancer, particularly in individuals with persistent infections.  The causative role of HPV 
infection in cervical cancer is the rationale for immunotherapy9 since PD-L1 expression is 
enhanced in cervical neoplasia and cancer24.  Therefore, it is theorized that blocking the PD-L1 
receptor, PD-1, will subsequently restore the anti-tumor immune responses evoked by HPV 
infection.  Encouragingly, this hypothesis has been supported in other tumor types, particularly in 
melanoma25.  Tumor cell killing by cytotoxic chemotherapy expose the immune system to high 
levels of tumor antigens.  Invigorating tumor-specific T-cell immunity in this setting by inhibiting 
PD-L1/PD-1 signaling may result in deeper and more durable responses compared with standard 
chemotherapy alone. 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 16 of 85
Combining immunotherapy with cytotoxic chemotherapy historically was not accepted due to a 
perceived incompatibility with immune-suppressive chemotherapy.  Evidence from clinical 
studies and general practice, however, suggests a synergy between these two modalities.  
1.5 Rationale for Pembrolizumab Dose/Regimen Selection
Based on the totality of data generated in the pembrolizumab development program, 200 mg 
Q3W is the appropriate dose of Pembrolizumab for adults across all indications and regardless of 
tumor type.20  As outlined below, this dose is justified by:
• Consistency in pharmacokinetics (PK) across tumor types.
• Clinical data from 8 randomized studies in melanoma and non-small cell lung cancer (NSCLC) 
indications demonstrating flat dose and exposure (or dose) and efficacy or safety relationships 
within the dose range of 2 mg/kg Q3W to 10 mg/kg Q2W representing an approximate 5- to 7.5-
fold exposure range.
• Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of exposures, 
supporting suitability of fixed dose of 200 mg Q3W [refer to the Investigator’s Brochure].
• Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg Q3W 
across multiple indications.
• Pharmacology data showing full target saturation in both systemic circulation (inferred from 
PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W.
Based on this body of work, we have selected a fixed dose of 200 mg Pembrolizumab to be 
administered Q3W in combination with standard chemotherapy and Bevacizumab.  A fixed dose 
regimen will simplify the dosing regimen to be more convenient for physicians and to reduce 
potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the logistical 
chain at treatment facilities and reduce wastage. 
1.6 Rationale for Correlative Studies
Although the immune system is suspected to play a role in tumor development and recurrence, the 
specific mediators of immune surveillance and suppression of tumor growth are largely unknown.  
Additionally, we have learned from analysis of patients treated thus far with PD-1-directed therapy 
that biomarkers of response to immunotherapy are extremely complex.  Although PD-L1 
expression in tumor cells and the presence of lymphocyte infiltration with PD-1/PD-L1 expression 
seem to be the best predictors of response, 10-15% of patients without tumor PD-L1 expression 
have responded to therapy, suggesting that other immunomodulatory factors must be playing a 
role.  In addition to CTLA4 expression, other negative regulatory receptors have also been 
implicated, including LAG-3 and TIM-3, with pre-clinical blockade of some of these pathways 
resulting in improved anti-tumor response.15,16 Finally, the presence of myeloid-derived suppressor 
cells (MDSCs) and regulatory T-cells have been shown to negatively impact response to therapy 
in many cancers, though these are also understudied in sarcomas.31-35 
A translational component will aim to evaluate the tumor immune microenvironment and to further 
explore an immunologic profile that may be a predictive biomarker of treatment response and PFS.  
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 17 of 85
We will assess intra-tumoral variations in perforin+, CD+ T lymphocytes, FOXP3 expression, 
expression of PD-L1 and PD-L2, and a broad immune gene expression analysis (based on an anti-
tumor immune effector gene signature).  We will aim to perform molecular analysis on tumor 
specimens pre- and post-treatment based on tissue availability.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version #: 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 18 of 85
2.0 OBJECTIVES AND ENDPOINTS
2.1 Primary Objective
To determine the objective response rate (ORR) (partial or complete response) of patients treated 
with combination Pembrolizumab, chemotherapy and Bevacizumab.
2.2 Secondary Objectives

To determine PFS. 

To determine OS.

To determine the safety and tolerability of Pembrolizumab in combination with 
chemotherapy and Bevacizumab.
 
2.3 Exploratory Objectives

To determine if a specific immunologic profile will be a useful biomarker of treatment 
response and PFS.

To perform exploratory translational studies on biopsies at the time of recurrence, 
persistence, or metastatic disease compared to post-treatment samples.
2.4 Primary Endpoint
The primary endpoint is the objective response rate (ORR), defined as the proportion of patients 
with partial or complete response.  Patients will be evaluated for response during treatment and 
at follow-up assessments post-treatment (Section 10). 
2.4.1 Evaluable for ORR
Eligible patients who receive at least one dose of Pembrolizumab in combination with 
chemotherapy and Bevacizumab.
2.5 Secondary Endpoints

Progression-free survival (PFS):  the time from start of treatment until documented disease 
progression or death (by any cause in the absence of progression).  In alive, progression-free 
patients, PFS will be censored at the last evaluable tumor assessment.

Overall survival (OS):  the time from start of treatment until death due to any cause.

Treatment-related adverse events (AEs), including serious adverse events (SAEs) will be 
evaluated with respect to grade and relationship to treatment.  AEs will be assessed using the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
Version 4.03.
2.5.1 Evaluable for PFS, OS, and Adverse Events
Eligible patients who receive at least one dose of Pembrolizumab in combination with 
chemotherapy and Bevacizumab.
2.6 Exploratory Endpoints
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 19 of 85

To determine if a specific immunologic profile will be a useful biomarker in predicting 
response.  For example, PD-L1 immunohistochemistry.  These are exploratory analyses and 
as such cannot be precisely defined. 
2.6.1 Evaluable for Exploratory Endpoints

Eligible patients who receive at least one dose of Pembrolizumab in combination with 
chemotherapy and Bevacizumab will undergo blood sample collection and have a pre-
treatment tumor biopsy and at least one post-treatment tumor biopsy. 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 20 of 85
3.0 SUBJECT RECRUITMENT & SCREENING
3.1 Patient Selection
3.1.1 Inclusion Criteria
1. Patients must have histologically-confirmed recurrent, persistent or metastatic (primary stage 
IVB) squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma of the cervix 
that is not amenable to curative treatment with surgery and/or radiation therapy.
2. Patients must have measurable disease as defined by Response Evaluation Criteria In Solid 
Tumors (RECIST) 1.1.  
3. Patients must have recovered from effects of recent surgery, radiotherapy or 
chemoradiotherapy.
4. Patients should be free of active infections requiring antibiotics (with the exception of 
uncomplicated urinary tract infection).
5. Tissue from an archival sample or newly obtained core or excisional biopsy of a tumor lesion 
confirming diagnosis.
6. Age ≥ 18 years.
7. Life expectancy > 3 months.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. See Appendix 
B: Performance Status Scales for more information.
9. Patients must have normal organ and marrow function as defined below:
SYSTEM
LABORATORY VALUE
Hematological
Absolute neutrophil count 
(ANC)
≥1,500 cells/mcL
Platelets
≥100,000 cells/mcL
Hemoglobin
≥8 g/dL or ≥5.6 mmol/L without transfusion or 
erythropoietin (EPO) dependency
Renal
Serum creatinine OR
Measured or calculateda 
creatinine clearance
(glomerular filtration rate 
(GFR) can also be used in place 
of creatinine or creatinine 
clearance [CrCl])
≤1.5 X upper limit of normal (ULN) 
OR
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN
Hepatic
Serum total bilirubin
≤ 1.5 X ULN 
OR
Direct bilirubin ≤ ULN for subjects with total bilirubin 
levels > 1.5 ULN
Aspartate aminotransferase 
(AST; serum glutamic-
oxaloacetic transaminase 
≤ 2.5 X ULN  
OR
≤ 5 X ULN for subjects with liver metastases
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 21 of 85
[SGOT]) and alanine 
transaminase (ALT; serum 
glutamic-pyruvic 
transaminase[SGPT])
Albumin
>2.5mg/dL
Coagulation
International Normalized Ratio 
(INR) or Prothrombin Time 
(PT)
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy
OR
as long as PT or partial thromboplastin time (PTT) is 
within therapeutic range of intended use of 
anticoagulants
Activated Partial 
Thromboplastin Time (aPTT)
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy
OR
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
10. Negative urine or serum pregnancy test ≤72 hours (i.e., 3 days) prior to receiving the first 
dose of study medication if not surgically sterilized.  If the urine test is positive or cannot 
be confirmed as negative, a serum pregnancy test will be required.
11. Female subjects of childbearing potential (i.e., have not been surgically sterilized or have 
not been without menses for >1 year) should be willing to use 2 methods of birth control 
at the same time, be surgically sterile, or abstain from heterosexual activity for the course 
of the study and at least 120 days after the last study dose.  See Appendix F: Protocol-
Approved Methods of Contraception for further details.
12. Ability to understand and the willingness to sign a written informed consent document.
3.1.2 Exclusion Criteria
1. Patients with a history of other invasive malignancies, with the exception of non-melanoma 
skin cancer, are ineligible if there is any evidence of other malignancy being present within 
the last 5 years.
2. Patients who have had prior chemotherapy except when used concurrently with radiation 
therapy. 
3. Patients who have received prior radiotherapy to any portion of the abdominal cavity or 
pelvis other than for the treatment of cervical cancer within the last 5 years are excluded.  
Prior radiation for localized cancer of the breast, head and neck, or skin is permitted provided 
that it was completed more than 3 years prior to registration, and the patient remains free of 
recurrent or metastatic disease.
4. Patients with an ECOG performance status of 2, 3 or 4 (Appendix B).
5. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
6. Patients with known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  
7. Patients with a known history of human immunodeficiency virus (HIV) or active bacillus 
tuberculosis (TB).
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 22 of 85
8. Known psychiatric or substance abuse disorders that would interfere with cooperation with 
requirements of the study
9. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).  
Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.
10. History of non-infectious pneumonitis that required steroids, evidence of interstitial lung 
disease or active, non-infectious pneumonitis, or history of pneumonitis requiring treatment.
11. Is pregnant, breastfeeding or expecting to conceive within the projected duration of the study, 
starting with the pre-screening or screening visit through 120 days after the last dose of study 
treatment.
12. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) 
infection.  Note:  no testing for Hepatitis B and Hepatitis C is required unless mandated by 
local health authority.
13. Received live vaccine within 30 days prior to the first dose of study treatment.  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.
14. Patient with known hypersensitivity to Pembrolizumab or any of its excipients (active 
ingredients).
15. Patient receiving concurrent additional biologic therapy.
16. Patients who are adults and unable to consent, who are not yet adults, pregnant and nursing 
women, and prisoners are ineligible.
17. Has an active infection requiring systemic therapy.
18. Thromboembolism (either arterial or venous) within 6 weeks of initiation of treatment. 
19. Has significant cardiovascular disease, such as New York Heart Association cardiac disease 
classification of Class II or greater (See Appendix C: NYHA Classification of Heart Disease 
for more information), myocardial infarction, or cerebrovascular accident within 3 months 
prior to initiation of study treatment, unstable arrhythmias, or unstable angina.  Patients with 
known coronary artery disease, congestive heart failure not meeting the above criteria, or left 
ventricular ejection fraction <50% must be on a stable medical regimen that is optimized in 
the opinion of the treating physician in consultation with a cardiologist if appropriate.
20. Has undergone major surgical procedure within 28 days prior to first Bevacizumab dose or 
anticipation of the need for a major surgical procedure during the course of the study. 
21. Has proteinuria, as demonstrated by urine dipstick or >2.0 g of protein in a urine protein-to-
creatinine ratio and/or 24 hr urine collection.  All patients with ≥2+ protein on dipstick 
urinalysis at baseline must undergo a urine-to-protein ratio and/or 24 hr urine collection and 
demonstrate <2.0 g of protein.
3.2
Strategies for Recruitment and Retention
Women of all races and ethnic groups are eligible for this trial.  Prospective subjects will be 
recruited at Sylvester Comprehensive Cancer Center (SCCC)/University of Miami Health 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 23 of 85
(UMH) inclusive of constituent satellite sites.  Informed consent forms (ICF) will be translated to 
Spanish and be available.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 24 of 85
4.0 STUDY DESIGN
This is a single arm, two-stage, open-label, phase II study to assess objective response to treatment 
with Pembrolizumab in combination with chemotherapy agents Paclitaxel, Cisplatin (or 
Carboplatin if previously received Cisplatin as radiosensitizing agent), and Bevacizumab for 
recurrent, persistent, or metastatic cervical cancer.  Objective response rate (ORR), PFS, and OS 
will be assessed in patients treated with this combination.
Eligible patients will require tissue biopsy for diagnostic confirmation of metastatic disease, 
disease recurrence or persistence. Patients will be treated with 3 cycles of combination therapy.  A 
cycle will consist of Pembrolizumab at 200 mg (intravenous [IV]), Paclitaxel 175 mg/m2 or 135 
mg/m2 (IV), Cisplatin 50 mg/m2 (or Carboplatin area under the concentration curve [AUC] 5) IV 
and Bevacizumab 15 mg/kg (IV) on Day 1 of a 21-day cycle.  This regimen will be followed by 
imaging to determine response to treatment at which time repeat biopsies will be obtained if 
measurable disease remains and is accessible (paired tissue samples).
If patients demonstrate at least stable disease, they will then receive additional cycles of 
chemotherapy and Bevacizumab plus Pembrolizumab given every 3 weeks with imaging obtained 
every 3 cycles until disease progression or complete resolution of disease.  Blood collection will 
be performed before and after Pembrolizumab treatment and at the end of study.
Forty subjects total, 25 in Stage 1 and an additional 15 in Stage 2, will be accrued and treated at 
University of Miami (UM)/SCCC, inclusive of its satellite sites, for approximately 24 months.  
Therapy will be administered until study completion, withdrawal of consent, disease progression 
and/or unacceptable toxicity, whichever occurs first.
All subjects will be followed for a Safety Evaluation at approximately 30 days (+/-7 days) after 
study discontinuation.  Post-treatment, patients will be followed for survival.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version #: 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 25 of 85
5.0 TREATMENT PLAN
5.1 Chemotherapy Discontinuation at the PI’s Discretion
If patient is deriving clinical benefit from treatment, Bevacizumab and pembrolizumab may be 
continued while chemotherapy is discontinued at the PI’s discretion following a discussion with 
the patient.  Election of withholding Bevacizumab may be made at the PI’s discretion based on 
the clinical scenario.  The rationale for this update in the treatment plan is supported by data 
from the Phase 3 Keynote 836 and GOG 240 studies.8 
5.2 Pembrolizumab
Pembrolizumab 200 mg flat dose shall be administered in the outpatient setting per standard of 
care.  For further information, please refer to the Investigator’s Brochure. 
5.3 Paclitaxel 
Paclitaxel will be administered based on the patient’s body surface area (BSA) in m2 according to 
the manufacturer guidelines and institutional policy.  Paclitaxel dose will be capped at a BSA of 
2.0m2.  Where Paclitaxel is to be administered, it is recommended that a preparative regimen be 
employed to reduce the risk associated with hypersensitivity reactions.  An example of this 
regimen is dexamethasone (either IV or oral), anti-histamine H1 (such as diphenhydramine) and 
anti-histamine H2 (such as cimetidine, ranitidine or famotidine).  
5.4 Cisplatin (or Carboplatin)
Cisplatin will be administered per standard of care and institutional practices.  Carboplatin may be 
administered if patient has previously received Cisplatin. 
Carboplatin dose will be calculated to reach a target area under the curve (AUC) of concentration 
x time according to the Calvert formula using an estimated Cockroft and Gault-calculated 
creatinine clearance to present the GFR.
Carboplatin dose (mg) = (Target AUC) x (GFR + 25)
For this protocol, GFR = CrCl (ml/min) = (140-age in years) x (ABW*) x (0.85) [female]/ (72 x 
serum creatinine mg/dL)
*ABW:  actual body weight:  In patients with an abnormally low serum creatinine due to reduced 
protein intake and/or low muscle mass, the creatinine clearance should be estimated using a 
minimum value of 0.7 mg/dL.
5.5 Bevacizumab
Bevacizumab will be prepared and administered as per institutional practices. 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 26 of 85
Table 1:  Treatment Schema
Agent
Premedication(s)*
Dose
Route
Schedule
Cycle 
Length
Pembrolizumab
Monitor for infusion 
reactions with 
hypersensitivity kit at 
bedside.
Grade 2 infusion 
reactions will be 
premedicated with 
diphenhydramine 50 mg 
IV and acetaminophen 
1,000 mg PO prior to 
subsequent infusions.
Diet:  Subjects should 
maintain a normal diet 
unless modifications are 
required to manage an 
AE such as diarrhea, 
nausea or vomiting.
200 mg
IV (prior to 
TC)
21 
days
Paclitaxel**
Dexamethasone, 
Diphenhydramine and 
Famotidine 30 minutes 
prior
175 
mg/m2
IV (before 
Cisplatin)
Cisplatin (or 
Carboplatin)
NK1R antagonist, 5-
HT3 receptor 
antagonist, 
dexamethasone +/-
olanzapine
50
mg/m2
(AUC 5)
IV (after 
Paclitaxel)
Day 1
of each 
cycle
Bevacizumab
15 
mg/kg
IV (after 
Cisplatin)
*Premedications are suggestions only; use institutional and investigator discretion.
** At the discretion of the treating physician, Paclitaxel 135 mg/m2 IV every (q) 21 days may be 
administered.
5.6 Concurrent Medications (as Applicable)
Because there is a potential for interaction of Paclitaxel with other concomitantly administered 
drugs through the cytochrome P450 system (Appendix E:  CYP1A2, CYP2C8, CYP2C19, 
CYP3A4 Substrates, Inhibitors, & Inducers), the case report form (CRF) must capture the 
concurrent use of all other drugs, over-the-counter (OTC) medications, or alternative therapies.  
The Principal Investigator (PI) should be alerted if the patient is taking any agent know to affect 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 27 of 85
or with the potential to affect selected CYP450 isoenzymes.  
5.7  Acceptable Medications
All treatments that the Investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the CRF including all prescription, 
OTC, herbal supplements, and IV medications and fluids.  If changes occur during the trial period, 
documentation of drug dosage, frequency, route, and date may also be included on the CRF.
All concomitant medications from  first dose of trial treatment and 30 days after the last dose of 
trial treatment should be recorded.  
5.8  Prohibited Medications
The Exclusion Criteria describes medications which are prohibited in this trial. See Section 3.1.2.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
5.9  Duration of Treatment
Trial therapy will last until completion (if complete response), withdrawal of consent, disease 
progression, unacceptable toxicity, study end and/or other criteria for treatment discontinuation 
is met, whichever occurs first. See Section 7.3 for treatment discontinuation criteria.
5.10  Duration of Follow-Up
All subjects will be followed after the last dose of trial treatment only for survival data.  
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version #: 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 28 of 85
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version #: 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 29 of 85
6.0  TREATMENT/DOSE MODIFICATIONS
6.1 Assessment for Causality
Causality for all adverse events will be evaluated for degree of attribution to Pembrolizumab.  See 
also Appendix A for Expedited AE Reporting Requirements.
6.2 
General Procedure for Supportive Care
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
Investigator.  Adverse events (AEs) associated with Pembrolizumab exposure may represent an 
immunologic etiology.  The AEs may occur shortly after the first dose or several months after the 
last dose of treatment.  The treatment guidelines are intended to be applied when the investigator 
determines the events to be related to Pembrolizumab.  Refer to Table 2: Supportive Care 
Guidelines.
6.3 Dose Interruptions and Supportive Care Guidelines for AEs associated with 
Pembrolizumab
6.3.1
Dose Modifications
No dose modification is recommended for Pembrolizumab.
6.3.2
Dose Interruptions
Dose interruptions of Pembrolizumab are permitted in the case of medical/surgical events or 
logistical reasons not related to study therapy (i.e., elective surgery, unrelated medical events, 
patient vacation, and/or holidays).  Patients should be placed back on study therapy within 3 weeks 
of the scheduled interruption, unless otherwise discussed with the PI.  The reason for interruption 
should be documented in the patient’s study record.
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of Pembrolizumab should be discontinued from study 
treatment.
6.3.3 Supportive Care Guidelines for AEs associated with Pembrolizumab
6.3.3.1 Immune-mediated adverse reactions
Immune-mediated adverse reactions, including severe and fatal cases, have occurred in patients 
receiving Pembrolizumab.  Immune-mediated adverse reactions can occur after discontinuation of 
treatment.  In clinical trials, most immune-mediated adverse reactions were reversible and 
managed with interruptions of Pembrolizumab, administration of corticosteroids and/or supportive 
care.  Immune-mediated adverse reactions affecting more than one body system can occur 
simultaneously.
For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology 
or exclude other causes.  Based on the severity of the adverse reaction, withhold Pembrolizumab 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 30 of 85
and consider administration of corticosteroids.  Upon improvement to Grade 1 or less, initiate 
corticosteroid taper and continue to taper over at least 1 month.  Based on limited data from clinical 
studies in patients whose immune-related adverse reactions could not be controlled with 
corticosteroid use, administration of other systemic immunosuppressants can be considered.  
Restart Pembrolizumab if the adverse reaction remains at Grade 1 or less following corticosteroid 
taper.  If another episode of a severe adverse reaction occurs, permanently discontinue 
Pembrolizumab.
Immune-mediated pneumonitis
Pneumonitis (including fatal cases) has been reported in patients receiving Pembrolizumab.  
Monitor patients for signs and symptoms of pneumonitis.  If pneumonitis is suspected, evaluate 
with radiographic imaging and exclude other causes.  Administer corticosteroids for Grade 2 or 
greater events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper), 
withhold Pembrolizumab for moderate (Grade 2) pneumonitis, and permanently discontinue 
Pembrolizumab for severe (Grade 3), life-threatening (Grade 4) or recurrent moderate (Grade 2) 
pneumonitis.
Immune-mediated colitis
Colitis has been reported in patients receiving Pembrolizumab.  Monitor patients for signs and 
symptoms of colitis and exclude other causes.  Administer corticosteroids for Grade 2 or greater 
events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper), withhold 
Pembrolizumab for moderate (Grade 2) or severe (Grade 3) colitis, and permanently discontinue 
Pembrolizumab for life-threatening (Grade 4) colitis.
Immune-mediated hepatitis
Hepatitis has been reported in patients receiving Pembrolizumab.  Monitor patients for changes in 
liver function (at the start of treatment, periodically during treatment and as indicated based on 
clinical evaluation) and symptoms of hepatitis and exclude other causes.  Administer 
corticosteroids (initial dose of 0.5-1 mg/kg/day [for Grade 2 events] and 1-2 mg/kg/day [for Grade 
3 or greater events] prednisone or equivalent followed by a taper) and, based on severity of liver 
enzyme elevations, withhold or discontinue Pembrolizumab.
Immune-mediated nephritis
Nephritis has been reported in patients receiving Pembrolizumab.  Monitor patients for changes in 
renal function and exclude other causes.  Administer corticosteroids for Grade 2 or greater events 
(initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper), withhold 
Pembrolizumab for moderate (Grade 2), and permanently discontinue Pembrolizumab for severe 
(Grade 3) or life-threatening (Grade 4) nephritis.
Immune-mediated endocrinopathies
Adrenal insufficiency (primary and secondary) has been reported in patients receiving 
Pembrolizumab.  Hypophysitis has also been reported in patients receiving Pembrolizumab.  
Monitor patients for signs and symptoms of adrenal insufficiency and hypophysitis (including 
hypopituitarism) and exclude other causes.  Administer corticosteroids to treat adrenal 
insufficiency and other hormone replacement as clinically indicated, withhold Pembrolizumab for 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 31 of 85
moderate (Grade 2), withhold or discontinue Pembrolizumab for severe (Grade 3) or life-
threatening (Grade 4) adrenal insufficiency or hypophysitis.
Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients receiving 
Pembrolizumab.  Monitor patients for hyperglycemia or other signs and symptoms of diabetes.  
Administer insulin for type 1 diabetes, and withhold Pembrolizumab in cases of severe 
hyperglycemia until metabolic control is achieved.
Thyroid disorders, including hyperthyroidism, hypothyroidism and thyroiditis, have been reported 
in patients receiving Pembrolizumab and can occur at any time during treatment; therefore, 
monitor patients for changes in thyroid function (at the start of treatment, periodically during 
treatment and as indicated based on clinical evaluation) and clinical signs and symptoms of thyroid 
disorders.  Hypothyroidism may be managed with replacement therapy without treatment 
interruption and without corticosteroids.  Hyperthyroidism may be managed symptomatically.  
Withhold or discontinue Pembrolizumab for severe (Grade 3) or life-threatening (Grade 4) 
hyperthyroidism.
For patients with severe (Grade 3) or life-threatening (Grade 4) endocrinopathy that improves to 
Grade 2 or lower and is controlled with hormone replacement, continuation of Pembrolizumab 
may be considered.
Severe skin reactions
Immune-mediated severe skin reactions have been reported in patients treated with 
Pembrolizumab.  Monitor patients for suspected severe skin reactions and exclude other causes. 
Based on the severity of the adverse reaction, withhold or permanently discontinue Pembrolizumab 
and administer corticosteroids.
Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with fatal 
outcome, have been reported in patients treated with Pembrolizumab.  For signs or symptoms of 
SJS or TEN, withhold Pembrolizumab and refer the patient for specialized care for assessment and 
treatment.  If SJS or TEN is confirmed, permanently discontinue Pembrolizumab.
Other immune-mediated adverse reactions
The following additional clinically significant, immune-mediated adverse reactions were reported 
in less than 1% of patients treated with Pembrolizumab in KEYNOTE-001, KEYNOTE-002, 
KEYNOTE-006, and KEYNOTE-010:  uveitis, myositis, Guillain-Barré syndrome, pancreatitis, 
encephalitis, sarcoidosis, myasthenic syndrome/myasthenia gravis (including exacerbation), 
myelitis, and vasculitis.  The following were reported in other clinical studies with Pembrolizumab 
or in postmarketing use:  myocarditis and sclerosing cholangitis.
Cases of these immune-mediated adverse reactions, some of which were severe, have been 
reported in clinical trials or in postmarketing use.
Transplant-related adverse reactions
Solid organ transplant rejection has been reported in the postmarketing setting in patients treated 
with Pembrolizumab.  Treatment with Pembrolizumab may increase the risk of rejection in solid 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 32 of 85
organ transplant recipients.  Consider the benefit of treatment with Pembrolizumab versus the risk 
of possible organ rejection in these patients.
Acute graft-versus-host-disease (GVHD), including fatal GVHD, after treatment with 
Pembrolizumab has been reported in patients with a history of allogeneic hematopoietic stem cell 
transplant (HSCT).  Patients who experienced GVHD after their transplant procedure may be at 
increased risk for GVHD after treatment with Pembrolizumab.  Consider the benefit of treatment 
with Pembrolizumab versus the risk of possible GVHD in patients with a history of allogeneic 
HSCT.
6.3.3.2 Infusion-related reactions
Severe infusion reactions, including hypersensitivity and anaphylaxis, have been reported in 6 
(0.2%) of 2799 patients receiving Pembrolizumab in KEYNOTE-001, KEYNOTE-002, 
KEYNOTE-006, and KEYNOTE-010.  For severe infusion reactions, stop infusion and 
permanently discontinue Pembrolizumab.  Patients with mild or moderate infusion reaction may 
continue to receive Pembrolizumab with close monitoring; premedication with antipyretic and 
antihistamine may be considered.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version #: 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 33 of 85
Table 2:  Pembrolizumab:  Supportive Care Guidelines for Immune-Mediated Drug-Related Adverse Events
General instructions:
1. Based on the severity of the adverse reaction, withhold Pembrolizumab and consider administration of corticosteroids.  
Administration of other systemic immunosuppressants can be considered for patients whose immune-related adverse events 
(irAEs) are not controlled with corticosteroid use.
1. 2.  Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 1 month.  
Restart Pembrolizumab if the AE remains at Grade 1 or less following corticosteroid taper.  If another episode of a severe 
adverse reaction occurs, permanently discontinue Pembrolizumab.3.  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.
Immune-related 
AEs
Toxicity grade 
or conditions 
(CTCAE v4.03)
Action taken to 
Pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies
Monitor and follow-up
Severe Skin 
Reaction
Any
Withhold or 
permanently 
discontinue
Refer patient for 
specialized care for 
assessment and treatment.
If SJS or TEN confirmed, 
permanently discontinue 
Pembrolizumab.
Grade 2
Withhold 
Pneumonitis 
Grade 3 or 4 or 
recurrent Grade 2
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1-2 
mg/kg/day prednisone or 
equivalent) followed by 
taper.

Monitor participants for signs and 
symptoms of pneumonitis.

Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
exclude other causes.  Initiate 
corticosteroid treatment.
Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1-2 
mg/kg/day prednisone or 
equivalent) followed by 
taper.
Monitor participants for signs and 
symptoms of colitis (i.e., diarrhea, 
abdominal pain, blood or mucus in 
stool with or without fever) and 
exclude other causes.


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 34 of 85
Grade 4
Permanently 
discontinue
Grade 2
Withhold
Administer corticosteroids 
(initial dose of 0.5-
1mg/kg/day prednisone or 
equivalent) followed by 
taper.
Hepatitis
Grade 3 or 4
Withhold or 
permanently 
discontinue*
Administer corticosteroids 
(initial dose of 1-2 
mg/kg/day prednisone or 
equivalent) followed by 
taper.

Monitor patients for changes in 
liver function with liver function 
tests (at the start of treatment, 
periodically during treatment and 
as indicated based on clinical 
evaluation) and symptoms of 
hepatitis.  Exclude other causes 
for hepatitis.

Based on severity of liver 
enzyme elevations, withhold or 
discontinue Pembrolizumab.


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 35 of 85
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia**
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold until 
metabolic control 
is achieved.

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
Adrenal 
insufficiency and 
hypophysitis 
(including 
hypopituitarism)*
*
Grade 3 or 4
Withhold or 
permanently 
discontinue
Administer corticosteroids 
to treat adrenal 
insufficiency and other 
hormone replacement as 
clinically indicated.
Monitor patients for signs and 
symptoms of adrenal insufficiency 
and exclude other causes.
Grade 2
Continue 
Thyroid disorders 
(including 
hyperthyroidism, 
hypothyroidism, 
and thyroiditis)** 
Grade 3 or 4 
Withhold or 
permanently 
discontinue

Hypothyroidism may 
be managed with 
replacement therapy 
without treatment 
interruption and 
without corticosteroids.

Hyperthyroidism may 
be managed 
symptomatically.

Monitor for changes in thyroid 
function (at the start of treatment, 
periodically during treatment and 
as indicated based on clinical 
evaluation) and clinical signs and 
symptoms of thyroid disorders. 
Grade 2
Withhold 
Renal failure and 
immune-
mediated 
nephritis
Grade 3 or 4 
Permanently 
discontinue
Administer corticosteroids 
(prednisone 1-2mg/kg/day 
or equivalent) followed by 
taper.
Monitor changes of renal function 
and exclude other causes.
Grade 2
Withhold
Myocarditis
Grade 3 or 4
Permanently 
discontinue

For grade 2 immune-
mediated myocarditis, 
administer prednisone 
corticosteroid or 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes.


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 36 of 85
equivalent at an initial 
dose of 1-2 mg/kg/day 
followed by taper.

Permanently 
discontinue 
Pembrolizumab for 
grade 3 or 4 
myocarditis OR if 
toxicity does not 
resolve within 12 
weeks of start of grade 
2 toxicity or inability to 
reduce corticosteroid to 
10 mg or less of 
prednisone or 
equivalent per day 
within 12 weeks.
*For grade 3 liver toxicity with elevated AST and/or ALT.  Since HCC patients may have grade 1-2 elevation of AST/ALT at 
baseline, if these patients have Grade 3 elevation of AST/ALT, hold therapy and resume treatment when AST/ALT return to 
baseline or Grade ≤1.  The AST/ALT should return to baseline or < 5 x ULN within 12 weeks from start of grade 3; 
otherwise, patient should be discontinued from study.
**
For participants with Grade 3 (severe) or 4 (life-threatening) endocrinopathy that improves to Grade 2 or lower and is controlled 
with hormone replacement or achieved metabolic control (in case of T1DM), continuation of Pembrolizumab may be 
considered.


CONFIDENTIAL
Version #: 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 37 of 85
6.4 Paclitaxel (Taxol®), Cisplatin (Carboplatin), and Bevacizumab
6.4.1
Dose Modifications
Treatment modifications regarding Paclitaxel, Cisplatin (Carboplatin may be used if patient has 
had previous Cisplatin), and Bevacizumab will be employed in a sequential manner using cycle 
delay and dose reduction.
Table 3:  Dose Reduction Sequence for Paclitaxel at 175 mg/m2 Cisplatin or Carboplatin  
*First dose reduction Paclitaxel to 150 mg/m2 and/or Cisplatin to 40 mg/m2 and Bevacizumab to 
be held at the discretion of the treating Investigator.
Drug
Initial Dose
1st Reduction*
2nd Reduction
Units
Paclitaxel
175
150
135*
mg/m2
Cisplatin
50
40
40
mg/m2
Carboplatin
5
4
4
AUC
Bevacizumab
15
15
15
mg/kg
Table 4:  Dose Reduction Sequence for Paclitaxel at 135 mg/m2 Cisplatin and Carboplatin
*First dose reduction of Paclitaxel or Cisplatin/Carboplatin at the discretion of treating 
Investigator.  Bevacizumab to be held at discretion of treating Investigator
Drug
Initial Dose
1st Reduction*
2nd Reduction
Units
Paclitaxel
135
135
135*
mg/m2
Cisplatin
50
40
30
mg/m2
Carboplatin
5
4
4
AUC
Bevacizumab
15
10
10
mg/kg
The following are criteria for Cisplatin (Carboplatin), Paclitaxel and Bevacizumab treatment 
modifications and management of toxicities (in relation to Pembrolizumab):
Table 5:  Treatment Modifications and Management of Toxicities for Paclitaxel and Cisplatin
Worst toxicity (CTCAE Grade)**
Recommended Dose Modifications & Management of 
Toxicities
None
No Toxicity
Maintain dose level
Hematological
Neutropenia (ANC)
Grade 1 (ANC< LLN-1.5x109 
cells/L)
Grade 
2 
(ANC<1.5-1.0x109 
cells/L)
Hold treatment until ANC ≥ 1.5 x 109 cells/L.  May 
maintain dose level (i.e., no need to dose reduce or add G-
CSF at discretion of Investigator).
Grade 3 (ANC<1-0.5x109 cells/L)
Grade 4 (ANC<0.5x109 cells/L)
First occurrence:
Hold all treatment (chemotherapy & Pembrolizumab) 
until ANC ≥ 1.5 x 109 cells/L, give G-CSF.

If resolved in ≤7 days, then maintain dose level.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 38 of 85

If resolved in >7 days, then ↓1 dose level.
Second occurrence:
Hold all treatment (give G-CSF) until ANC ≥1.5x109 
cells/L, then ↓dose level.
Febrile neutropenia
(ANC< 1.0x109 cells/L, fever 
≥38.5 °C) or Grade 3/4 
neutropenia with documented 
infection
First occurrence:
Hold all treatment until resolved to ≤Grade 2 (give G-CSF), 
then:

If resolved in ≤7 days, then maintain dose level.

If resolved in >7 days, then ↓1 dose level.
Second occurrence:
Hold all treatment until resolved to ≤ Grade 2 (give G-CSF) 
then ↓ dose level or discontinue patient from study 
treatment at the Investigator’s discretion.
Thrombocytopenia
Grade 1 (Platelet [PLT]<LLN-
75x109 cells/L)
Grade 2 (PLT <75-50 x109 
cells/L)
Hold treatment until Platelets >100K. May maintain dose 
level.
Grade 3 (PLT<50-25 x109 cells/L)
First occurrence:
Hold all treatment until resolved to ≤Grade 1, then:

If resolved in ≤7 days, then maintain dose level.

If resolved in >7 days, then ↓1 dose level.
Second occurrence:
Hold all treatment until resolved to ≤ Grade 1, then ↓dose 
level.
Grade 4 (PLT<25x109 cells/L)
First occurrence:
Hold all treatment until resolved to ≤Grade 1, then ↓ 1 dose 
level. 
Second occurrence:
Hold all treatment until resolved to ≤ Grade 1, then ↓ dose 
level or discontinue patient from study treatment at the 
Investigator’s discretion.
Bilirubin
(For patients with Gilbert Syndrome:  these dose modifications apply to changes in direct 
bilirubin only)
Grade 1 (> ULN - 1.5 x ULN)
Maintain dose level
Grade 2 (> 1.5 - 3.0 x ULN) with 
ALT or AST ≤ 3.0 x ULN
Hold all treatment and monitor LFTs* weekly until 
resolved to ≤ Grade 1, then:

If resolved in ≤ 7 days, then maintain dose level.

If resolved in > 7 days, then  1 dose level. 
Grade 3 (> 3.0 - 10.0 x ULN) with 
ALT or AST ≤ 3.0 x ULN
Hold all treatment and monitor LFTs* weekly until 
resolved to ≤ Grade 1, then:

If resolved in ≤ 7 days,  1 dose level. 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 39 of 85

If resolved in  7 days, discontinue patient from study 
treatment**.
Continue to monitor LFTs* every other week or more 
frequently if clinically indicated until the end of treatment 
with study medication.
Grade 4 (> 10.0 x ULN)
Hold all treatment and discontinue patient from 
Pembrolizumab therapy**.
AST or ALT**
Grade 1 (> ULN - 3.0 x ULN)
Grade 2 (> 3.0 - 5.0 x ULN) if not 
increased 
from 
baseline 
and  
without bilirubin elevation to > 2.0 
x ULN
Maintain dose level
Grade 2 (> 3.0 - 5.0 x ULN) if 
increased 
from 
baseline 
and 
without bilirubin elevation to > 2.0 
x ULN
Hold all treatment and monitor LFTs* weekly until 
resolved to ≤ grade 1, then:

If resolved in ≤ 7 days, then maintain dose level.

If resolved in > 7 days, then ↓ 1 dose level. 
Grade 3 (> 5.0 - 20.0 x ULN) 
without bilirubin elevation to > 2.0 
x ULN
Hold all treatment and monitor LFTs* weekly until 
resolved to ≤ Grade 1 (or ≤ Grade 2 in case of liver 
metastasis), then:

If resolved in ≤ 7 days, then maintain dose level.

If resolved in > 7 days, then  1 dose level.
Continue to monitor LFTs* every other week or more 
frequently if clinically indicated until the end of 
treatment with study medication.
Grade 4 (> 20.0 x ULN) without 
bilirubin elevation to > 2.0 x ULN
Hold all treatment until resolved to ≤ grade 1, then ↓ 1 dose 
level. 
Drug-Induced Liver Injury
Patients with AST/ALT > 3 x ULN and total bilirubin > 2 x ULN with no evidence of obstruction 
(such as elevated ALP, malignancy, impaired glucuronidation (Gilbert syndrome) or 
pharmacologic factors) with no other explanation (e.g., viral, alcoholic or autoimmune hepatitis, 
hepatobiliary disorders, cardiovascular causes, concomitant medications) may have drug-
induced liver injury.
In such cases,

discontinue** the patient from Pembrolizumab (remove from study but may continue 
chemotherapy at discretion of PI) and report as SAE.
In any case,

monitor patient, including LFTs* weekly or more frequently if clinically indicated until 
resolved to ≤ grade 1 or stabilization.
* LFTs include: albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), 
AP (fractionated if AP is grade 2 or higher) and GGT).  For patients with Gilbert Syndrome:  
total and direct bilirubin must be monitored; intensified monitoring applies to changes in direct 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 40 of 85
bilirubin only.
** Patients who discontinue study treatment should be monitored weekly including LFTs or 
more frequently if clinically indicated until resolved to ≤ grade 1 or stabilization (no CTCAE 
grade change over 4 weeks).
Fatigue (Asthenia)
Grade 1 or 2
Maintain dose level
Grade 3
Hold all treatment until resolved to ≤ Grade 2, then:

If resolved in ≤ 7 days, maintain dose level.

If resolved in  7 days,  1 dose level. 
Grade 4
Hold all treatment and discontinue patient from 
Pembrolizumab (may continue chemotherapy at discretion 
of PI).
Peripheral Neuropathy
Grade 1 or 2
Maintain dose level.
Grade 3
Hold all treatment until resolved to ≤ Grade 2, then:

If resolved in ≤ 7 days, maintain dose level.

If resolved in  7 days,  1 dose level (Paclitaxel only).
Grade 4
Hold all treatment and discontinue patient from 
Pembrolizumab (may continue chemotherapy at discretion 
of PI).
**Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
22.
6.4.2
Dose Interruptions
Under certain conditions, a dose interruption of Carboplatin or Paclitaxel may be required.  
Should the dose interruption last for greater than 21 days, the patient should be discontinued 
from study treatment.  Further, if a patient does not tolerate the lowest possible dose, treatment 
with Pembrolizumab must be discontinued.
7.0 TREATMENT DISCONTINUATION
Treatment may be discontinued for any of the following reasons:

The patient demonstrates progression of disease.  Exception:  Patients may remain on the 
study if in the opinion of the Investigator, he/she is deriving clinical benefit from study 
treatment.

The patient (or legally authorized representative) withdraws consent from the study.

Study treatment for participant is past due for >28 days due to an AE (or other such toxicity).

The patient experiences an AE that in the opinion of the Investigator makes continued study 
treatment an unacceptable risk.

The patient becomes pregnant.

The patient requires continuous treatment with a prohibited concomitant drug(s) for which no 
safe alternatives can be substituted.

The patient is significantly noncompliant with the requirements of the protocol.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 41 of 85
Should discontinuation of study therapy occur, all efforts should be made to execute/report End-
of-Treatment and Follow-up Evaluations as completely as possible and to determine/document the 
reason for discontinuation (unless the patient withdraws consent for follow-up).
Although unexpected termination of study treatment may occur, it is possible the subject may still 
agree to survival data collection.  
If a patient wishes to withdraw consent from the study, the PI must be notified.  The information 
regarding withdrawal (i.e., subject identifiers and date of withdrawal) should be documented in 
the subject’s record and updated within any other research database(s).
8.0 SCHEDULE OF CLINICAL & LABORATORY EVALUATIONS
Prior to performing any study-specific procedures or evaluations, written informed consent and 
authorization for the use of protected health information (HIPAA) must be obtained in accordance 
with all applicable policies, regulations and laws.  Correlative evaluations must also be performed 
at specified visits for patients who consent to these activities.  Please refer to Section 10.0, 
Correlative Studies for specific details.
All evaluations should be completed as detailed below prior to the administration of trial treatment 
on Day 1 of each cycle.  All evaluations will be administered on an outpatient basis.
8.1 Pre-Treatment Evaluations (Screening)
The following must be collected/performed within 30 days prior to Cycle 1, Day 1 of treatment 
unless otherwise specified.  Clinical and laboratory evaluations performed as part of routine 
standard of care do not need to be repeated if performed within the appropriate window.

Informed Consent

Complete medical history, disease history and prior medical treatments

Concomitant Medications

Demographic data

Height

Weight

Vital signs (V/S)
o
Oral temperature
o
Blood pressure
o
Heart rate
o
Respiratory rate

Complete physical examination (PE)

ECOG Performance Status (PS) (See Appendix B)

12-Lead Electrocardiogram (ECG)

Urine or serum pregnancy test for women of child-bearing potential (WoCBP) ≤72 hours 
(i.e., 3 days) prior to Cycle 1, Day 1

Laboratory Evaluations:  (if within 7 days of treatment initiation, Cycle 1, Day 1, do not need 
to repeat)
o
Complete Blood Count (CBC) with differential (diff)
o
Coagulation studies:
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 42 of 85

Prothrombin Time (PT)/International Normalized Ratio (INR)

Activated partial thrombobplastin time (aPTT)
o
Comprehensive Serum Chemistry Panel

Triiodothyronine (T3)

Thyroxine (T4)

Thyroid-stimulating hormone (TSH)
o
Urinalysis (U/A)

IR-guided core biopsy, biopsy obtained by surgeon on exam (fresh tissue) or archival tissue 
(formalin-fixed paraffin-embedded; FFPE)

Correlative Studies (See Section 10.0: Schedule of Correlative Evaluations):  Blood samples

Imaging Studies:  Imaging studies for tumor assessment for all known sites of disease 
(including computed tomography (CT) or magnetic resonance imaging (MRI) of the 
abdomen or pelvis with contrast or positron-emission tomography (PET)-CT).  CT imaging 
is the preferred method, but where warranted, PET-CT is allowable.  Imaging method used at 
baseline for tumor assessment should be the same throughout the study.
*Unless laboratory tests obtained within 7 days during screening to start of Cycle 1, Day 1.
8.2  Evaluations on Treatment
Collection of Concomitant Medications and AEs should occur throughout the study as described.  
Any SAE or follow up to a SAE including death due to any cause other than progression of the 
cancer under study that occurs to any subject from the time the consent is signed through 90 days 
following end of treatment, or the initiation of new anti-cancer therapy, whichever is earlier, 
whether or not related to the Merck product, must be reported within 24 hours to the Sponsor and 
within 2 working days to Merck Global Safety.  All subjects with SAEs must be followed up for 
outcome.  (See Section 12.3 and Appendix A for details).
8.3 All Cycles*, Day 1 (±3 days)

Medical History

Physical Exam

Concomitant Medications

ECOG PS

V/S (temperature, blood pressure, heart rate, respiratory rate)

Weight

CBC with diff

Comprehensive Serum Chemistry Panel

Urine protein/creatinine ratio (every other cycle, C1, C3, C5, etc.)

T3

T4

TSH

Correlative Studies (Optional, See Section 10.0):  Blood collected before and after 
administration of Pembrolizumab; tissue samples collected after 3–4 cycles of treatment.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 43 of 85

Imaging studies for tumor assessment for all known sites of disease (including CT or MRI of 
abdomen or pelvis with contrast or PET CT).  CT imaging is the preferred method, but where 
warranted, PET-CT is allowable.  Imaging method used at baseline for tumor assessment 
should be the same throughout the study.  Imaging will only be obtained every 3-4 cycles to 
assess for response unless CR is achieved including confirmatory scan; then imaging 
thereafter may be obtained at Investigator’s discretion.

Administration of Study Agents (See Section 5.0: Treatment Plan).

AE reporting
8.4 Safety Evaluation Visit
The following safety assessments must be performed at 30 days (+/-7 days) after study 
discontinuation for all subjects.  These patients will then be followed for survival data only.

Medical History

Physical Exam

Concomitant Medications  

V/S

Weight

ECOG PS

CBC with diff

Coagulation studies (PT/INR, aPTT)

Comprehensive Serum Chemistry Panel

T3

T4

TSH

Correlative Studies (Optional, see Section 10.0): Blood

AE reporting.  Any SAE, or follow up to a SAE, including death due to any cause other than 
progression of the cancer under study that occurs to any subject from the time the consent is 
signed through 90 days following end of treatment or the initiation of new anti-cancer 
therapy, whichever is earlier, whether or not related to the Merck product, must be reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety.  All 
subjects with SAEs must be followed up for outcome.  (See Section 12.3 and Appendix A for 
details.)
8.5 Follow-up Evaluations
For all patients, follow up will be survival data only.  Data will be collected via standard of care 
visits or telephone call to patient or family member.  Imaging during follow-up will be at 
Investigator’s discretion.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version #: 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 44 of 85
8.6 Calendar of Clinical and Laboratory Evaluations
Table 6:  Calendar of Clinical and Laboratory Evaluations
Screening
Treatment Cycle(s) 
(q21 days)
Safety Evaluation K
Follow-UpL
≤30 days prior A
Day 1 
(±3 days unless specified)
30-days (+/-7 days) after 
study discontinuation
Informed Consent
X
Eligibility
X
Demographics B
X
History & Physical C
X
X
X
Height
X
Weight
X
X
X
Vital Signs D
X
X
X
ECOG PS
X
X
X
12-Lead ECG
X
CBC with diff
X*
X
X
Comp Serum Chemistry Panel
X*
X
X
T3, T4 and TSH
X*
X
X
PT/INR, aPTT
X*
X
Urine or serum pregnancy test E
X
Urinalysis, urine protein/creatinine 
ratio
X*
X+
Pembrolizumab IV
X
Paclitaxel IVF
X 
Cisplatin (Carboplatin) IVF
X
Bevacizumab IV
X
Core biopsy (fresh tissue sample if 
possible, will accept archival tissue 
[FFPE])
X
Correlative Studies: Tissue Sample 
G (fresh tissue sample, paired)
X 


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 45 of 85
Correlative Studies:  Blood H
X
X H
X H
Imaging I
X
X
X
Adverse Events J
X
Concomitant Medications
X
Post-Study Status M
X
A Screening evaluations should be done within 30 days prior unless otherwise specified.
*Screening labs must be done within 30 days of treatment initiation though if within 7 days of treatment initiation, Cycle 1 Day 1, they 
do not need to be repeated.
+ Urine protein/creatinine ratio should be obtained every other cycle (C1, C3, C5, etc.)
B Demographic data includes age, gender and racial/ethnic background.
C Complete Medical History includes disease history and prior medical treatments. 
D Vital signs include oral temperature, blood pressure, respiratory rate and heart rate.
E Urine or serum (beta-HCG) pregnancy test is required for women of childbearing potential within 72 hours (i.e., 3 days) prior to Cycle 
1, Day 1 of trial treatment.
F If patient is deriving clinical benefit from Bevacizumab and Pembrolizumab, chemotherapy may be discontinued at the PI’s discretion 
following a discussion with the patient.
G Tissue sample collection during Treatment (i.e., following 3–4 cycles) is optional for correlative studies (see Section 10.0 for details).
H Collection of serum for biomarkers will be obtained before and after Pembrolizumab treatment and at the end of the study.
I Imaging for tumor assessment for all known sites of disease (including CT, PET-CT or MRI of abdomen or pelvis with contrast):  
preferably with CT imaging for RECIST interpretation, but PET-CT is allowable.  Imaging method used at baseline for tumor assessment 
should be the same throughout the study.  Imaging will be done at baseline and after every 3-4 cycles. If CR attained with follow up 
confirmation, further imaging may be obtained at Investigator’s discretion.  Imaging during follow up will be at Investigator’s discretion.
J AE/SAE collections should continue for at least 90 days after the last dose of treatment.  All subjects with SAEs must be followed up 
for outcome.  (See Section 12.3 and Appendix A for details.)
K Safety Evaluation visit for all patients; these safety assessments must be performed at 30 days (+/-7 days) after study discontinuation.  
L Follow-up for all patients will be for survival data only, which will be obtained with a phone call or at regularly scheduled visits with 
their doctor.


CONFIDENTIAL
Version #: 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 46 of 85
9.0 SCHEDULE OF CORRELATIVE EVALUATIONS
For those patients who consent to additional correlative evaluations, the following procedures will 
be performed:
Collection of blood will be performed on each cycle of treatment before Pembrolizumab infusion 
and post infusion.  In addition to the study laboratory evaluations (i.e., CBC with differential, 
comprehensive serum chemistry panel) the patient’s immune phenotyping (markers including but 
not limited to CD3, CD4, CD8, PD-1, PD-L1, Foxp3) will be determined.  Intracellular cytokine 
levels in circulating blood monocytes and the patients’ blood concentration of Pembrolizumab will 
be also measured.31, 34, 35
Tumor specimens will be obtained at baseline diagnostic surgery or IR-guided for disease 
confirmation if no archival tissue is available and following 3-4 cycles of treatment if measurable 
disease remains and is amenable to biopsy.  Immunohistochemistry will be performed to determine 
tumor expression of PD-1, PD-L1, CD8, FOXP3 on FFPE tumor specimens.35  Immune gene 
expression profiling will be performed on snap frozen tumor specimens.36
9.1 Pre-Treatment Specimen Collection
The following should be collected at baseline/screening (30 days prior to Cycle 1, Day 1):

Tumor specimens (archival or fresh – tissue or core) 

Blood (20 mL)
9.2 All Cycles, Day 1
Blood (20 mL) (2 tubes of blood collected per procedures outlined in the lab manual)
9.1.2 On Treatment Specimen Collection
Tissue samples may be collected following every 3-4 cycles if patient consents to biopsy.
9.3 Off Treatment Specimen Collection
9.3.1 Early Treatment Discontinuation OR Safety Evaluation
Patients who discontinue study treatment early and those who complete study treatment will be 
asked to provide an extra blood sample after their last treatment dose; this may be done during the 
Safety Evaluation Visit (see Section 8.4).

Blood (20 mL)
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 47 of 85
10.0 AGENTS (DRUG FORMULATION AND PROCUREMENT)
10.1 Pembrolizumab
Refer to the FDA-approved package insert and current version of the Investigator’s Brochure 
(IB) for more information.20
10.1.2 Mechanism of Action
Pembrolizumab (MK-3475, KEYTRUDA®) is a potent and highly selective humanized 
monoclonal antibody (mAb) designed to block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  Pembrolizumab potently blocks binding to both ligands with half maximal 
inhibitory concentration (IC50) values below 1 nM in humans and cynomolgus monkey. 
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.20
10.1.2 Composition
The commercial formulation of Pembrolizumab is being used in this study.  Pembrolizumab drug 
product (DP) (solution for infusion, 100 mg/vial) is packaged in vials that contain 4 mL of sterile 
solution for IV infusion and 25 mg/mL Pembrolizumab.
10.1.3 Storage Recommendations and Dosage Forms
Two Drug Product (DP) dosage forms are available for Pembrolizumab (MK-3475): a 
subcutaneous injection form and an IV form.  For the purposes of this study, only the IV form of 
Pembrolizumab will be used.  For instructions on dose preparation and administration, refer to 
the KEYTRUDA® package insert.
Reconstituted vials should be used immediately to prepare the infusion solution in the IV bag, 
and the infusion solution should be administered immediately.  If the diluted Pembrolizumab 
solution is not used immediately, it may be stored at room temperature for no more than 6 hours 
from the time of dilution.  This hold time includes room temperature storage of the diluted 
solution and the duration of infusion.  The product can also be stored under refrigeration at 2°C 
to 8°C (36°F to 46°F) for no more than 96 hours from the time of dilution.  If refrigerated, the 
diluted solution must be allowed to come to room temperature prior to administration.  Do not 
shake.  The solution must be discarded after 6 hours at room temperature or 96 hours under 
refrigeration.
Do not freeze the diluted solution!
10.1.4 Dispensation and Accountability
For this study, Pembrolizumab will be provided by Merck as the commercial formulation of 
Pembrolizumab at 100 mg/4mL vial (25 mg/mL) as a solution for injection which is labeled as for 
investigational use.  For further details on drug preparation, please refer to the most recent version 
of the KEYTRUDA® (MK-3475) Pharmacy Manual.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 48 of 85
11.0 MEASUREMENT OF EFFECT
11.1 RECIST Guidelines 
New measurable lesions:  incorporated into tumor burden (i.e., added to the target lesion 
measurements).  A lymph node has to be ≥ 15 mm in short axis to be a measurable new lesion, 
and its short axis measurement is included in the sum.  Up to 2 new lesions per organ and up to 5 
new lesions in total can be added to the measurements. 
11.2  Antitumor Effect – Solid Tumors
For the purposes of this study, patients should be re-evaluated for response after completion of 3-
4 cycles of therapy and again after every 3-4 cycles.  In addition to a baseline scan, confirmatory 
scans should also be obtained no less than 4 weeks following initial documentation of objective 
response.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST 1.1) guideline 
(version 1.1).37, 38  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria.
11.2.1 Definitions
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with Pembrolizumab, chemotherapy and Bevacizumab.
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified according 
to the definitions stated below.  (Note:  Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.)
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.
11.2.2 Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters).
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 49 of 85
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the Investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol.
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI) are considered as non-measurable.
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions if 
they meet the definition of measurability described above.  However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions.
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total representative of all involved organs should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, and in addition should be those that 
lend themselves to reproducible repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease.
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.
11.2.3 Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 50 of 85
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is 
also acceptable in certain situations (e.g., for body scans).
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 that greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is variable 
globally.  As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease.  Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans.  Body scans should be performed 
with breath-hold scanning techniques, if possible.
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an Investigator if it is not routinely or serially performed.
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 51 of 85
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 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 patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published39-41.  In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria that are to be integrated with 
objective tumor assessment for use in first-line trials in ovarian cancer42.
Cytology, Histology:  These techniques can be used to differentiate between PR and CR.
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 SD is mandatory to 
differentiate between response or SD (an effusion may be a side effect of the treatment) and PD.
Fluorodeoxyglucose (FDG)-PET/CT:  While FDG-PET response assessments need additional 
study, it is reasonable to incorporate the use of FDG-PET scanning to complement CT scanning 
in assessment of progression (particularly possible 'new' disease) and is part of standard of care in 
the treatment of cervical cancer.  New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm:

Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.

No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan).  If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.

FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring.  
The use of FDG-PET in this circumstance should be prospectively described in the protocol 
and supported by disease-specific medical literature for the indication.  However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity.
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
11.2.4 Response Criteria – Evaluation of Target Lesions
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 52 of 85
Table 7:  Response Criteria (Target Lesions)
Complete Response (CR)
Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short 
axis to <10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of the diameters of target 
lesions taking as reference the baseline sum diameters.
Progressive Disease (PD)
At least a 20% increase in the sum of the diameters of target 
lesions taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also considered 
progression.)
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as reference the smallest sum 
diameters while on study.
11.2.5 Response Criteria – Evaluation of Non-Target Lesions
Table 8:  Response Criteria (Non-Target Lesions)
Complete Response (CR)
Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis).
Note:  If tumor markers are initially above the upper normal limit, 
they must normalize for a patient to be considered in complete 
clinical response.
Non-CR/Non-PD
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.
Progressive Disease (PD)
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  It 
must be representative of overall disease status change, not a 
single lesion increase.
11.2.6 Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started).  The patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria.
For Patients with Measurable Disease (i.e., Target Disease):
Table 9:  Best Overall Response - Measurable Disease
Target Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks. Confirmation**
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 53 of 85
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not evaluated
No
PR
>4 wks. Confirmation**
SD
Non-CR/Non-
PD/not evaluated
No
SD
Documented at least once 
>4 wks. from baseline**
PD
Any
Yes 
or 
No
PD
Any
PD***
Yes 
or 
No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.37, 38
**    Only for non-randomized trials with response as primary endpoint.
*** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment.
For Patients with Non-Measurable Disease (i.e., Non-Target Disease):
Table 10:  Best Overall Response - Non-measurable Disease
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
Not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in some 
trials so to assign this category when no lesions can be measured is not advised.
11.2.7 Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for PD the smallest 
measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that PD is objectively documented.
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 54 of 85
11.2.8 Progression-Free Survival (PFS)
PFS is defined as the elapsed time from start of treatment to first documentation of progression or 
date of death.  In alive progression-free patients, PFS will be censored at the last evaluable tumor 
assessment.
11.2.9 Overall Survival (OS)
OS is defined as the elapsed time from start of treatment to date of death.  Alive patients will be 
censored at date last known to be alive. 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version #: 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 55 of 85
12.0  ADVERSE EVENTS
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for AE reporting.43
12.1 Purpose
AE data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents.  AEs are reported in a routine manner at scheduled times during a 
trial.  Additionally, certain AEs must be reported in an expedited manner for timelier monitoring 
of patient safety and care. See Appendix A for more information.
12.2 Adverse Event
Adverse Event (AE):  Can be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, medical treatment, or 
procedure without judgment about causality. An AE can arise from any use and from any route of 
administration, formulation, or dose including an overdose.  This includes any newly occurring 
event or a previous condition that has increased in severity or frequency since initiation of a drug, 
medical treatment, or procedure.
Abnormal Findings
In any clinical assessment, a value outside the normal or reference range (such as a clinical 
laboratory, vital sign, or ECG) will not be reported or assessed as an AE unless that value is 
considered to be of clinical significance by the Investigator. A value of clinical significance is one 
that leads to discontinuation or delay in protocol treatment, dose modification, therapeutic 
intervention*, or is considered to be a clinically significant new finding or change from baseline 
by the Investigator.
*Transfusion support administered to offset clinical symptoms of anemia or thrombocytopenia 
will not be considered therapeutic intervention.
Signs and Symptoms
Signs/symptoms resulting from an underlying clinical diagnosis should be documented as one 
comprehensive AE. If no underlying clinical diagnosis can be identified, each sign/symptom 
should be reported as a separate independent event.  (A new or worsening event resulting from an 
underlying clinical diagnosis or a reaction to concurrent medications should be documented as a 
separate independent AE unless it is within the normal range of fluctuation for that patient.)
Grade Changes/Fluctuations
AEs will be reported at the maximum grade/severity experienced for the duration of the event. 
Should one particular event warrant further investigation, additional details may be collected at 
the discretion of the PI.
Progression of Disease
Progression of disease, if documented in accordance to standard of care, should not be reported as 
an AE.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 56 of 85
Tests and Procedures
Tests and procedures should not be reported as AEs.  The underlying clinical diagnosis (or 
sign/symptom in the event an underlying clinical diagnosis is not known) requiring testing or a 
procedure should be reported as an AE if it meets criteria for reporting.
12.3 Serious Adverse Events (see also Appendix A)
Serious AE (SAE) means any untoward medical occurrence that occurs at any dose that:
1. Results in death.
2. Is life-threatening.
The term "life-threatening" in the definition of "serious" refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.
3. Requires inpatient hospitalization or prolongation of present hospitalization.
Elective hospitalization to simplify protocol treatment/evaluations or to treat a baseline 
condition that did not worsen from baseline will not be considered an SAE.
4. Results in persistent or significant disability/incapacity.
Disability is defined as a substantial disruption of a person’s ability to conduct normal life 
functions.
5. Is a congenital anomaly/birth defect.
6. Is a medically important event.
A medically important event may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above or involves suspected transmission via a medicinal 
product of an infectious agent.   Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse; any organism, virus, or infectious particle (e.g., prion protein transmitting Transmissible 
Spongiform Encephalopathy), pathogenic or nonpathogenic, is considered an infectious agent.
Clarification should be made between the terms serious and severe because they ARE NOT 
synonymous.  The term severe is often used to describe the intensity (severity) of a specific event 
(as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as a severe headache).  This is NOT the same as 
serious, which is based on patient/event outcome or action criteria described above and is usually 
associated with events that pose a threat to a patient’s life or functioning.  A severe AE does not 
necessarily need to be considered serious.  For example, persistent nausea of several hours duration 
may be considered severe nausea but not an SAE.  On the other hand, a stroke resulting in only a 
minor degree of disability may be considered mild but would be defined as an SAE based on the 
above noted criteria.  Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations.
12.4 Adverse Event Collection Period
In this study, AE include only treatment-emergent AE.  A treatment-emergent adverse event 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 57 of 85
(TEAE) is defined as any event that begins or worsens after the start of protocol treatment.  All 
baseline-emergent AE, any event that begins or worsens after completion of the informed consent 
but prior to the start of protocol treatment, should be reported as a Baseline/Comorbid Condition.
Adverse events collection period will end with end of treatment (EOT).
12.5 Adverse Event Reporting Requirements
The information to be reported in AEs will be assessed by and assigned severity using the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
Version 4.03.  The NCI CTCAE provides descriptive terminology and a grading scale for each 
AE listed.  A copy of the NCI CTCAE v4.03 can be downloaded from the Cancer Therapy 
Evaluation Program (CTEP) home page (http://evs.nci.nih.gov/ftp1/CTCAE/About.html).
Information to be reported in the description of each AE may be included, but is not limited to:
1. Clinical Diagnosis of the event as determined by NCI CTCAE, Version 4.03 descriptive 
terminology.  If no clinical diagnosis can be identified, each sign/symptom should be 
reported as a separate independent event.
2. Date of onset of the AE (start date).
3. Date of resolution of the AE (end date) if available by EOT.
4. Severity of the event determined by NCI CTCAE, Version 4.03 grading scale.
5. Relationship of the AE to study therapy.  Categorized as follows:
Definite
The adverse event is clearly related to the investigational agent(s)
Probable
The adverse event is likely related to the investigational agent(s)
Possible
The adverse event may be related to the investigational agent(s)
Unlikely
The adverse event is doubtfully related to the investigational agent(s)
Unrelated
The adverse event is clearly not related to the investigational agent(s)
6. Whether or not the AE is Serious or Not:  Serious as defined in Section 12.3 Serious Adverse 
Events.
7. Whether the AE is Suspected and/or Unexpected.
Suspected
Any AE for which there is a reasonable possibility that the drug caused 
the AE.  For the purposes of expedited safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship 
between the drug and the AE.
Unexpected
Any AE for which the nature or severity of the event is not consistent 
with the applicable product information, e.g., the Investigator’s 
Brochure or Package Insert.
8. Action taken as a result of the AE.
9. Outcome
12.6 Expedited Adverse Event Reporting Requirements
All AEs, regardless if serious or not, will be described in the source documents, reported on the 
applicable AE page of the CRFs, and entered into Velos.  However, certain AEs must also be 
reported in an expedited manner for timelier monitoring of patient safety and care.  Appendix A 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 58 of 85
provides information about these expedited reporting requirements.
12.7 Events of Clinical Interest
Not applicable.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version #: 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 59 of 85
13.0 STATISTICAL CONSIDERATIONS
This is a single arm, two-stage, open-label, phase II study to assess efficacy of Pembrolizumab, 
Paclitaxel, Cisplatin (Carboplatin) and Bevacizumab for recurrent, persistent, or metastatic 
cervical cancer.  The primary efficacy endpoint is objective response rate (ORR; partial or 
complete response). 
Secondary objectives include to determine (1) PFS,  (2) OS, and (3) safety and tolerability of 
Pembrolizumab in combination with chemotherapy and Bevacizumab.  Exploratory analyses will 
be to determine if an immunologic profile will be a useful biomarker of treatment response and 
to perform exploratory translational studies on tissue biopsies at the time of recurrence, 
persistence, or metastatic disease compared to post-treatment samples. 
13.1 Planned Statistical Analysis
Statistical analysis will be based on evaluable patients as defined in Section 8.2.  Baseline 
characteristics will be summarized using descriptive statistics:  counts and percentages, ranges, 
median, mean, and standard deviation as appropriate.  This will include demographics (age, 
weight, and race/ethnicity), performance status, time since diagnosis, and prior treatment. 
Safety analysis will include detailed tabulation of worst toxicity and toxicity by type, grade, 
duration, and attribution to treatment (unrelated, unlikely, possible, probable, or definite) using 
the NCICTCAE, version 4.03. 
The primary study endpoint ORR (partial or complete response) will be reported with 
corresponding 95% CI calculated using the binomial method.  The secondary endpoints PFS and 
OS will be analyzed with the Kaplan-Meier method.44 
For the exploratory endpoints, we will evaluate the immunologic profile in predicting response to 
treatment and PFS.  Changes in immune endpoints pre- vs. post- treatment will be compared 
using paired t-test.  The effect of the specific pre-treatment immune potential biomarker on 
treatment response will be assessed using logistic regression and on PFS using Cox regression 
analysis. 
13.2 Sample Size Justification
In this single-arm, two-stage, open-label phase II study, we plan to enroll at most 40 evaluable 
patients with planed enrollment of 25 patients in the first stage and possibly an additional 15 
patients in the second stage.  Based on our institution’s enrollment capacity, we anticipate 
successful enrollment of 40 patients within 24 months with an estimated accrual of 2 patients per 
month.  The expected study duration is 4 years including a desirable minimum follow up of 24 
months for progression and survival data. 
GOG240 demonstrated 48% ORR (CR+PR) with the addition of Bevacizumab to chemotherapy.8  
We hypothesize that our proposed treatment with Pembrolizumab, Paclitaxel, Cisplatin 
(Carboplatin) and Bevacizumab will result in ORR greater than 55%.  Using PASS 15, we 
calculated sample size for a Simon’s two-stage design setting null hypothesis of ORR<38% (that 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 60 of 85
is, ORR lower by absolute 10% from the observed 48% ORR in GOG240), one-sided 5% 
significance level and 80% power to detect ORR=58% under the alternative hypothesis that 
ORR≥38%8,45,46. We determined a minimax two-stage design enrolling at most 40 patients with a 
probability of early termination of 0.66 after evaluating the proposed treatment in 25 patients in 
the first stage.  The trial will be terminated early if 10 or fewer responses out of the 25 evaluable 
patients (≤40%) are observed in the first stage.  If the trial goes on the second stage (that is, 11 or 
more responses in the first 25 patients), an additional 15 evaluable patients will be assessed for 
response in the second stage for a total of 40 study patients.  If the total number responding is less 
than or equal to 20 among 40 total patients (ORR≤50%), the null hypothesis is rejected and the 
proposed treatment considered not effective.  Otherwise, if the total number of CR+PR is greater 
or equal to 21 among 40 total patients (ORR ≥52.5%), the null hypothesis is rejected and the 
proposed treatment is considered effective.  Under this design, the actual significance level is 
4.3%; that is, if the treatment is actually not effective, there is a 0.043 probability of concluding 
that it is effective (type I error).  The actual power is 81.2% yielding 18.8% actual type II error; 
this is, if the treatment is actually effective, there is a 0.18.8 probability of concluding that it is not 
effective (type II error). 
13.3 Stopping Rules
We propose the following guidelines for the Data and Safety Monitoring Committee (DSMC) 
consideration in its review of accumulating study data.  The proposed guidelines were developed 
using Bayesian methods, which can be applied at any stage of enrollment without advance 
specification of the number of interim analyses to be performed, or the number of evaluable 
patients at the time such assessments are made.  Under the Bayesian method, we assign a prior 
probability (level of belief at the start of the trial) to a range of possible values for the true response 
rate and similarly, a prior distribution for the true toxicity rate47,48.  As treatment response and 
toxicity data on study patients become available, each of these prior probability distributions is 
revised and the resulting posterior probabilities become the basis for recommending either early 
termination or continuation of the study.  The following sections provide specific stopping 
guidelines and underlying assumptions for the prior distributions.
13.3.1 Early Stopping Due to Toxicity
The clinical Investigators and the SCCC DSMC will monitor the study patients for study-related 
toxicities.  Toxicities encountered in this trial will be reported according to the NCI CTCAE, 
version 4.03.  
For the purposes of safety monitoring, we define unacceptable toxicity to be any treatment-related 
(possible, probable, or definite) grade 3 or higher toxicity.  Unacceptable toxicity is expected to 
occur in no more than 20% of patients.  If there is evidence that the true rate of this toxicity 
exceeded 30%, then the study will be suspended and possibly terminated early.  Specifically, we 
suggest as a guideline for early termination a posterior probability of 80% or higher that the true 
rate exceeds 30%.  The table below shows specific instances where this guideline is met and 
suggests early termination due to evidence of excessive unacceptable toxicity.  
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 61 of 85
Table 11.  Stopping Boundaries for Toxicity
(Stop if the number of unacceptable toxicity in N evaluable patients is greater than or equal to X.)
X: Number (%) of patients 
with unacceptable toxicity*
N:  Total evaluable patients 
assessed for toxicity
Observed unacceptable 
toxicity rate ≥
4
6 to 8
50.0%
5
9 to 11
45.5%
6
12 to 13
46.2%
7
14 to 16
43.8%
8
17 to 19
42.1%
9
20 to 22
40.9%
10
23 to 25
40.0%
11
26 to 28
39.3%
12
29 to 31
38.7%
13
32 to 34
38.2%
14
35 to 37
37.8%
15
38 to 39
39.5%
* Possible, probable, or definite treatment-related grade 3 toxicity
To illustrate the stopping guidelines, suppose that 11 evaluable patients have been assessed for 
toxicity and 5 of them have experienced grade 3 treatment-related toxicity (row 2 of the above 
table).  Under this circumstance, the observed rate of grade 3+ of such toxicity is 45.5%, resulting 
in a posterior probability of >90% that the true underlying rate exceeds 30% thereby suggesting 
early termination.
Posterior probabilities for the above table are calculated under a weak prior beta distribution with 
parameters 1 =0.4 and 2 =1.6, which corresponds to an expected unacceptable-toxicity rate of 
20% based on very limited information roughly equal to having studied 2 patients.  This prior 
distribution implies also a priori chance of 26.2% that true rate of unacceptable toxicity is 30% or 
greater.
23.
13.3.2 Early Stopping Due to Lack of Efficacy
As per Section 13.2, this is a two-stage design enrolling at most 40 patients with a probability of 
early termination of 0.664 after evaluating the treatment in 25 patients in the first stage.  The trial 
will be terminated if it is observed 10 or fewer responses (CR+PR) out of 25 evaluable patients 
in the first stage. 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 62 of 85
14.0 DATA REPORTING, MONITORING, AND AUDITING
Data must be submitted according to the protocol requirements for all patients registered.  
Patients for whom documentation is inadequate to determine eligibility will generally be deemed 
ineligible.
14.1
Data and Safety Monitoring
The SCCC DSMC will monitor this clinical trial according to the Cancer Center’s data safety 
monitoring (DSM) Plan.  In its oversight capacity, the DSMC bears responsibility for suspending 
or terminating this study.  DSMC oversight of the conduct of this trial includes ongoing review 
of accrual and AE data and periodic review of the study therapy.  The guidelines appearing in the 
Section 13.3 are offered for DSMC consideration in assessing AEs and pathologic objective 
response.  In addition, the DSMC will review reports from all audits, site visits, or study reviews 
pertaining to this clinical trial and take appropriate action.  The SCCC DSM Plan to which this 
study is subject can also be found at www.sylvester.org.
14.2
Study Auditing and Monitoring
This study will be audited and/or monitored (as applicable) according to UM requirements.  See 
also http://uresearch.miami.edu/regulatory-compliance-services/rcqa and 
http://research.med.miami.edu/clinical-research/crors.
15.0 INVESTIGATOR RESPONSIBILITIES
15.1 Investigator Responsibility/Performance
The Investigator will ensure that this study is conducted in accordance with all regulations 
governing the protection of human subjects.  The Investigator will ensure that all work and services 
described in or associated with this protocol will be conducted in accordance with the 
investigational plan, applicable regulations, and the highest standards of medical and clinical 
research practice.
15.2 Confidentiality
The Investigator must ensure that each subject’s anonymity will be maintained and each subject’s 
identity will be protected from unauthorized parties.  A number will be assigned to each subject 
upon study entry and the number and the subject’s initials will be used to identify the subject for 
the duration of the study.  The Investigator will maintain all documents related to this study in 
strict confidence.
15.3 Informed Consent and Permission to Use Protected Health Information
It is the responsibility of the Investigator to obtain written informed consent from each subject 
participating in this study after adequate explanation, in lay language, of the methods, objectives, 
anticipated benefits, and potential hazards of the study.  The Investigator must also explain that 
the subject is completely free to refuse to enter the study or to discontinue participation at any time 
(for any reason) and receive alternative conventional therapy as indicated.  Prior to study 
participation, each subject will sign an IRB approved informed consent form and receive a copy 
of same (and information leaflet, if appropriate).  The Investigator or designee must explain to the 
subject before enrollment into the study that for evaluation of study results, the subject’s protected 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 63 of 85
health information obtained during the study may be shared with the study sponsor, regulatory 
agencies, and the IRB.  It is the Investigator’s (or designee’s) responsibility to obtain permission 
to use protected health information per HIPAA from each subject or if appropriate, the subjects’ 
parent or legal guardian.
15.4 Source Documentation and Investigator Files
The Investigator must maintain adequate and accurate records to fully document the conduct of 
the study and to ensure that study data can be subsequently verified.  Subject clinical source 
documents may include hospital/clinic patient records; physician's and nurse's notes; appointment 
book; original laboratory, electroencephalogram (ECG), EEG, radiology, pathology, and special 
assessment reports; pharmacy dispensing records; subject diaries; signed informed consent forms; 
and consultant letters.  When the CRF or any form is used as the source document, this must be 
clearly stated in the Investigator study file. 
15.5 Recording and Processing of Data
If using hard copies of CRFs, study center personnel will complete individual CRFs in ink.  All 
corrections to entered data will be made by drawing a single line through the information to be 
corrected without obscuring it.  All corrections will be initialed, dated and explained, if necessary.  
The use of “white-out” or obscuring correction tape will be prohibited.  A CRF is required for 
every patient who received any amount of study treatment.  The Investigator will ensure that the 
CRFs are accurate, complete, legible and timely.  Separate source records are required to support 
all CRF entries except those for which use of the CRF as source document is clearly allowed per 
note in the Investigator study file.
Data must be submitted according to the protocol requirements for ALL patients registered.  
Patients for whom documentation is inadequate to determine eligibility will generally be deemed 
ineligible.
Data must be submitted according to the protocol requirements for ALL patients registered.  
Patients for whom documentation is inadequate to determine eligibility will generally be deemed 
ineligible.
15.6 Non-Protocol Research
No investigative procedures other than those described in this protocol will be undertaken on the 
enrolled subjects without the agreement of the IRB.
15.7 Ethics
The Investigator agrees to conduct the study in compliance with the protocol, current good clinical 
practices, and all applicable (local, FDA) regulatory guidelines and standard of ethics.
UM Ethics Programs’ Research Ethics Consultation Service (RECS) is a free resource for UM 
Researchers.  See the website for further information: https://bioethics.miami.edu/clinical-and-
research-ethics/research-ethics-consultation-service/index.html. 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 64 of 85
REFERENCES
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. Ca Cancer J Clin. 2015;65:5-29.
2. Monk BJ, Tewari KS, Koh WJ. Multimodality therapy for locally advanced cervical 
carcinoma: state of the art and future directions. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 2007; 25(20): 2952-65.
3. Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four Cisplatin-containing doublet 
combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic 
Oncology Group study. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 2009; 27(28): 4649-55.
4. Tewari KS, Monk BJ. The rationale for the use of non-platinum chemotherapy doublets for 
metastatic and recurrent cervical carcinoma. Clinical advances in hematology & oncology : 
H&O 2010; 8(2): 108-15.
5. Tewari KS, Monk BJ. Gynecologic oncology group trials of chemotherapy for metastatic and 
recurrent cervical cancer. Current oncology reports 2005; 7(6): 419-34.
6. Hong JH, Tsai CS, Lai CH, et al. Recurrent squamous cell carcinoma of cervix after 
definitive radiotherapy. International journal of radiation oncology, biology, physics 2004; 
60(1): 249-57.
7. Quinn MA, Benedet JL, Odicino F, et al. Carcinoma of the cervix uteri. FIGO 26th Annual 
Report on the Results of Treatment in Gynecological Cancer. International journal of 
gynaecology and obstetrics: the official organ of the International Federation of 
Gynaecology and Obstetrics 2006; 95 Suppl 1: S43-103.
8. Tewari KS, Sill MW, Long HJ, 3rd, et al. Improved survival with Bevacizumab in advanced 
cervical cancer. The New England journal of medicine 2014; 370(8): 734-43.
9. Sasagawa T, Takagi H, Makinoda S. Immune responses against human papillomavirus 
(HPV) infection and evasion of host defense in cervical cancer. Journal of infection and 
chemotherapy : official journal of the Japan Society of Chemotherapy 2012; 18(6): 807-15.
10. Patel S, Chiplunkar S. Host immune responses to cervical cancer. Current opinion in 
obstetrics & gynecology 2009; 21(1): 54-9.
11. Ladoire S, Mignot G, Dabakuyo S, et al. In situ immune response after neoadjuvant 
chemotherapy for breast cancer predicts survival. The Journal of pathology. 2011; 224 (3): 
389-400. 
12. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity.  
Immunological reviews. 2010; 236: 219-42.
13. Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the 
CTLA-4 and PD-1 pathways. Immunological reviews. 2008; 224: 166-82.
14. Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer- preclinical 
background: CTLA-4 and PD-1 blockage. Seminars in oncology. 2010; 37 (5): 430-9. 
15. Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new 
immunomodulatory targets. Nature reviews drug discovery.  2015; 14 (8): 561-84.
16. Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets 
tumor-specific mutant antigens. Nature. 2014; 515 (7528): 577-81.  
17. Ngiow SF, Young A, Jacquelot N, et al.  A threshold level of intratumor CD8+ T cell PD-1 
expression dictates therapeutic response to anti-PD-1. Cancer research 2015. 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 65 of 85
18. Gowrishankar K, Gunatilake D, Gallagher SJ, Tiffen J, Rizos H, Hersey P. Inducible but not 
constitutive expression of PD-L1 in human melanoma cells is dependent on activation of NF-
kappaB. PloS one. 2015; 10 (4): 30123410.
19. Hersey P, Gowrishankar K.  Pembrolizumab joins the anti-PD-1 armamentarium in the 
treatment of melanoma. Future oncology. 2015; 11 (1): 133-40.
20. Investigator’s Brochure. Investigator’s Brochure for Pembrolizumab (Keytruda). Merck; 2 
Sept  2021, 2021. 
21. Stewart TY, Burtness B, Weiss J, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 6011)
22. Brahmer JS, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in 
patients with advanced cancer. The New England Journal of Medicine. 2012; 366 (26): 2455-
65.
23. Walboomers JM, Jacobs MV, Janos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, 
Peto J, Meijer CJ, Muñoz N. Human papillomavirus is a necessary cause of invasive cervical 
cancer worldwide. J Pathol. 1999;189(1):12-9. 
24. Mezache L, Paniccia B, Nyinawabera A, Nuovo GJ. Enhanced expression of PD L1 in 
cervical intraepithelial neoplasia and cervical cancers. Mod Pathol 2015 Dec;28(12):1594-
602. 
25. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, 
Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake 
CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMller TL, Xu H, 
Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, 
Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. NEJM 
2012;366:2443-2454.
26. Ramakrishnan R, Gabrilovich DI. Novel mechanism of synergistic effects of conventional 
chemotherapy and immune therapy of cancer. Cancer Immunol Immunother 2013 
Mar;62(3):405-10.
27. Papadimitrakopoulou V,Patnaik A, Hossein B, Stevenson J, Gandhi L, Gubens MA, Chih-
Hsin Yang J, Sequist LV, Ge JY, Bourque J, Bachman RD, Im E, Gadeel KM. 
Pembrolizumab (pembro; MK-3475) plus platinum double chemotherapy (PDC) as front-line 
therapy for advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 Cohorts A and 
C. J Clin Oncol 2015 May (33):8031.
28. Robert C, Ribas A, Wolchok JD, Hodi S, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu 
WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H et al. Anti-programmed –death-receptor-
1 treatment with Pembrolizumab in ipilimumab-refractory advanced melanoma: a 
randomized dose-comparison cohort of a phase I trial. The Lancet. 2014; 382 (9948): 1109-
1117.
29. Ribas A, Puzanov I, Dummer R, Schadendorf D. et al. Pembrolizumab versus investigator-
choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomized, 
controlled, phase 2 trial. Lancet Oncol. 2015; 16: 908-18. 
30. Garon EB, Rizvi NA, Hui R, et al.  KEYNOTE-001 Investigators. Pembrolizumab for the 
treatment of non-small cell lung cancer. N Engl J Med. 2015; 372; 2018-2028. 
31. Budiu RA, Mantia-Smaldone G, Elishaev E, et al. Soluble MUC1 and serum MUC1-specific 
antibodies are potential prognostic biomarkers for platinum-resistant ovarian cancer. Cancer 
immunology, immunotherapy : CII 2011; 60(7): 975-84.
32. Katoh H, Watanabe M. Myeloid-derived suppressor cells and therapeutic strategies in cancer. 
Mediators Inflamm 2015; 2015: 159269.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 66 of 85
33. Qian F, Liao J, Villella J, et al. Effects of 1-methyltryptophan stereoisomers on IDO2 
enzyme activity and IDO2-mediated arrest of human T cell proliferation. Cancer 
immunology, immunotherapy : CII 2012; 61(11): 2013-20.
34. Vlad AM, Budiu RA, Lenzner DE, et al. A phase II trial of intraperitoneal interleukin-2 in 
patients with platinum-resistant or platinum-refractory ovarian cancer. Cancer immunology, 
immunotherapy : CII 2010; 59(2): 293-301.
35. Budiu RA, Diaconu I, Chrissluis R, Dricu A, Edwards RP, Vlad AM. A conditional mouse 
model for human MUC1-positive endometriosis shows the presence of anti-MUC1 
antibodies and Foxp3+ regulatory T cells. Disease models & mechanisms 2009; 2(11-12): 
593-603.
36. Suryawanshi S, Vlad AM, Lin HM, et al. Plasma microRNAs as novel biomarkers for 
endometriosis and endometriosis-associated ovarian cancer. Clinical cancer research : an 
official journal of the American Association for Cancer Research 2013; 19(5): 1213-24.
37. Bohnsack O, Ludajic K, Hoos A. Adaptation of the immune-related response criteria: 
irRECIST. Ann Oncol. 2014;25(suppl 4):iv361, iv372.
38. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). European journal of cancer (Oxford, 
England : 1990) 2009; 45(2): 228-47.
39. Rustin GJS, Quinn M, Thigpen T, et al. Re: New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors (Ovarian Cancer). 2004; 96(6): 487-8.
40. Bubley GJ, Carducci M, Dahut W, et al. Eligibility and Response Guidelines for Phase II 
Clinical Trials in Androgen-Independent Prostate Cancer: Recommendations From the 
Prostate-Specific Antigen Working Group. JCO 1999; 17(11): 3461-7.
41. Scher HI, Halabi S, Tannock I, et al. Design and End Points of Clinical Trials for Patients 
With Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of 
the Prostate Cancer Clinical Trials Working Group. JCO 2008; 26(7): 1148-59.
42. Vergote I, on behalf of the Gynecologic Cancer I, Rustin GJS, et al. Re: New Guidelines to 
Evaluate the Response to Treatment in Solid Tumors [Ovarian Cancer]. 2000; 92(18): 1534-5
43. Cancer Therapy Evaluation Program. Common terminology criteria for adverse events. 
Version 4.0 DCTD, NCI, NIH, DHHS. Publish Date: 2010 June 14. Cited: 2016 May 05. 
Available from: http://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
44. Armitage P, Berry G, and Matthews J N.  Statistical Methods in Medical Research, Fourth 
Edition.  Oxford: Blackwell Scientific, 2001.
45. Simon, Richard. Optimal Two-Stage Designs or Phase II Clinical Trials. Controlled Clinical 
Trials. 1989, Vol 10 pages 1-10.
46. PASS 14 Power Analyskis and Sample Size Software (2015). NCSS, LLC. Kaysville Utah, 
USA. Ncss.com/software/pass
47. Spiegelhalter DJ, Freedman LS, Parmar MK. Bayesian approaches to randomized trials. J 
Royal Stat Soc Ser A 1994; 157: 357-416.
48. Favers PM, Ashby D, Parmar MKB. Tutorial in biostatistics: Bayesian data monitoring in 
clinical trials. Stat Med. 1997; 16: 1413-30. 
 
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 67 of 85
APPENDIX A:  EXPEDITED ADVERSE EVENT (AE) REPORTING REQUIREMENTS
For all AEs that meet criteria for expedited reporting, the Principal Investigator (PI) is obligated 
to pursue and provide follow-up reporting information until the event has resolved or until an 
acceptable medical endpoint has been reached (i.e., for the duration specified in the protocol), or 
the patient is lost to follow-up.
The PI and all applicable research study team members should become familiar with the safety 
profile of the investigational agent(s) and/or intervention at the start of the study and for the 
duration of the research, e.g., by reviewing the Investigator’s Brochure (IB) and any Safety Reports 
released by the Sponsor as applicable.
FDA Expedited Reporting
FDA Expedited Reporting Sponsor-Investigators (i.e., IND Holders) have additional reporting 
requirements to the FDA and other committees and should consult the applicable regulations and 
agency guidelines for these requirements.
Since this protocol involves the use of FDA IND agent(s), completion of the FDA MedWatch 
3500A Reporting Form is required for Sponsor-Investigators.  The Form can be obtained 
electronically at: 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf
All serious, unexpected (unanticipated) and suspected adverse events must be directly reported to 
the FDA within 15 calendar days of being made known to the PI.
All fatal or life-threatening AEs must be directly reported to the FDA within 7 calendar days of 
being made known to the PI.
For more information regarding reporting to the FDA, please refer to the FDA website for 
REPORTING GUIDELINES:  http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm
IRB Expedited Reporting
All Investigators should also be aware of local Institutional requirements for AE reporting.  For 
more information regarding the IRB policy, please refer to the UM HSRO’s Investigator Manual: 
http://hsro.med.miami.edu/documents/HRP-103_-
_INVESTIGATOR_MANUAL_4.11.2014.docx and the UM HSRO SOP on New Information 
(HRP-024) 
https://eprost.med.miami.edu/eProst/Doc/0/HLJ5OTJVQEH419E0I6QPT3B199/HRP-024%20-
%20SOP%20-%20New%20Information.docx
All AEs that are serious, unanticipated and possibly related will be reported to the IRB within ten 
(10) working days of being made known to the PI.
Events that are more frequent than anticipated or more severe than expected must be reported to 
the IRB within ten (10) working days of being made known to the PI.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 68 of 85
All unanticipated deaths must be reported to the IRB within 24 hours of being made known to 
the PI.
Merck Expedited Reporting (Events of Clinical Interest or ECIs)
A. In addition to the mandatory MedWatch 3500A Form, the PI is also required to comply with 
all reporting requirements as supplied by the Investigational Drug Sponsor:  Merck.
B. Any serious adverse event (SAE) or follow up to an SAE including death due to any cause 
other than progression of the cancer under study that occurs to any subject from the time the 
consent is signed through 90 days following cessation of treatment or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety.
C. All reports of overdose with and without an adverse event (AE) must be reported within 24 
hours to the PI and within 2 working days to Merck Global Safety.  (Attn: Worldwide Product 
Safety; FAX 215 993-1220.)
D. Non-serious ECI will be forwarded to Merck Global Safety and will be handled in the same 
manner as SAEs.
E. Additionally, any SAE considered by an Investigator who is a qualified physician to be 
related to Merck product 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 and to Merck. 
F. SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:   +1-215-993-1220. 
G. A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators.  Investigators will cross reference this submission according to local regulations 
to the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally, Investigators will submit a copy of these reports to Merck & Co., Inc.  (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA.
H. All subjects with SAEs must be followed up for outcome.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 69 of 85
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 70 of 85
APPENDIX B: PERFORMANCE STATUS SCALES
As published in Am J Clin Oncol: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, 
McFadden ET, Carbone PP. Toxicity and Response Criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982;5:649-655. The Eastern Cooperative Oncology Group, 
Robert Comis, MD, Group Chair.
PERFORMANCE STATUS CRITERIA (ECOG)
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light housework, office work).
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of walking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of walking 
hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to a bed or 
chair.
5
Dead.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 71 of 85
APPENDIX C: NYHA CLASSIFICATION OF HEART DISEASE
New York Heart Association (NYHA) classification of heart disease:
NYHA Class
Symptoms
I
No symptoms and no limitation in ordinary physical activity, e.g. shortness of 
breath when walking, climbing stairs etc.
II
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity.
III
Marked limitation in activity due to symptoms, even during less-than-
ordinary activity, e.g., walking short distances (20–100 m).
Comfortable only at rest.
IV
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 72 of 85
APPENDIX D: BIOMARKER, CORRELATIVE AND SPECIAL STUDIES
Samples will be processed and stored at the University of Miami (UM) in Dr. Sophia George’s 
laboratory. Biomarker analysis (PDL-1) will be performed by QualTek Molecular Laboratories. 
Additional biomarker analysis will be performed through the UM.
1. Email Notification
Dr. Marilyn Huang and collaborator Dr. Sophia George should be contacted via email to notify 
them of all specimen submissions for banking.  The Subject line should read: 
“Chemo+Pembro_Cervix Cancer_Biospecimen Banking”
Dr. Huang:  m.huang@med.miami.edu
Laboratory Collaborator:  sophia.george@med.miami.edu; sramakrishnan@miami.edu
2. Blood Samples Collection
Collection of blood will be performed before and after Pembrolizumab treatment and at EOT 
visit.
Plasma and blood monocytes will be obtained, aliquoted and stored following the Standard 
Operating Procedures (SOP) for handling the blood samples, which will be supplied in the Study 
Manual.
3. Tissue Samples Collection
Collection of tissue samples will be performed pre-treatment (needle core biopsy or vaginal 
biopsy) and possibly following 3-4 cycles.
For each time point, two (2) specimens will be collected.  The first one will be fixed in formalin 
and submitted to the Pathology Department for paraffin embedding and the second one will be 
immediately frozen for molecular profiling.  Details for sample collection and processing will be 
available on the study SOPs supplied in the Study Manual.
4. Sample Banking
Upon collection of the tissue samples from the patients, a code system will be used to de-identify 
all samples, assigning a unique code to each specimen.  The samples will be tied to patient-
identifying information only at the time of sample collection.  The patient's name will be written 
on the specimen collection case.  Once the samples are de-identified, which will happen as soon 
as the specimens arrive in the TBCF, the patient's name will be blacked out on the original 
sample case and the original casing will be discarded in biohazardous waste, which is 
subsequently sent for incineration.  Samples will be then identified with a code identified (study 
number).  The list where patient's names will be tied to their code will be kept on a password-
protected computer in the TBCF.  The only information that will be stored with the actual 
samples in the bank is the code identifier used to identify each sample.  No samples will be 
accepted into the bank unless the subject's signed consent form has first been submitted.  The 
only Investigators who will have access to samples and data being kept in the bank are Dr. 
Huang and her research collaborator(s) named in this study.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 73 of 85
Samples in the bank will be stored indefinitely or until the patient withdraws consent for 
inclusion in the protocol.  At that time, all samples and data will be destroyed.
Researchers wishing to gain access to either the clinical data (de-identified) or samples must first 
submit the appropriate IRB protocol for use and analysis of the information.  Upon approval, the 
investigator will then be granted appropriate access to the data and/or samples as indicated by 
his/her respective protocol.
Study-related data will be maintained entirely in an online platform behind the university 
firewall and requiring UM CaneID password identification.  Additional IRB approval will be 
necessary to use and publish any research performed using the study data and the specimens.
Specimen Storage Conditions
Formalin-fixed, paraffin-embedded (FFPE) blocks will be stored at room temperature 15-25○C
Plasma and blood monocytes will be stored in a -80○C freezer
Flash frozen samples will be stored in liquid nitrogen (-150○C)
DNA/RNA will be stored in a -80○C freezer
Contact Info for Dr. George Lab
Sylvester Comprehensive Cancer Center
Papanicolau Building
1550 NW 10th Ave.
Miami, FL 33136-1013
305-243-2036
5. Biomarker Analysis
All biomarker measurements will be performed at the end of study. Five (5) unstained slides cut 
from an FFPE block will be provided to QualTek as described below.
A. Sample Requirements 

For patient samples, the provided positively charged ProbeOn Plus slides (Fisher ProbeOn 
Plus Catalog Number 22-230-900) must be used for tissue sections.  Slide measurements are 
75 mm x 25 mm x 1 mm (other slide sizes cannot be accommodated).  In the event this 
requirement cannot be met, please contact QualTek to discuss alternative options.

Tumor tissue for biomarker analysis must be provided as five (5) unstained slides cut from an 
FFPE tissue block.  Five (5) sectioned slides per patient are required for PD-L1 testing.  If 
additional markers beyond PD-L1 are required to be tested as per the service contract 
established between QualTek and the Investigator Site, 5 additional sections per marker will 
be required.

Samples may be held as blocks indefinitely at the site and then cut in batches.  Slides must be 
shipped to QualTek immediately after sectioning to comply with the protocol’s testing 
requirements.  If patient slides are not received by QualTek within seven (7) days of 
sectioning, new sections may be requested and additional processing charges may be 
assessed.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 74 of 85

As per Merck protocol requirements, sectioned slides must be shipped cold (2-8°C) and in 
the dark using the shipping materials provided by QualTek pages 7-8.  Be advised that slides 
received that do not meet these conditions may affect PD-L1 staining.

Sectioned slides provided should contain tumor specimen sufficient for pathology review and 
analysis of tumor sample.  If available, greater than 50% tumor content is preferred.

Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, lavage 
specimen, frozen sample, plastic embedded sample, or formalin fixed sample that was frozen 
at any point will not be accepted for IHC analysis.  Needle core biopsies that are formalin-
fixed and paraffin-embedded are acceptable.
B. Sectioning of Tissue onto ProbeOn Plus Slides from Formalin-Fixed, Paraffin-
Embedded (FFPE) Block(s)
1. Prepare exactly five (5) freshly-cut serial sections at 4 micron thickness onto the provided 
Fisher ProbeOn Plus Slides, Cat Number 22-230-900.  Sections must be placed on the 
painted/textured side of the slide.

Other standard-sized positively-charged slides (75 mm x 25 mm x 1 mm) are acceptable 
as a last resort, however, QualTek must be notified as there is a risk that outside slides 
cannot be stained.  The slides must be sized as described above or the sample cannot be 
tested and will be returned.

No adhesives should be used in the water bath since the slides are positively-charged.
2. Ensure that the sample has the institutional block ID clearly marked on each 
slide as well as the slide section levels, if possible.

Ensure that the block ID is referenced on the manifest.

Note that the sample must be labeled with 2 patient identifiers (Refer to the 
label provided for the slide holder).
3. When placing the sections onto the slides, ensure that the tissue is towards the 
bottom third of the slide as pictured at right.

Ensure tissue sections are oriented the same direction on all slides.

No adhesive labels directly on slides.  Slide / patient identifiers must be 
hand written with indelible / chemical proof ink.

Number the slides sequentially (serially), one section per slide.
4. DO NOT OVEN DRY SLIDES.  Air dry until completely dry (12-24 hours).
5. Complete an electronic Sample Manifest for each shipment (Excel Spreadsheet provided by 
QualTek to the Site Contact at study initiation).

Email the completed electronic manifest prior to shipment to: 
MISPsamples@qmlabs.com. 

Make a copy of the manifest to include with the sample(s).

Retain the original at the site for your records.
6. Email or a de-identified (redacted) pathology report(s) if available.  Write the block ID on the 
top of each page of the pathology report.
7. Prepare samples for shipping as detailed on pages 5-6.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 75 of 85
C. Packaging Instructions for Formalin-Fixed Paraffin Embedded Slides
1. Affix and complete the label provided for the slide holder with Unique Patient ID number, 
Site Number/Identifier and Sectioning Date using indelible ink ensuring that the patient 
identifiers on the slide holder match the patient slides.
Top line of the label are the Study Identifiers 
and will be pre-printed for the specific study
Left - Investigator Study Number
Center – Merck Protocol Number
Right – QualTek Project Number
2. Place the newly sectioned slides (air dried until completely dry (12-24 hours), exactly five 
(5) slides, into the labeled slide holder.  Ensure only one patient per slide holder.
3. Place the piece of small foam between the top of the slides and the holder’s lid to prevent the 
slides from breaking.  Tape the lid closed.
4. Insert the slide holders into the Amber UV bag labeled as “Biohazard” and seal the bag.
5. Place the Amber UV bag into a bubble wrap bag or wrap in a sheet of bubble wrap.
6. More than one shipping box size may have been provided, choose the appropriate size as 
follows:

If shipping 1 patient slide holder:
Use a 9x12 Insulated Shipping mailer.  Place 1 freezer pack in the cooler liner, place the 
bubble wrap bag containing slides on top of the freezer pack.

If shipping between 2 and 10 patient slide holders:
Use a 10x10x10 Shipping box and cooler box liner.  Place 1 freezer pack on the bottom 
of the cooler liner, place the bubble wrap bag containing slides on top of the freezer pack 
and include 1 freezer pack on top of the bubble wrap bag. 

If shipping between 11 and 20 patient slides holders:
Use a 12x12x12 shipping box and cooler box liner.  Place 2 freezer packs on the bottom 
of the cooler liner, place the bubble wrap bag containing the slides on top of the freezer 
pack and include 2 freezer packs on top of the bubble wrap bag.
7. Fill remaining space with appropriate cushioning, i.e., additional bubble wrap or other 
packing material.  For extreme temperature conditions additional ice packs may be required.  
Samples must be shipped cold (2-8°C) and in the dark.
8. Enclose the de-identified (redacted) pathology report and the Sample Manifest, ensure that an 
electronic copy of the Manifest has been emailed to MISPsamples@qmlabs.com.  
9. Seal the mailer/box to ensure it will not open during shipping.  Package & ship same day to 
QualTek. 
10. Complete the pre-printed air bill provided by QualTek with sender information. 
11. Verify correct shipping address as:
QualTek Molecular Laboratories
MISP Receiving
300 Pheasant Run
Newtown, PA USA 18940
12. Adhere the pre-printed air bill to the top of the shipping mailer/box.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 76 of 85
13. Ship Standard Overnight Monday through Thursday; do not ship Friday, Saturday or 
Sunday.
D. Investigator Studies Supply List for FFPE Sectioned Slides Shipping to QualTek
The following supplies or their equivalent will be provided by QualTek:
1. Positively charged microscope slides used for sectioning 
of slides (5 per patient)

Fisher ProbeOn Plus 25 mm x 75 mm x 1 mm 
Capillary Gap Microscope Slides catalog 22-230-900
http://www.fishersci.com
2. Plastic slide holders (1 per patient, each hold maximum 
of 5 slides)

Catalog 12-587-17B
http://www.fishersci.com
3. Paraffin embedding cassette sponge to cushion slides in 
the plastic slide holder during shipping

“square” biopsy foam pad sized 1 7/8” x 1” x 1/16” 
(catalog 60872‐492) 
http://us.vwr.com 
4. Amber UV bags with biohazard sticker (to keep the 
slides in dark)

Amber UV bag (6x8 inches) – catalog 89005-326
http://us.vwr.com

Biohazard Sticker – catalog ML1022
http://www.marketlab.com
5. Shippers

9x12 (Mailer) For shipping 1 sample holder – 
catalog S18306 
http://www.uline.com

10x10x10 (Small) For shipping between 2 to 10 
patient slide holders – catalog s4105 
http://www.uline.com

12x12x12 (Large) For bulk shipments, between 11 to 
20 patient slide holders – catalog s18283 
http://www.uline.com

Insulated shippers – catalog s18282 
http://www.uline.com
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 77 of 85
6. Cold Packs (12 oz. Ice Packs, 1 for the Mailer, 2 for the 
Small Shipper, 4 for the Large Shipper)

Catalog s7889
http://www.uline.com
7. Bubble wrap

Catalog s-683
http://www.uline.com
8. Miscellaneous

Labels for the slide holders

FedEx Pre‐Printed Air bills

Site Supply Inventory

Sample Manifest Template (Excel Spreadsheet 
provided electronically to site contact)
E. (EXAMPLE) Site Supply Inventory
Date
QualTek Project #
Investigator Study #
Merck Protocol #
Site Name
Site Address
Address Continued
Quantity
Description
Quantity
Description
Positively Charged Capillary Gap 
(ProbeOn Plus) Microscope 
Slides
Freezer Packs
Plastic Five (5) Slide Holder 
(with small Foam Pad)
Fed-Ex Pre-Printed Air Bill(s)
Labels for Slide Holder
10x10x10 Shipping Box with 
Cooler Box Liner
Amber UV Bags (labeled 
Biohazard)
12x12x12 Shipping Box with 
Cooler Box Liner
Bubble Wrap Bags
Other (If Applicable)
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 78 of 85
F. Unpacking Instructions
1. Confirm material counts and check for breakage.
2. Remove freezer packs and place in freezer as soon as possible.
3. Retain all other materials for return of samples to QualTek Molecular Labs. 
4. When ready to section, remove Positively Charged Capillary Gap (ProbeOn Plus) 
Microscope Slides from slide holder and use only this slide type for sectioning.  Retain foam 
pad for repackaging.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 79 of 85
APPENDIX E: CYP1A2, CYP2C8, CYP2C19, CYP3A4 SUBSTRATES, INHIBITORS & 
INDUCERS *
SUBSTRATE(S)
1A2
2C8
2C19
3A4
Amitriptyline
caffeine
clomipramine
clozapine
cyclobenzaprine
duloxetine
estradiol
fluvoxamine
haloperidol
imipramine N-DeMe
mexiletine
naproxen
olanzapine
ondansetron
phenacetin
acetaminophenNA
PQI
propranolol
riluzole
ropivacaine
tacrine
theophylline
tizanidine
triamterene
verapamil
(R)warfarin
zileuton
zolmitriptan
[Paclitaxel]
torsemide
amodiaquine
cerivastatin
repaglinide
sorafinib
Proton Pump
Inhibitors (PPIs):
esomeprazole
lansoprazole
omeprazole
pantoprazole
rabeprazole
Anti-epileptics:
diazepamNor
phenytoin(O)
S-mephenytoin
phenobarbitone
amitriptyline
carisoprodol
citalopram
chloramphenicol
clomipramine
chlopidogrel
cyclophosphamid
e
hexobarbital
imipramine N-
DeME
indomethacin
labetalol
R-mephobarbital
moclobemide
nelfinavir
nilutamide
primidone
progesterone
proguanil
propranolol
teniposide
R-warfarin8-
OH
voriconazole
Macrolide antibiotics:
clarithromycin
erythromycin (not 3A5)
NOT azithromycin
telithromycin
Anti-arrhythmics:
quinidine3OH (not 
3A5)
Benzodiazepines:
alprazolam
diazepam3OH
midazolam
triazolam
Immune Modulators:
cyclosporine
tacrolimus (FK506)
HIV Antivirals:
indinavir
nelfinavir
ritonavir
saquinavir
Prokinetic:
cisapride
Antihistamines:
astemizole
chlorpheniramine
terfenadine
Calcium Channel 
Blockers:
amlodipine
diltiazem
felodipine
lercanidipine
nifedipine
nisoldipine
nitrendipine
verapamil
Steroid 6beta-OH:
estradiol
hydrocortisone
progesterone
testosterone
Miscellaneous:
alfentanyl
aprepitant
aripiprazole
boceprevir
buspirone
carbamazepine
cafergot
caffeineTMU
cilostazol
cocaine
codeine-N-
demethylation
dapsone
dexamethasone
dextromethorphan
docetaxel
domperidone
eplerenone
fentanyl
finasteride
gleevec
haloperidol
irinotecan
LAAM
lidocaine
methadone
nateglinide
nevirapine
ondansetron
pimozide
propranolol
quetiapine
quinine
risperidone
romidepsin
NOT rosuvastatin
salmeterol
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 80 of 85
SUBSTRATE(S)
1A2
2C8
2C19
3A4
HMG CoA Reductase
Inhibitors:
atorvastatin
cerivastatin
lovastatin
NOT pravastatin
NOT rosuvastatin
simvastatin
sildenafil
sirolimus
sorafenib
tamoxifen
taxol
telaprevir
terfenadine
torisel
trazodone
vemurafenib
vincristine
zaleplon
ziprasidone
zolpidem
INHIBITOR(S)
1A2
2C8
2C19
3A4
fluvoxamine
ciprofloxacin
cimetidine
amiodarone
efavirenz
fluoroquinolones
fluvoxamine
furafylline
interferon
methoxsalen
mibefradil
ticlopidine
gemfibrozil
trimethopri
m
glitazones
montelukast
quercetin
PPIs:
Esomeprazole
lansoprazole
omeprazole
pantoprazole
Other:
rabeprazole
chloramphenicol
cimetidine
felbamate
fluoxetine
fluvoxamine
indomethacin
ketoconazole
modafinil
oral 
contraceptives
oxcarbazepine
probenicid
ticlopidine
topiramate
voriconazole
HIV Antivirals:
indinavir
nelfinavir
ritonavir
clarithromycin
itraconazole
ketoconazole
nefazodone
saquinavir
telithromycin
aprepitant
erythromycin
fluconazole
grapefruit juice
verapamil
diltiazem
cimetidine
amiodarone
NOT azithromycin
Chloramphenicol
boceprevir
ciprofloxacin
delaviridine
diethyldithiocarbamate
fluvoxamine
gestodene
imatinib
mibefradil
mifepristone
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 81 of 85
norfloxacin
norfluoxetine
star fruit
telaprevir
voriconazole
INDUCER(S)
1A2
2C8
2C19
3A4
broccoli
brussel sprouts
carbanazepine
char-grilled meat
insulin
methylcholanthrene
modafinil
nafcillin
beta-naphthoflavone
omeprazole
rifampin
tobacco
rifampin
carbamazepine
nevirapine
phenobarbital
rifampin
secobarbital
St. John’s Wort
HIV Antivirals:
efavirenz
nevirapine
barbiturates
carbamazepine
glucocorticoids
modafinil
oxcarbazepine
phenobarbital
phenytoin
pioglitazone
rifabutin
rifampin
St. John's wort
troglitazone
*Reference: http://medicine.iupui.edu/clinpharm/ddis/main-table/
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 82 of 85
APPENDIX F: PROTOCOL-APPROVED METHODS OF 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.
Female subjects will be considered of non-reproductive potential if they are either:
(1) postmenopausal (defined as at least 12 months with no menses without an alternative medical 
cause; in women < 45 years of age, a high follicle stimulating hormone (FSH) level in the 
postmenopausal range which may be used to confirm a post-menopausal state in women not 
using hormonal contraception or hormonal replacement therapy. In the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient);
OR
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion at least 6 weeks prior to screening;
OR
(3) has a congenital or acquired condition that prevents childbearing.
Female subjects of reproductive potential must agree to avoid becoming pregnant while 
receiving study drug and for 120 days after the last dose of study drug by complying with one of 
the following:
(1) practice abstinence† from heterosexual activity;
OR
(2) use (or have their partner use) acceptable contraception during heterosexual activity.
Combination method (requires use of two of the following):

diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide)

cervical cap with spermicide (nulliparous women only)

contraceptive sponge (nulliparous women only)

female condom (cannot be used together)

hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if 
it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and Ethics Review Committees (ERCs)/Institutional 
Review Boards (IRBs).  Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-
ovulation methods, etc.) and withdrawal are not acceptable methods of contraception.
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does 
not qualify as an acceptable method of contraception for subjects participating at sites in this 
country/region.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 83 of 85
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, subjects of childbearing potential must adhere to the contraception requirement (described 
above) from the day of study medication initiation (or 14 days prior to the initiation of study 
medication for oral contraception) throughout the study period up to 120 days after the last dose 
of trial therapy.  If there is any question that a subject of childbearing potential will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study.
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 staff 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 Sponsor and to Merck without delay and 
within 24 hours to the Sponsor 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 the Sponsor.
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.
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 84 of 85
-
Study #: 20170846        Effective Date: 8/22/2023


CONFIDENTIAL
Version # 6.1
eProst# 20170846
Version Date: 28/OCT/2022 
Page 85 of 85
-
Study #: 20170846        Effective Date: 8/22/2023