Clinical trial NCT02834975
Conditions: Fallopian Tube Cancer Peritoneum Cancer Epithelial Ovarian Cancer
Sponsor: University of Miami
Start date: 2016-12-22; Completion date: 2022-12-01
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The investigators hypothesize that tumor cell killing by cytotoxic chemotherapy exposes the immune system to high levels of tumor antigens.The combination of Paclitaxel/Carboplatin and Pembrolizumab may result in deeper and more durable responses compared with standard chemotherapy alone.

Detailed description:

Arms: arm 1: The following therapy will be administered during each 21-day cycle for a maximum of eight (8) cycles:

* Pembrolizumab 200mg intravenously (IV);
* Paclitaxel 175 mg/m2 IV in a neoadjuvant setting (NACT);
* Paclitaxel same as NACT, OR 80 mg/m2 IV dose dense option in an adjuvant setting (ACT);
* Carboplatin IV area under the curve (AUC) of 6.
Interventions: intervention 1: Pembrolizumab intervention 2: Paclitaxel intervention 3: Carboplatin
Intervention descriptions: intervention 1: Pembrolizumab on Day 1 of each cycle. intervention 2: * NACT: Paclitaxel on Day 1 of each cycle;
* ACT: Paclitaxel same as NACT OR; dose-dense option weekly per protocol. intervention 3: Carboplatin IV on Day 1 of each cycle.

Protocol documents:
Prot_SAP_000.pdf: 
 
Page 1 of 84 
 
 
 
EProst # 20160477 
IND # 131448 
 
Phase II Single Arm Study of Combination Pembrolizumab, Paclitaxel, and 
Carboplatin in Patients with Advanced Stage Ovarian, Fallopian Tube, or 
Peritoneal Carcinoma Receiving Neoadjuvant Chemotherapy 
VERSION # 
6.0 
VERSION DATE 
1 September 2023 
NCT # 
02834975 
 
PRINCIPAL INVESTIGATORS (PI) 
Abdulrahman Sinno, MD 
 
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Confidentiality Statement: The information contained in this document, especially unpublished 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. 
 
 


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CONTACT INFORMATION 
PRINCIPAL 
INVESTIGATOR 
Abdulrahman Sinno, MD 
Division of Gynecologic Oncology 
University of Miami (UM)/ Sylvester Comprehensive Cancer Center 
(SCCC) 
Telephone: 305-243-2233 
Email: ak.sinno@med.miami.edu  
 
Protocol Writer  
Norma Magallanes, MS, CCRP 
Sylvester Comprehensive Cancer Center 
University of Miami 
Phone: 305-243-3379 
Email: nkm42@med.miami.edu 
STATISTICIAN 
Isildinha M. Reis, DrPH 
University of Miami 
Telephone: 305-243-5884 
Email: ireis@med.miami.edu 
FUNDING SOURCE 
Merck, Inc. 
 
Regulatory Sponsor 
Abdulrahman Sinno, MD 
 
Funding Source(s) 
Merck, Inc. 
 
Investigational 
Agent(s) 
Pembrolizumab – provided by: Merck; commercial formulation 
 
Other Agent(s) 
Paclitaxel – commercial supply 
Carboplatin – commercial supply 
 
IND Status 
IND Number: 131448 
IND Sponsor-Investigator: Abdulrahman Sinno, MD 


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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: 
 
Protocol Version Number: 
Protocol Version Date: 
 
 
Signature of Investigator: 
Date: 
 
Name of Investigator (printed): 
Institution: 
 


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Table of Contents 
CONTACT INFORMATION ......................................................................................................... 2 
INVESTIGATOR AGREEMENT.................................................................................................. 3 
ABBREVIATIONS & DEFINITIONS .......................................................................................... 9 
PROTOCOL SYNOPSIS ............................................................................................................. 10 
 
BACKGROUND AND RATIONALE .............................................................................. 12 
 
Epithelial Ovarian Cancer (EOC) .................................................................................. 12 
 
Neoadjuvant Chemotherapy (NACT) in Epithelial Ovarian Cancer (EOC) .......... 12 
 
Cancer Immune Surveillance and PD-1 ......................................................................... 13 
 
Anti-PD-1/PD-L1 Agents ............................................................................................... 14 
1.3.1 
Pembrolizumab ....................................................................................................... 14 
1.3.2 ....................................................................................................................................... 15 
Carboplatin/Paclitaxel plus Pembrolizumab ...................... Error! Bookmark not defined.15 
 
Rationale for Chemotherapy Dose and Frequency of Administration ........................... 15 
 
15 
 
Rationale for Pembrolizumab Dose/Regimen Selection ................................................ 16 
 
Correlative Studies ......................................................................................................... 16 
 
OBJECTIVES .................................................................................................................... 17 
 
Primary Objectives ......................................................................................................... 17 
 
Secondary Objectives ..................................................................................................... 17 
 
Exploratory Objectives ................................................................................................... 17 
 
ENDPOINTS ..................................................................................................................... 17 
 
Primary Endpoints .......................................................................................................... 17 
 
Evaluable for pORR:............................................................................................... 17 
 
Secondary Endpoints ...................................................................................................... 18 
 
Evaluable for PFS: .................................................................................................. 18 
 
Evaluable for Safety and Tolerability: .................................................................... 18 
 
Exploratory Endpoints.................................................................................................... 18 
 
Evaluable for Predictive Biomarkers: ..................................................................... 18 
 
Evaluable for Health Status: ................................................................................... 18 
 
PATIENT SELECTION .................................................................................................... 18 
 
Inclusion Criteria ............................................................................................................ 18 


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Exclusion Criteria ........................................................................................................... 20 
4.3 
Strategies for Recruitment and Retention ...................................................................... 21 
 
STUDY DESIGN............................................................................................................... 21 
 
TREATMENT PLAN ........................................................................................................ 22 
 
Pembrolizumab............................................................................................................... 22 
 
Paclitaxel (Taxol®) ........................................................................................................ 22 
 
Carboplatin ..................................................................................................................... 23 
 
Treatment Schema .......................................................................................................... 23 
 
Concurrent Medications (as Applicable)........................................................................ 24 
 
Acceptable Medications ................................................................................................. 24 
 
Prohibited Medications .................................................................................................. 24 
 
Duration of Treatment .................................................................................................... 24 
 
Duration of Follow-Up ................................................................................................... 24 
 
TREATMENT/DOSE MODIFICATIONS ....................................................................... 24 
7.1 Assessment for Causality .................................................................................................... 24 
7.2 General Procedure for Supportive Care .............................................................................. 24 
7.3 Dose Interruptions and Supportive Care Guidelines for AEs associated with 
Pembrolizumab.......................................................................................................................... 25 
7.3.1 Dose Modifications....................................................................................................... 25 
7.3.2 Dose Interruptions ........................................................................................................ 25 
7.3.3 Supportive Care Guidelines for Pembrolizumab AEs .................................................. 25 
7.4 
Paclitaxel (Taxol®) and Carboplatin ............................................................................. 32 
7.4.1 Dose Modifications....................................................................................................... 32 
7.4.2. Dose Interruptions ....................................................................................................... 34 
 
TREATMENT DISCONTINUATION ............................................................................. 34 
 
SCHEDULE OF CLINICAL & LABORATORY EVALUATIONS ............................... 35 
 
Pre-Treatment Evaluations (Screening) ......................................................................... 35 
 
Evaluations on Treatment............................................................................................... 36 
 
All Cycles, Day 1 (±3 days) .................................................................................... 37 
 
Early Treatment Discontinuation Evaluations ............................................................... 38 
 
Safety Evaluation Visit................................................................................................... 38 
 
Follow-up Evaluations ................................................................................................... 38 


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Calendar of Clinical and Laboratory Evaluations .......................................................... 40 
 SCHEDULE OF CORRELATIVE EVALUATIONS....................................................... 42 
 Pre-Treatment Specimen Collection .............................................................................. 42 
 On Treatment Specimen Collection (during Neoadjuvant and Adjuvant treatment)..... 42 
 
All Cycles, Day 1 prior to infusion and following completion of pembrolizumab 
infusion prior to chemotherapy initiation .............................................................................. 42 
 
Interval Debulking Surgery (IDS) .......................................................................... 42 
 Off Treatment Specimen Collection .............................................................................. 42 
 
Safety Evaluation .................................................................................................... 42 
 
Follow-Up ............................................................................................................... 43 
 
Specimen Collection for Correlative Studies ................................................................. 43 
 43 
 AGENTS (DRUG FORMULATION AND PROCUREMENT) ...................................... 43 
 Pembrolizumab............................................................................................................... 43 
11.1.2 Mechanism of Action ................................................................................................. 43 
11.1.4 
Composition ............................................................................................................ 43 
11.1.5 
Storage Recommendations and Dosage Forms....................................................... 43 
 
Dispensation and Accountability ............................................................................ 44 
 MEASUREMENT OF EFFECT........................................................................................ 44 
 Pathologic Response ...................................................................................................... 44 
 Antitumor Effect – Solid Tumors................................................................................... 44 
 
Definitions............................................................................................................... 45 
 
Disease Parameters ................................................................................................. 45 
 
Methods for Evaluation of Measurable Disease ..................................................... 46 
 
Response Criteria – Evaluation of Target Lesions ................................................. 48 
 
Response Criteria – Evaluation of Non-Target Lesions ......................................... 49 
 
Evaluation of Best Overall Response ..................................................................... 49 
 
Duration of Response .............................................................................................. 50 
 
Progression-Free Survival (PFS) ............................................................................ 50 
 ADVERSE EVENTS ......................................................................................................... 51 
 Purpose ........................................................................................................................... 51 
 Adverse Event ................................................................................................................ 51 


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 Serious Adverse Events (See also Appendix A.) ........................................................... 52 
 Adverse Event Collection Period ................................................................................... 53 
 Adverse Event Reporting Requirements ........................................................................ 53 
 Expedited Adverse Event Reporting Requirements ....................................................... 54 
 Events of Clinical Interest .............................................................................................. 54 
 STATISTICAL CONSIDERATIONS............................................................................... 54 
 Overview ........................................................................................................................ 54 
 Definitions and Study Endpoints ................................................................................... 55 
 Patient Enrollment, Follow-Up, and Sample Size Justification ..................................... 56 
 Planned Statistical Analysis ........................................................................................... 57 
 DATA REPORTING ......................................................................................................... 58 
 Data and Safety Monitoring ........................................................................................... 58 
 Stopping Rules ............................................................................................................... 58 
 
Early Stopping Due to Toxicity .............................................................................. 58 
 
Early Stopping Due to Lack of Efficacy. ................................................................ 59 
 STUDY AUDITING AND MONITORING ..................................................................... 60 
 INVESTIGATOR RESPONSIBILITIES .......................................................................... 60 
 Investigator Responsibility/Performance ....................................................................... 60 
 Confidentiality ................................................................................................................ 60 
 Informed Consent and Permission to Use Protected Health Information ...................... 60 
 Source Documentation and Investigator Files ............................................................... 60 
 Recording and Processing of Data ................................................................................. 61 
 Non-Protocol Research .................................................................................................. 61 
 Ethics .............................................................................................................................. 61 
REFERENCES ............................................................................................................................. 63 
APPENDIX A: EXPEDITED ADVERSE EVENT (AE) REPORTING REQUIREMENTS ..... 68 
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 *................................................................................................................................ 80 
APPENDIX F: PROTOCOL-APPROVED METHODS OF CONTRACEPTION ..................... 83 


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ABBREVIATIONS & DEFINITIONS 
 
Term 
Abbreviation Definition 
Adjuvant chemotherapy 
ACT 
Treatment provided after the primary treatment 
to prevent cancer recurrence. 
Neoadjuvant chemotherapy NACT 
Treatment given to shrink tumors prior to 
surgical removal. 
Overall Survival 
OS 
The length of time from the date of first dose of 
study 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. 
Pathologic Objective 
Response Rate 
pORR 
The percentage of patients whose cancer shrinks 
or disappears after treatment (subjects that have 
achieved a pathologic complete response [pCR] 
or pathologic partial response [pPR]). 
Time to Progression 
TTP 
The length of time from the date of diagnosis or 
the start of treatment for a disease until the 
disease starts to get worse or spread to other 
parts of the body. 
 
Reference: National Cancer Institute (NCI) Dictionary of Cancer Terms: 
http://www.cancer.gov/dictionary    
 
 
 


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PROTOCOL SYNOPSIS 
 
Protocol 
Title 
Phase II Single Arm Study of Combination Pembrolizumab, Paclitaxel and 
Carboplatin in Patients with Advanced Stage Ovarian, Fallopian Tube, or 
Peritoneal Carcinoma Receiving Neoadjuvant Chemotherapy 
Objectives 
Primary Objectives 
• To determine the pathologic objective response rate (pORR) (complete 
response [CR] + partial response [PR]) of pembrolizumab in combination 
with paclitaxel and carboplatin in patients with advanced Stage III or IV 
epithelial ovarian, primary peritoneal or fallopian tube carcinoma (EOC). 
 
Secondary Objectives 
• To determine the progression-free survival (PFS) in patients with advanced 
Stage III or IV EOC treated with pembrolizumab, paclitaxel and carboplatin. 
• To confirm the safety and tolerability (rate of toxicity) of pembrolizumab, 
paclitaxel and carboplatin in patients with stage III or IV EOC. 
 
Exploratory Objectives 
• To determine if an immunologic profile (defined as an increased intra-tumor 
infiltration of perforin+ CD8+ T lymphocytes) may be a useful predictive 
biomarker of response and PFS. 
• To determine changes in tumor and blood biomarkers after treatment and its 
correlation with pathological response to therapy. Biomarkers include but are 
not limited to PD-L1, PD-1, CD8, FOXP3. 
 
Targeted 
Patient 
Population 
Women with primary advanced Stage III or IV EOC who are candidates for 
diagnostic laparoscopy (or interventional radiology [IR]-guided core biopsy), 
and dispositioned to receive neoadjuvant chemotherapy (NACT) with 
combination carboplatin and paclitaxel. 
Expected 
Number of 
Patients 
40 
Study Design 
This is a single arm, open-label, phase II study to assess pORR (CR + PR) in 
patients treated with pembrolizumab, paclitaxel and carboplatin for advanced 
stage III or IV EOC. 
Treatment 
Schema 
Eligible patients will undergo tissue biopsies to confirm diagnosis, followed by 3 
to 4 cycles of NACT. NACT will be paclitaxel and carboplatin in combination 
with pembrolizumab. A cycle will consist of pembrolizumab at 200mg 


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intravenous (IV), paclitaxel 175mg/m2 IV, and carboplatin area under the curve 
(AUC) of 6 IV, on day 1 every 21 days. The length of each cycle is 21 days. 
This regimen will be followed by interval debulking surgery (IDS). Adjuvant 
chemotherapy (ACT) will consist of 3 to 4 more cycles of paclitaxel with 
carboplatin plus pembrolizumab once every 21 days. At the discretion of the 
treating physician, dose-dense paclitaxel may be administered weekly (instead 
of once every [q] 3 weeks) plus carboplatin once q21 days. 
Duration of 
Treatment 
Trial therapy may stop early due to withdrawal of consent, disease progression 
and/or other criteria for discontinuation is met (whichever occurs first). 
Treatment is considered complete following 6-8 cycles of NACT and ACT total 
(4 maximum for NACT and 4 maximum for ACT). See Section 8.0 for treatment 
discontinuation criteria. 
Follow-up 
Required 
Post-
Treatment 
All patients will be followed at approximately 30 days (±7 days) after the last 
dose of study therapy as part of the Safety Evaluation. Patients without 
documented evidence of objective disease progression will have the same 
imaging studies used at Baseline and during Treatment as well as performed at 
the Safety Evaluation. Thereafter, all subjects will be followed for survival every 
3 months for up to 24 months (i.e., 2 years) by phone call or standard of care 
visit. 
Expected 
Number of 
Centers 
Sylvester Comprehensive Cancer Center (SCCC)  
Note: SCCC is inclusive of the constituent satellite sites. 
Expected 
Duration of 
the Protocol 
Estimated time for accrual is approximately 36 months; estimated duration of the 
total protocol is approximately 60 months. 
 


 
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 BACKGROUND AND RATIONALE 
 
Epithelial Ovarian Cancer (EOC) 
EOC collectively refers to ovarian, fallopian tube, and primary peritoneum cancers 
because of their similar biology. 
Current standard treatment for advanced EOC in the US includes intravenous (IV) 
paclitaxel at 175mg/m2 in combination with a platinum-containing (carboplatin area 
under the curve [AUC] of 6) agent or an intraperitoneal regimen. These regimens are 
effective with a significant clinical response rate (80%) that prolongs progression-free 
survival (PFS) and overall survival (OS). However, these therapies have a limited 
potential for cure and little progress has been made over the past 20 years in terms of 
cure rates. The likelihood of relapse after initial therapy in advanced stage disease is 
80-85% with a median PFS of approximately 8-11 months. 1-3 
 Neoadjuvant Chemotherapy (NACT) in Epithelial Ovarian Cancer (EOC) 
Given the success of NACT in achieving less aggressive surgery without compromising 
survival benefit in other cancers, interest in NACT to treat EOC developed. The first 
prospective, randomized, controlled trial assessing the role of primary debulking surgery 
(PDS) in the treatment of advanced EOC was reported in 2010 (EORTC 55971). The 
study randomized 670 patients to either NACT followed by interval debulking surgery 
(IDS) or PDS followed by chemotherapy. The study demonstrated that NACT followed 
by IDS was not inferior to PDS followed by chemotherapy. 4 These results were then 
confirmed on a second randomized controlled phase III study (CHORUS). 5 
Retrospective studies examining the invasiveness of debulking surgery in patients 
receiving NACT compared to those undergoing PDS demonstrated that NACT groups 
had less blood loss, lower rate of bowel resection, splenectomy, surgical morbidities, 
shorter and less frequent intensive care unit (ICU) admissions, and shorter 
hospitalization. Additionally, the NACT groups had lower rate of permanent colostomy 
(6 vs 24%), lower rate of complications requiring surgery (3 vs 21%), and shorter 
duration of surgery. 6, 7 
Several advantages of NACT observed in these studies include (1) the identification of 
patients with chemoresistant disease; (2) no delay in up-front therapy; (3) lower incidence 
of surgical morbidity; and most importantly (4) higher interval surgical success by 
attaining no gross residual disease at the time of surgery. 8 
These advantages, in conjunction with a growing body of literature demonstrating non-
inferiority of NACT as primary treatment, have led to a shift in practice patterns toward 
increasing utilization of this modality. Further, there is also significant data 
demonstrating that the previous definition of optimal response with a residual of <1cm 
may be inferior to no gross residual disease (R0). Patients that have an R0 at the 
completion of surgical cytoreduction have greater PFS and OS compared to patients with 
residual disease. 7, 8 Unfortunately, the selection criteria for this approach remains unclear 


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and there is currently no consensus as to which patients would benefit the most with this 
approach. 
The vast majority of women with advanced stage EOC will have chemosensitive disease. 
However, the retrospectively reported magnitude of response to NACT is highly variable. 
This is likely due to the relatively new adoption of NACT as well as the reporting 
methodology. Petrillo et al. reported on pathologic response to NACT. Response was 
categorized as complete pathologic response, microscopic response and macroscopic 
partial response (6.5%, 32.3%, and 61.2%, respectively). 9 Colombo et al, examined 
cohorts separated by less than 4 cycles or greater than 4 cycles of NACT. In both groups, 
the rate of microscopic residual disease was 62-65%, and macroscopic disease was 35%-
38%. Reported complete pathologic response has been as high as 23%. 10 Further, a 
recent study demonstrated that complete pathologic response may be a highly valuable 
prognostic tool. 9 
A system for grading response to NACT in advanced stage EOC based on minimal 
residual disease after IDS has been proposed by Bohm et al. 11 The study demonstrated 
that chemotherapy response score (CRS) has prognostic implications, particularly in 
patients achieving complete or near complete response. CRS was categorized as CRS 1 
(no or minimal tumor response), CRS 2 (appreciable tumor response amid viable tumor 
that is readily identifiable), and CRS 3 (complete or near-complete response with no 
residual tumor OR minimal irregularly scattered tumor). This system was then applied in 
a test cohort followed by a validation cohort, demonstrating reproducible results with 
prognostic significance. 11 Other studies have also shown that recurrences after clinical 
complete response are observed in about 75% of patients at a median of 10 months to as 
high as 28 months in the R0 cohort. 12-14 This emphasizes the urgent need for 
improvement(s) in current frontline therapy, as recurrent disease is largely incurable. As 
such, novel biological agents have been or are currently under investigation in the front-
line setting in large phase III studies (GOG 218, ICON-7 with bevacizumab, nintedanib, 
trebananib, and veliparib). Thus far, there has been no significant improvement in OS 
and only modest impact on PFS. 
 Cancer Immune Surveillance and PD-1 
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, which is expressed 
on the cell surface of activated T-cells, is to down-modulate unwanted or excessive 
immune responses including autoimmune reactions. 15 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 on engagement of its ligands, programmed death ligand-1(PD-L1) and/or 
programmed death ligand-2(PD-L2). 16 CTLA-4 and PD-1 normally function to 
counteract T-cell activation to self-antigens. 17-19  


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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 immunosurveillance. 18, 19 Blocking the PD-1/PD-L1 pathway may reduce the 
development of EOC tumor immune evasion and is an attractive target for therapeutic 
intervention especially in combination with standard lines of treatment. 20-22 
Invigorating tumor-specific T-cell immunity by inhibiting PD-L1/PD-1 signaling in 
conjunction with cytotoxic chemotherapy may result in deeper and more durable 
responses compared with standard chemotherapy alone. 23,24In ovarian cancer patients, 
Polcher et al. observed a significant increase in CD4+, CD8+, and granzyme B+ 
infiltration with the administration of NACT and no change in the accumulation of 
immunosuppressive Foxp3+ cells. 25 Low immunosuppressive Foxp3+ cell density was 
associated with longer PFS and improved OS. Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable 
prognosis in various malignancies.  In particular, the presence of CD8+ T-cells and the 
ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with 
improved prognosis and long-term survival in many solid tumors. 26 
These results suggest that the development of an immunogenic profile combining the 
absence of FOXP3 cells and the presence of high CD8+ and cytotoxic T cells result in 
the induction of pathologic complete response to NACT. 27 In light of these observations, 
we will evaluate whether boosting an immunological response by adding a PD-1 
inhibitor, pembrolizumab, to NACT can result in a significant survival benefit and 
whether specific immune biomarkers could be identified that may predict overall 
response in patients with ovarian cancer. 
 
 
Anti-PD-1/PD-L1 Agents 
Clinical responses to agents targeting PD-1/PD-L1 and CTLA-4 have been observed in 
EOC patients enrolled in Phase I trials of solid tumors. The KEYNOTE-028 Phase Ib 
multi-cohort study of pembrolizumab in advanced solid tumors included 96 ovarian 
cancer patients, 49 of which had PD-L1 positive tumors (51%). In this study, 
pembrolizumab demonstrated antitumor activity and durability in a heavily pretreated 
metastatic ovarian cancer cohort with a manageable safety and toxicity profile. 28 
A multi-center Phase I study of pembrolizumab demonstrated durable tumor regression 
(objective response rate) and prolonged stabilization of disease in advanced cancers, 
including ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at 
least 1 year of follow-up. 27 
In another study, PD-L1 expression on monocytes in the ascites and blood of patients 
with malignant ovarian cancer was significantly higher than those with benign or 
borderline tumors suggesting that the PD-1 pathway may be a viable target for PD-1/PD-
L1 directed antibody immunotherapy. 29  
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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 or 
subcutaneously and is approved in the United States for many oncology indications alone 
and in combination with other chemotherapy regimens.30  
1.3.2 Carboplatin/Paclitaxel plus Pembrolizumab 
Safety data for the combination of paclitaxel/carboplatin and Pembrolizumab is 
available for multiple indications. Please refer to the Investigator Brochure for study 
details and results. 30 
 
Rationale for Chemotherapy Dose and Frequency of Administration 
Rosenberg et al. demonstrated that weekly administration of paclitaxel was as effective 
as the equivalent dosed schedule every 3 weeks (Q3W) and had a better safety profile in 
patients with advanced ovarian cancer who were previously treated with one platinum-
containing regimen. 31 Evidence suggesting that dose dense weekly paclitaxel is more 
effective than every 3 weeks paclitaxel emerged from the Japanese Gynecology 
Oncology Group (JGOG 3016). 32 In this phase III trial, women were randomized to 
either standard carboplatin (AUC 6 on day 1) and paclitaxel (180mg/m2 on day 1) Q3W 
versus carboplatin (AUC  6 on day 1) and paclitaxel (80mg/m2 on days 1, 8, and 15Q3W. 
Long term follow-up demonstrated improved survival with a median overall survival of 
100.5 months in the dose dense group compared to 62.2 months in the standard arm. 
Interestingly, the study stratified patients by residual disease ≤1cm versus >1cm 
(suboptimal cohort) at the time of cytoreductive surgery. The median PFS for the 
suboptimal >1cm group receiving the dose dense regimen compared to standard Q3W 
therapy was 17.6mo vs 12.1mo, respectively. The median OS for the suboptimal group 
was 51.2mo vs 33.5mo favoring the dose dense regimen. This study suggests that women 
with a suboptimal cytoreductive surgery may benefit from a dose dense regimen of 
paclitaxel. 
 
In studies conducted by the Gynecology Oncology Group (GOG, now NRG Oncology), 
the number of adjuvant cycles given to patients ranged from 6-9 cycles. GOG 182, which 
targeted patients with advanced stage (FIGO stage III or IV) ovarian or primary 
peritoneal carcinoma, 8 cycles of adjuvant treatment were administered.33 Additionally, 
retrospective studies have looked at 6 vs 8, 9, and 12 cycles of adjuvant therapy and 
found no clear benefit. Thus, there is no standard of practice for the total number of cycles 
of adjuvant treatment in patients previously treated with neoadjuvant therapy. Boisen et 
al. presented an abstract at the 2015 annual Society of Gynecologic Oncology meeting 
which suggested that pathologic response based on the number of cycles of chemotherapy 
received may be a surrogate marker for survival in patients receiving NACT (patients 
received 6-8 cycles of chemotherapy). Thus, patients receiving treatment on this protocol 
will be given 6-8 cycles of chemotherapy at the provider’s discretion depending on 
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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. As outlined below, this dose is justified by: 
• Consistency in PK across tumor types 
• Clinical data from 8 randomized studies in melanoma and 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 paclitaxel and carboplatin. 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. 
 
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.37,38  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 
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Thus, a key correlative component of our study will be to profile EOC tumors using pre- 
treatment tumor biopsies, surgical specimens and analysis of circulating peripheral blood 
mononuclear cells to better understand the immune environment in EOC patients and its 
modulation with treatment.  We aim to define changes in intra-tumoral and peripheral 
blood lymphocyte phenotypes, activation and differentiation markers, and checkpoint 
ligand expression after NACT with pembrolizumab. 
The tumor biomarkers include but are not limited to CD3, CD4, CD8, PD-1, PD-L1, 
and FOXP3, as defined by immunohistochemistry (IHC), quantitative real time 
polymerase chain reaction (qRT-PCR)39,42-45, or other methods. Additional 
pharmacodynamic analyses will be conducted as appropriate. See Appendix D: 
Biomarker, Correlative and Special Studies for further information. 
 OBJECTIVES 
 
Primary Objectives 
• To determine the pathologic objective response rate (pORR), complete response (CR) and 
partial response (PR) of pembrolizumab in combination with paclitaxel and carboplatin in 
patients with advanced Stage III or IV EOC. 
 
Secondary Objectives 
• To determine PFS in patients with advanced Stage III or IV EOC treated with 
pembrolizumab, paclitaxel and carboplatin. 
• To confirm the safety and tolerability (rate of toxicity) of pembrolizumab, paclitaxel and 
carboplatin in patients with stage III or IV EOC. 
 
Exploratory Objectives 
• To determine if an immunologic profile (defined as an increased intra-tumor infiltration of 
perforin+ CD8+ T lymphocytes) may be a useful predictive biomarker of response and PFS. 
To determine changes in tumor and blood biomarkers after treatment and its correlation with 
pathological response to therapy. Biomarkers include but are not limited to PD-L1, PD-1, 
CD8, and FOXP3. 
 ENDPOINTS 
 
Primary Endpoints 
Section 14.2 outlines pORR criteria for pembrolizumab in combination with paclitaxel 
and carboplatin. pORR will be calculated as the proportion of patients with best CR and 
PR overall. 
 Evaluable for pORR: 
• Eligible subject(s) who receive at least one dose of pembrolizumab in 
combination with paclitaxel and carboplatin will have tissue collected at 
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Secondary Endpoints 
• Patients will be evaluated during treatment and by follow-up assessments post-
treatment. 
 Evaluable for PFS: 
Eligible patients who receive at least one dose of pembrolizumab in combination with 
paclitaxel and carboplatin. 
• In progression-free patients, PFS will be censored at the last evaluable tumor 
assessment (RECIST v1.1).46 
 Evaluable for Safety and Tolerability: 
Eligible patients who receive at least one dose of pembrolizumab in combination with 
paclitaxel and carboplatin. 
• Treatment-related adverse events (AEs) and serious adverse events (SAEs) will be 
evaluated. AEs will be assessed by and assigned severity using the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
Version 4.03. 
 
Exploratory Endpoints 
• The quantity of perforin+ CD8+ T lymphocytes in tumor tissue (baseline and 
debulking). 
 Evaluable for Predictive Biomarkers: 
Eligible patients who receive at least one dose of pembrolizumab in combination with 
paclitaxel and carboplatin and successfully undergo at least one post-treatment tumor 
biopsy. 
 Evaluable for Health Status: 
Patients who complete at least one assessment post baseline and who have received at 
least one dose of pembrolizumab in combination with paclitaxel and carboplatin. All 
causality AEs/SAEs will be evaluated in addition to treatment-related AEs. 
 PATIENT SELECTION 
 
Inclusion Criteria 
1. No prior treatment for primary advanced (Stage III or IV) high grade EOC, primary 
peritoneal, or fallopian tube carcinoma such as irradiation, chemotherapy, hormonal 
therapy, immunotherapy, investigational therapy, and/or other concurrent agents or 
therapies. 
2. Patients must undergo diagnostic laparoscopy or IR core biopsy to collect tissue 
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3. Patients must be appropriate candidates for planned NACT with combination 
carboplatin and paclitaxel administered IV Q3W. 
4. Tissue from an archival sample or newly obtained core or excisional biopsy of a 
tumor lesion. 
5. Age ≥ 18 years 
6. Life expectancy > 3 months. 
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. See 
Appendix B: Performance Status Scores for more information.) 
8. Patients must have normal organ and marrow function as defined below: 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or 
erythropoietin (EPO) dependency 
Renal 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(glomular 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 [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) 
 
Activated Partial Thromboplastin 
Time (aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of intended 
use of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of intended 
use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 


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9. Negative urine or serum pregnancy ≤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. 
10. Female subjects of childbearing potential (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 or be surgically sterile or abstain from heterosexual activity 
for the course of the study and for at least 120 days after the last study dose. See 
Appendix F. Protocol-Approved Methods of Contraception for further details. 
11. Ability to understand and the willingness to sign a written informed consent 
document. 
 
Exclusion Criteria 
1. Patients who are currently in or have participated in a study of an investigational 
agent or used an investigational device within 4 weeks of the first dose of treatment. 
2. Histology showing mucinous or low grade epithelial ovarian cancer. 
3. Patients who will not be likely to undergo IDS either secondary to performance status 
or sites of disease. If at the time of surgery, the patient is deemed to be surgically 
resectable to no gross residual, the patient will not be eligible for the study. 
4. Patients with known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. Patients with previously treated brain metastases may 
participate provided they are stable (without evidence of progression by imaging for 
at least 4 weeks prior to the first dose of study treatment and any neurologic 
symptoms have returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids for at least 28 days prior to study treatment. 
5. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy. 
6. Has received prior therapy with an anti-PD1, anti-PDL1, anti-CD137, anti-cytotoxic 
T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any 
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways) or anti-PDL2 agent. 
7. Uncontrolled intercurrent illness including but not limited to ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
8. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of study 
treatment. 
9. Prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not 
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
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10. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 
weeks prior to study Day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to previously administered event. Note: Subjects with ≤ Grade 2 
neuropathy are an exception to this criterion and may qualify for this study. If subject 
received major surgery, they must have recovered adequately from the toxicity and/or 
complications from the intervention prior to starting therapy. 
11. Has active autoimmune disease that has required systemic treatment in the past two 
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. 
12. Evidence of interstitial lung disease or active, non-infectious pneumonitis. 
13. Is pregnant or 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. 
14. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
15. 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. 
16. 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. 
17. Patient has active bacillus tuberculosis (TB). 
18. Patient with known hypersensitivity to pembrolizumab or any of its excipients 
(inactive ingredients). 
19. Patient receiving concurrent additional biologic therapy. 
20. Any other serious medical or psychiatric illness/condition likely in the judgment of 
the Investigator(s) to interfere or limit compliance with study requirements/treatment. 
4.3 
Strategies for Recruitment and Retention 
Women of all races and ethnic groups are eligible for this trial. Prospective gynecologic subjects 
will be recruited at Sylvester Comprehensive Cancer Center (SCCC) inclusive of constituent 
satellite sites.  
 STUDY DESIGN 
This is a single arm, open-label, phase II study to evaluate the effects of standard chemotherapy 
paclitaxel and carboplatin administered in combination with an anti-PD1 antibody, 
pembrolizumab, NACT for advanced stage III or IV EOC. Pathologic objective response rates 
(CR+ PR) will be assessed in patients treated with this combination. 
Patients must undergo laparoscopy or IR-guided core biopsy to collect tissue biopsies and to 
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omentum (at least one metastatic peritoneal site). If at the time of surgery, the patient is 
deemed to be surgically resectable to no gross residual, the patient will not be eligible for the 
study. 
Patients will be treated with 3-4 cycles of NACT. A cycle of NACT will consist of 
pembrolizumab at 200mg IV, paclitaxel 175mg/m2 IV and carboplatin AUC 6 IV on day 1 as 
per institutional policies. This regimen will be followed by IDS at which time paired tissue 
samples will be collected. The IDS will be scheduled to take place within 8 to 10 weeks after 
last chemotherapy treatment.  
Following IDS, patients will receive 3-4 cycles of adjuvant chemotherapy (ACT) consisting 
of paclitaxel with carboplatin plus pembrolizumab, Q3W. At the discretion of the treating 
physician(s), dose-dense chemotherapy (weekly paclitaxel with carboplatin Q3W) may be 
administered in place of the regimen received during NACT. 
Blood collection will be performed before, during NACT and ACT, and at end of study. Blood 
samples for correlative studies will be collected before and after administration of 
pembrolizumab. 
Forty subjects will be accrued and treated at Sylvester Comprehensive Cancer Center (SCCC) 
for approximately 36 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 the last dose of study treatment or before the initiation of a new anti-cancer treatment, 
whichever occurs first. Thereafter, subjects will be followed every 3-months for up to 24 
months from treatment discontinuation. 
 TREATMENT PLAN 
Patients may receive up to a maximum of 8 cycles on trial (4 cycles of NACT and 4 cycles of 
ACT).  
 Pembrolizumab 
Pembrolizumab 200 mg flat dose shall be administered in the outpatient setting per 
standard of care procedures. For further information, please refer to the Investigator’s 
Brochure.30 
 Paclitaxel (Taxol®) 
In the neoadjuvant setting, paclitaxel 175mg/m2 shall be administered as per institutional 
policy. 
In the adjuvant setting, paclitaxel may be administered in the same way as in the 
neoadjuvant setting OR it may be administered as a dose dense treatment as in the JGOG 
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dense treatment, paclitaxel will be dosed at 80mg/m2 and given as per institutional policy. 
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. Premedications should be given as per institutional policy, 
such as, steroids, H1 and H2 blockers. For further information, please refer to the 
Investigator’s Brochure. 
 Carboplatin 
The carboplatin dose will be calculated using the Calvert formula using an estimated 
Cockroft and Gault-calculated creatinine clearance to present the GFR.  
An antiemetic regimen is recommended for carboplatin.  
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 (≤0.6 mg/dL), 
due to reduced protein intake and/or low muscle mass, the CrCl should be estimated using a 
minimum value of 0.7 mg/dL. 
 Treatment Schema 
Table 6.4 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 1000 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) 
Day 1 
of each 
cycle*** 
21 days 
Paclitaxel*** 
Dexamethasone, 
Diphenhydramine and 
Famotidine  
175 mg/m2 
IV as per 
institutional 
practice 
Carboplatin 
Zofran 
AUC 6 
IV as per 
institutional 
practice 
*May use other appropriate medications 
*** At the discretion of the treating physician, dose dense paclitaxel 80 mg/m2 IV 
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Concurrent Medications (as Applicable) 
Because there is a potential for interaction of paclitaxel (Taxol®) with other 
concomitantly administered drugs through the cytochrome P450 system (Appendix E), 
the case report form (CRF) must capture the concurrent use of all other drugs, over-the-
counter medications, or alternative therapies. The principal investigator (PI) should be 
alerted if the patient is taking any agent known to affect or with the potential to affect 
selected CYP450 isoenzymes.  
 
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 CRF 
including all prescription, over-the-counter (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. .  
 
Prohibited Medications 
The Exclusion Criteria describes medications which are prohibited in this trial.  
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
Duration of Treatment 
Trial therapy will last until completion, withdrawal of consent, disease progression, 
unacceptable toxicity, study end and/or other criteria for treatment discontinuation is 
met, whichever occurs first. See Section 8.0 for treatment discontinuation criteria. 
 
Duration of Follow-Up 
All subjects will be followed for a Safety Evaluation at approximately 30-days (±7 
days) after the last dose of study treatment or before the initiation of a new anti-cancer 
treatment, whichever occurs first (See Section 9.4). Thereafter, subjects will be 
followed every 3 months for survival data for up to 24 months from the treatment 
discontinuation with either a telephone call or office visit as per standard of care.  
 TREATMENT/DOSE MODIFICATIONS 
7.1 Assessment for Causality 
Causality for all AE should be assessed and if deemed attributable, attempts should be 
made to attribute to pembrolizumab. Appendix A. Expedited AE Reporting 
Requirements.  
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Subjects should receive appropriate supportive care measures as deemed necessary by 
the treating investigator. Adverse events 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 7.3.3 Supportive Care Guidelines. 
Note: if after the evaluation. the event is determined not to be related, the Investigator 
does not need to follow the treatment guidance (as outlined below and in Table 7.3.3).  
7.3 Dose Interruptions and Supportive Care Guidelines for AEs associated with 
Pembrolizumab 
7.3.1 Dose Modifications 
No dose modification is recommended for pembrolizumab. 
7.3.2 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. 
7.3.3 Supportive Care Guidelines for Pembrolizumab AEs 
Immune-mediated adverse reactions 
Immune-mediated adverse reactions, including severe and fatal cases, have occurred in 
patients receiving KEYTRUDA. 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 KEYTRUDA, 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 KEYTRUDA 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 
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adverse reaction remains at Grade 1 or less following corticosteroid taper. If another 
episode of a severe adverse reaction occurs, permanently discontinue KEYTRUDA. 
Immune-mediated pneumonitis 
Pneumonitis (including fatal cases) has been reported in patients receiving KEYTRUDA. 
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 KEYTRUDA for moderate (Grade 2) pneumonitis, and 
permanently discontinue KEYTRUDA for severe (Grade 3), life-threatening (Grade 4) 
or recurrent moderate (Grade 2) pneumonitis. 
Immune-mediated colitis 
Colitis has been reported in patients receiving KEYTRUDA. 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 KEYTRUDA for moderate (Grade 2) or severe (Grade 3) colitis, and 
permanently discontinue KEYTRUDA for life-threatening (Grade 4) colitis. 
Immune-mediated hepatitis 
Hepatitis has been reported in patients receiving KEYTRUDA. 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 
KEYTRUDA. 
Immune-mediated nephritis 
Nephritis has been reported in patients receiving KEYTRUDA. 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 KEYTRUDA for moderate (Grade 2), and permanently discontinue 
KEYTRUDA for severe (Grade 3) or life-threatening (Grade 4) nephritis. 
Immune-mediated endocrinopathies 
Adrenal insufficiency (primary and secondary) has been reported in patients receiving 
KEYTRUDA. Hypophysitis has also been reported in patients receiving KEYTRUDA. 
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 


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KEYTRUDA for moderate (Grade 2), withhold or discontinue KEYTRUDA 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 KEYTRUDA. Monitor patients for hyperglycemia or other signs and 
symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA 
in cases of severe hyperglycemia until metabolic control is achieved. 
Thyroid disorders, including hyperthyroidism, hypothyroidism and thyroiditis, have been 
reported in patients receiving KEYTRUDA 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 
KEYTRUDA 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 KEYTRUDA may be considered. 
Severe skin reactions 
Immune-mediated severe skin reactions have been reported in patients treated with 
KEYTRUDA. Monitor patients for suspected severe skin reactions and exclude other 
causes. Based on the severity of the adverse reaction, withhold or permanently 
discontinue KEYTRUDA 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 KEYTRUDA. For signs 
or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized 
care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue 
KEYTRUDA. 
Other immune-mediated adverse reactions 
The following additional clinically significant, immune-mediated adverse reactions were 
reported in less than 1% of patients treated with KEYTRUDA 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 KEYTRUDA 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. 


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Transplant-related adverse reactions 
Solid organ transplant rejection has been reported in the postmarketing setting in patients 
treated with KEYTRUDA. Treatment with KEYTRUDA may increase the risk of 
rejection in solid organ transplant recipients. Consider the benefit of treatment with 
KEYTRUDA versus the risk of possible organ rejection in these patients. 
Acute graft-versus-host-disease (GVHD), including fatal GVHD, after treatment with 
KEYTRUDA 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 KEYTRUDA. 
Consider the benefit of treatment with KEYTRUDA versus the risk of possible GVHD 
in patients with a history of allogeneic HSCT. 
Infusion-related reactions 
Severe infusion reactions, including hypersensitivity and anaphylaxis, have been 
reported in 6 (0.2%) of 2799 patients receiving KEYTRUDA in KEYNOTE-001, 
KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010. For severe infusion reactions, 
stop infusion and permanently discontinue KEYTRUDA. Patients with mild or moderate 
infusion reaction may continue to receive KEYTRUDA with close monitoring; 
premedication with antipyretic and antihistamine may be considered.


 
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Table 7.3.3: 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 irAEs are not controlled with corticosteroid use. 
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 v4.0) 
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. 
Pneumonitis  
Grade 2 
Withhold  
• 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. 
• 
 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
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  
• 
 
Grade 4 
Permanently 
discontinue 


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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAE v4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Hepatitis 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose 
of 
0.5-1 
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 and exclude other 
causes. 
• 
Based on severity of liver enzyme elevations, 
withhold or discontinue pembrolizumab. 
Grade 3 or 4  
Withhold or 
permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg/day prednisone 
or equivalent) followed by taper. 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia1 
 
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. 
Adrenal 
insufficiency and 
hypophysitis 
(including 
hypopituitarism)1 
Grade 2 
Withhold 
• 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 3 or 4 
Withhold or 
permanently 
discontinue 
Thyroid 
disorders 
(including 
hyperthyroidism, 
hypothyroidisim, 
and thyroiditis)1 
Grade 2 
Continue  
•  
• 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 3 or 4  
Withhold or  
permanently 
discontinue 
Renal failure and 
immune-
mediated 
nephritis 
Grade 2 
Withhold  
• Administer 
corticosteroids 
(prednisone 1-2 mg/kg/day or 
equivalent) followed by taper. 
• 
Monitor changes of renal function and 
exclude other causes. 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 2 
Withhold 
• For grade 2 immune-mediated 
myocarditis, 
administer 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes. 


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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAE v4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Grade 3 or 4 
Permanently 
discontinue 
prednisone 
corticosteroid 
or 
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. 
 
1.  
1For 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. 


 
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7.4 
Paclitaxel (Taxol®) and Carboplatin 
7.4.1 Dose Modifications 
Treatment modifications regarding paclitaxel and carboplatin chemotherapy will be 
employed in a sequential manner using cycle delay and dose reduction. 
Table7.4.1.1: Dose Reduction Sequence for Paclitaxel (Taxol(R)) and Carboplatin 
Drug 
Initial Dose 
1st Reduction 
2nd Reduction 
Units 
Paclitaxel 
175 
175 
135 
mg/m2 
Carboplatin 
6 
5 
5 
AUC 
 
The following are criteria for carboplatin and paclitaxel treatment modifications and 
management of toxicities (in relation to pembrolizumab): 
Table 7.4.1.2: Treatment Modifications and Management of Toxicities for Paclitaxel (Taxol(R)) 
and Carboplatin 
Worst toxicity (CTCAE Grade)** 
Recommended Dose Modifications & Management of Toxicities 
None 
No Toxicity 
Maintain dose level. 
HEMATOLOGICAL 
Neutropenia (ANC) 
Grade 1 (ANC<lower limit of normal 
(LLN): 1.5x109 cells/L) 
Grade 2 (ANC <1.5-1.0 x109 cells/L) 
Hold treatment until ANC ≥ 1.5x109 cells/L. May maintain dose 
level (i.e., no need to dose reduce or add GCSF at discretion of 
investigator). 
Grade 3 (ANC<1-0.5 x109 cells/L) 
Grade 4 (ANC<0.5x109 cells/L) 
First occurrence: 
Hold all treatment (chemotherapy & pembrolizumab) until ANC 
≥ 1.0 x 109 cells/L then may give G-CSF. 
• 
If resolved in ≤7 days, then maintain dose level. 
• 
If resolved in >7 days, then ↓1 dose level (all treatment). 
Second occurrence: 
Hold all treatment (may give G-CSF) until ANC ≥1.0x109 
cells/L, then ↓dose level (all treatment). 
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 (may give G-CSF), 
then: 
• 
If resolved in ≤7 days, then maintain dose level. 
• 
If resolved in >7 days, then ↓1 dose level (all treatment). 
Second occurrence: 
Hold all treatment until resolved to ≤ Grade 2 (may give G-CSF) 
then ↓dose level (all treatment) or discontinue patient from study 
treatment at the investigator’s discretion. 
Thrombocytopenia 
Grade 1 (platelets (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. 


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Worst toxicity (CTCAE Grade)** 
Recommended Dose Modifications & Management of Toxicities 
• 
If resolved in >7 days, then ↓1 dose level (all treatment). 
Second occurrence: 
Hold all treatment until resolved to ≤ Grade 1, then ↓dose level 
(all treatment). 
Grade 4 (ANC<25x109 cells/L) 
First occurrence: 
Hold all treatment until resolved to ≤Grade 1, then ↓1 dose level 
(all treatment). 
Second occurrence: 
Hold all treatment until resolved to ≤ Grade 1, then ↓dose level 
(all treatment) 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). 
Maintain dose level. 
Grade 2 (> 1.5 - 3.0 x ULN), with ALT or 
AST 
 
Hold all treatment and monitor liver function tests (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 (all treatment). 
Grade 3 (> 3.0 - 10.0 x ULN), with ALT 
or AST 
Hold all treatment and monitor LFTs* weekly until resolved to ≤ 
Grade 1, then: 
• 
If resolved in ≤ 7 days,  1 dose level (all treatment). 
• 
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.** 
 
Maintain dose level. 
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 (all treatment). 
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 (all treatment). 
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) 
Hold all treatment until resolved to ≤ grade 1, then ↓ 1 dose level 
(all treatment). 
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, 


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Worst toxicity (CTCAE Grade)** 
Recommended Dose Modifications & Management of Toxicities 
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 study chair) 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 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). 
 
 
• 
 
 
 
 
• 
 
pembrolizumab
 
 
7.4.2. 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. 
  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). 


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• The patient experiences an adverse event 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. 
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 follow-up. This is particularly important to distinguish if the protocol has a 
defined follow-up period. Therefore, in such a scenario, the end of treatment (EOT) visit and 
procedures shall occur, but it is important to understand that the subject is still in Follow-up. 
If, however, a subject withdraws consent to participate in the study, this constitutes the end 
of study for the patient. Even so, attempts should be made to obtain permission to record at 
least record survival data up until the protocol-specified end of follow-up period. Methods 
used for attempted contact must also be documented properly (e.g., number of telephone calls 
to subject, certified letters, etc.). 
If a patient wishes to withdraw consent from the study, the principal investigator (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). 
 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 correlative evaluations. 
Please refer to Section 10.0 Schedule of Correlative Evaluations for specific details. 
All evaluations should be completed as detailed below and prior to the administration of trial 
treatment on Day 1 of each cycle. All evaluations will be administered on an outpatient basis. 
 Pre-Treatment Evaluations (Screening) 
The following must be collected/performed within 28 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 Form (ICF) 


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• Eligibility 
• Demographic data (age, gender, and race) 
• Medical History 
• Complete physical examination (PE) 
• Height 
• Weight 
• Vital signs (V/S) 
o Oral temperature 
o Blood pressure 
o Heart rate 
o Respiratory rate 
• ECOG Performance Status (PS) 
• 12-Lead Electrocardiogram (ECG) 
• Urine or serum pregnancy test for women of child-bearing potential 
(WoCBP). 
• Laboratory Evaluations: 
o CA 125 
o Complete Blood Count (CBC) with differential (diff) 
o Comprehensive Serum Chemistry Panel 
o Coagulation studies: 
▪ Prothrombin Time (PT)/International Normalized Ratio (INR) 
▪ Activated partial thrombobplastin time (aPTT) 
o Thyroid Tests 
▪ Triiodothyronine (T3) 
▪ Thyroxine (T4) 
▪ Thyroid-stimulating hormone (TSH) 
o Urinalysis (U/A) 
• Correlative Studies: Diagnostic laparoscopy for tissue or IR-guided core 
biopsy. See Section 10.0 Schedule of Correlative Evaluations. 
• Correlative Studies: Blood (optional). See Section 10.0 Schedule of 
Correlative Evaluations. 
• Imaging studies for tumor assessment for all known sites of disease 
(including computed tomography (CT) or magnetic resonance imaging 
(MRI) of abdomen and pelvis with contrast): the same method of assessment 
and technique used at baseline will be used during treatment and follow-up at 
the discretion of the treating physician. 
• Concomitant medications 
  Evaluations on Treatment 
Collection of Concomitant Medications and AE should occur throughout the study as 
described. Any SAE, or follow up to an SAE, including death due to any cause other than 


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progression of the cancer under study that occurs to any subject from the time the consent 
is signed through 30 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-Investigator and within 2 working days to Merck 
Global Safety. All subjects with SAEs must be followed up for outcome. (See Section 
13.0 Adverse Events and Appendix A. Expedited AE Reporting Requirements for 
details). 
 All Cycles, Day 1 (±3 days) 
• Medical History 
• Complete PE; pelvic exam done at the discretion of the Investigator. 
• Weight 
• Vital signs (V/S) 
o Oral temperature 
o Blood pressure 
o Heart rate 
o Respiratory rate 
• ECOG PS 
• Laboratory Evaluations: 
o CA 125 
o CBC with diff 
o Comprehensive Serum Chemistry Panel 
o Thyroid Tests 
▪ T3 
▪ T4 
▪ TSH 
• Correlative Studies: Blood (optional). Blood samples will be collected before 
and after administration of pembrolizumab. See Section 10.0 Schedule of 
Correlative Evaluations. 
• Imaging studies for tumor assessment for all known sites of disease 
(including CT or MRI of abdomen and pelvis with contrast) prior to IDS per 
institutional standard of care procedures: the same method of assessment and 
technique used at baseline will be used during treatment and follow-up at the 
discretion of the treating physician. 
• Genetic testing results per standard of care procedures 
• Correlative Studies; Tissue Sample (newly obtained at IDS). See Section 
10.0 Schedule of Correlative Evaluations. 
• Urine or serum pregnancy test for women of child-bearing potential 
(WoCBP) ≤72 hours (i.e., 3 days) prior to day 1 all cycles.  
• AE reporting 
• Concomitant medications  


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Patients may receive up to a maximum of 8 cycles of combination treatment (4 as 
NACT and 4 after IDS [ACT]) while on study. 
 Early Treatment Discontinuation Evaluations 
 If discontinuing treatment early, these subjects should then proceed to the Safety 
Evaluation Visit (Section 9.4) and Follow-Up Evaluation Visit(s) (Section 9.5) of the 
study. 
 Safety Evaluation Visit 
The following safety assessments must be performed at 30 days (±7 days) after the last 
dose of study treatment for all subjects. These subjects should then proceed to the 
Follow-Up Evaluation Visit(s) of the study (Section 9.54). 
• 
Medical History 
• 
Complete PE, pelvic exam done at the discretion of the Investigator. 
• 
Weight 
• 
V/S 
o Oral temperature 
o Blood pressure 
o Heart rate 
o Respiratory rate 
• 
ECOG PS 
• 
Laboratory Evaluations 
o CA 125 
o CBC with diff 
o Comprehensive Serum Chemistry Panel 
o Coagulation studies: 
▪ PT/INR 
▪ aPTT 
o Thyroid Tests 
▪ T3 
▪ T4 
▪ TSH 
• 
Correlative Studies: Blood (optional). See Section 10.0 Schedule of 
Correlative Evaluations.  
• 
Imaging studies for tumor assessment for all known sites of disease (including 
CT or MRI of abdomen and pelvis with contrast): the same method of 
assessment and technique used at baseline will be used during treatment and 
follow-up at the discretion of the treating physician. 
• 
AE reporting 
• 
Concomitant Medications 
 
Follow-up Evaluations 


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All subjects will be followed for a Safety Evaluation at approximately 30 days (±7 days) after the 
last dose of study treatment or before the initiation of a new anti-cancer treatment, whichever 
occurs first (See Section 9.4). Thereafter, subjects will be followed every 3 months for survival 
data for up to 24 months from the date of treatment discontinuation with either a telephone call 
or office visit as per standard of care.  
. 


 
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  Calendar of Clinical and Laboratory Evaluations 
 
Screening 
Treatment Cycle(s) q21 
days 
 
Safety Evaluation M 
30 days (±7 days) after treatment 
discontinuation 
Follow-Up N 
≤28 days 
prior A 
Day 1 (±3 days unless 
specified) 
Q3mos x 2 years after 
Safety Evaluation N 
ICF 
X 
 
 
 
Eligibility  
X 
 
 
 
Demographics B 
X 
 
 
 
Medical 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 
 
 
 
CA 125 
X 
X 
X 
 
CBC with diff E 
X 
X 
X 
 
Comp Serum Chemistry Panel E 
X 
X 
X 
 
PT/INR, aPTT 
X 
 
X 
 
T3, T4 and TSH 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
Correlative Studies: Diagnostic 
laparoscopy OR IR-guided core biopsy F 
X 
 
 
 
Correlative Studies: Blood G 
X 
X G 
 
X G 
 
Imaging H 
X 
X (prior to Interval 
Debulking Surgery) 
(X)H 
Baseline Symptoms 
X 
 
 
 
Genetic Testing I 
 
X 
 
 
Correlative Studies: Tissue Sample J 
(newly obtained) 
 
X (at IDS) 
 
 
Urine or serum pregnancy test K 
X 
X 
 
 
Pembrolizumab IV 
 
X 
 
 
Paclitaxel IV 
 
X (or dose-dense option: 
every (q) 7 days in 
adjuvant setting plus 
carboplatin q21 days) 
 
 
Carboplatin IV 
 
X 
 
 
Adverse Events 
 
X 
(X) L 


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Screening 
Treatment Cycle(s) q21 
days 
 
Safety Evaluation M 
30 days (±7 days) after treatment 
discontinuation 
Follow-Up N 
≤28 days 
prior A 
Day 1 (±3 days unless 
specified) 
Q3mos x 2 years after 
Safety Evaluation N 
Concomitant Medications 
X 
 
Post-Study Status O 
 
 
 
X 
A Screening evaluations should be done within 28 days prior to initiation of study treatment unless otherwise specified. 
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 Complete Blood Count (CBC) with differentials and Comprehensive Serum Chemistry Panel. 
F Tumor specimens (archival or fresh – tissue or core) will be obtained at baseline diagnostic surgery (laparoscopy or IR-guided) at baseline/screening (28 days prior 
to Cycle 1, day 1). 
G Blood (20 mL) will be collected at baseline/screening, on day 1 of NACT and ACT, prior to pembrolizumab and following pembrolizumab, and prior to IDS to 
characterize serum biomarkers.  
H Imaging for tumor assessment for all known sites of disease (including CT or MRI of abdomen or pelvis with contrast) prior to IDS per institutional standard of 
care procedures: the same method of assessment and technique used at baseline will be used during treatment and follow-up at the discretion of the treating physician. 
Imaging will be done at baseline, prior to IDS, at the end of treatment and during follow-up, as per standard of care. 
I Genetic panel testing will be performed as per institutional practice. 
J Tissue sample collection during Treatment (i.e., at IDS) is optional and for correlative studies (see Section 10.0 for details). IDS to be scheduled within 10 weeks 
from the last chemotherapy treatment. If longer than 10 weeks, it must be discussed with the PI. 
K Urine or serum (beta-HCG) pregnancy test is required for women of childbearing potential at screening and within 3-days prior to Day 1 of each cycle treatment 
and should be conducted until women have surgery.  
L AE/SAE collections should continue for at least 30 days after the last dose of treatment. All subjects with SAEs must be followed up for outcome. (See Section 
13.0 and Appendix A for details). 
M Safety Evaluation visit for all patients; these safety assessments must be performed at 30 days (±7 days) after the last dose of study treatment. 
N All subjects will be followed for a Safety Evaluation at approximately 30 days (±7 days) after the last dose of study treatment or before the initiation of a new anti-
cancer treatment, whichever occurs first (See Section 9.4). Thereafter, subjects will be followed every 3 months for survival data for up to 24 months from the 
treatment discontinuation with either a telephone call or office visit as per standard of care.  
O To follow-up on patients’ post-study anticancer therapy and survival status by means of a phone call or office visit per standard of care. 


 
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 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 neoadjuvant 
treatment before and after pembrolizumab 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 and other evaluations based on available modalities at time of 
evaluation.39, 42, 45 
 
Tumor specimens will be obtained at baseline diagnostic surgery (laparoscopy or IR-guided) 
and at IDS. 
 
Immunohistochemistry and additional interrogations will be performed to determine tumor 
expression of biomarkers (including but not limited to CD3, CD4, CD8, PD-1, PD-L1, 
FOXP3), on formalin fixed paraffin embedded tumor specimens.45 
 
Immune gene expression profiling via qRT-PCR and/or other evaluations will be performed 
on available snap frozen tumor specimens.45 
 
 
Pre-Treatment Specimen Collection 
The following should be collected at baseline/screening (28 days prior to Cycle 1, Day 
1): 
• Tumor specimens (archival or fresh – tissue or core) 
• Blood (20 mL) 
 
On Treatment Specimen Collection (during Neoadjuvant and Adjuvant treatment) 
 All Cycles, Day 1 prior to infusion and following completion of pembrolizumab 
infusion prior to chemotherapy initiation 
• Blood (20 mL) 
 Interval Debulking Surgery (IDS) 
• Blood (20 mL) just prior to IDS 
• Tumor specimens 
 
Off Treatment Specimen Collection 
 Safety Evaluation 
•  All subjects will be followed for a Safety Evaluation at approximately 30-days 
(±7 days) after the last dose of study treatment or before the initiation of a new 
anti-cancer treatment, whichever occurs first (See Section 9.4). The following 
sample collection activities for correlative studies are performed during the 
Safety Evaluation visit. Blood (20 mL) 


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 Follow-Up  
Subjects will be followed every 3 months for survival data for up to 24 months from the 
treatment discontinuation with either a telephone call or office visit as per standard of 
care.  
 
Specimen Collection for Correlative Studies  
Timepoints 
Tumor Collection 
Blood 
Screening 
X* 
X 
All NACT and ACT Treatment 
Cycles, Day 1 
 
X** 
Interval Debulking Surgery 
(IDS) 
X 
X 
Safety Evaluation 
 
X 
Follow-Up (q3mo x 2 years 
after last treatment) 
 
 
*Tumor sample collected laparoscopically or IR-guided core biopsy. 
**Blood samples for correlative studies will be collected before and after administration of 
pembrolizumab. 
 
 
AGENTS (DRUG FORMULATION AND PROCUREMENT) 
 
Pembrolizumab 
Refer to the FDA-approved package insert and current version of the Investigator’s Brochure 
(IB) for more information.30 
11.1.2 Mechanism of Action 
MK-3475 is a potent and highly selective humanized mAb designed to block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2. MK-3475 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. 
11.1.4 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.  
11.1.5 Storage Recommendations and Dosage Forms 


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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! 
 
 Dispensation and Accountability 
For this study, pembrolizumab will be provided by Merck as the commercial formulation of 
pembrolizumab at 100 mg/4 mL 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. See Section 8.5 Treatment Dispensation, 
Compliance and Accountability for Pembrolizumab for instructions on dispensing, accounting, 
and disposal. 
 
MEASUREMENT OF EFFECT 
Patient’s response(s) to study treatment will be assessed pathologically. 
 
Pathologic Response 
The main specimen will be sampled uniformly with intervals of at least one section per 
centimeter. The secondary specimens (e.g., omentum, colon, appendix) will be grossly 
evaluated for the presence of macroscopic disease, and representative sections will be taken. 
For this protocol, pathologic complete response (pCR) will be defined as no residual 
macroscopic or (viable) microscopic disease. Pathologic partial response (pPR) will be 
defined as the presence of residual (viable) microscopic tumor, and the size of the largest 
focus will be provided for possible outcome correlation. A percentage (residual 
tumor/background of necrosis and fibrosis) will also be documented for the main specimen.  
 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response after completion 
of 3-4 cycles of NACT and after 3-4 cycles of ACT. In addition to a baseline scan, 
confirmatory scans should also be obtained no less than 4 weeks following initial 
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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)https://ctep.cancer.gov/protocoldevelopment/docs/recist_guideline.pdf.47 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.47 
 Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with pembrolizumab, paclitaxel and carboplatin. 
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. 
 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). 
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 
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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, but in addition 
should be those that lend themselves to reproducible repeated measurements. It may be the 
case that, on occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly should be 
selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression 
in the measurable dimension of the disease. 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline. Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow-
up. 
 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
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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, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type 
of scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
 
Positron Emission Tomography (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. 
 
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 
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the Gynecologic Cancer Intergroup has developed CA 125 progression criteria which are to 
be integrated with objective tumor assessment for use in first-line trials in ovarian cancer.50  
Cytology, Histology: These techniques can be used to differentiate between PR and CR in 
rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known 
residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
 
Fluorodeoxyglucose (FDG)-PET: While FDG-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement 
CT scanning in assessment of progression (particularly possible 'new' disease). New lesions 
on the basis of FDG-PET imaging can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a sign of 
progressive disease (PD) based on a new lesion. 
b. 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. 
c. 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. 
 Response Criteria – Evaluation of Target Lesions 
Table 12.2.4: 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 
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increase of at least 5 mm.  (Note:  the appearance of one or more new 
lesions is also considered progressions). 
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. 
 Response Criteria – Evaluation of Non-Target Lesions 
Table 12.2.5.1: 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. 
 
 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease): 
 
Table 12.2.5.2: 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** 
CR 
Non-
CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once >4 
wks from baseline** 
PD 
Any 
Yes or No 
PD 
 


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Any 
PD*** 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.46 
**    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 12.2.5.3: 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. 
 
 Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements. 
 Progression-Free Survival (PFS) 
PFS is defined as the duration of time from start of treatment to time of disease 
progression or death, whichever occurs first. 


 
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ADVERSE EVENTS 
The descriptions and grading scales found in the revised NCI CTCAE version 4.03 will be 
utilized for adverse event (AE) reporting. 
 
Purpose 
Adverse event (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. Adverse events (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. 
 
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 
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Progression of Disease 
Progression of disease (PD), if documented in accordance to standard of care, should not 
be reported as an AE. 
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. 
 
Serious Adverse Events (See also Appendix A.) 
Serious AE (SAE) means any untoward medical occurrence that occurs at any dose: 
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 


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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. 
 
Adverse Event Collection Period 
In this protocol, AE include only treatment-emergent AEs. A treatment-emergent adverse 
event (TEAE) is defined as any event that begins or worsens after the start of protocol 
treatment. All baseline-emergent AEs, 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. 
 
All AEs that occur ≤ 30 days of the last dose of study therapy will be reported as well as 
until end of treatment or end of safety follow up visit whichever occurs last. Resolution 
is defined as a return to baseline status or the stabilization of an event with the expectation 
that it will remain chronic. (Exception: If a patient begins an alternative therapy that 
confounds accurate assessment of AEs within ≤ 30 days of the last dose of study therapy, 
all AE collection will stop and any ongoing events closed out.) 
 
Adverse Event Reporting Requirements 
The information to be reported in AEs will be assessed by and assigned severity using 
the NCI CTCAE, Version 4.03. The NCI CTCAE provides descriptive terminology and 
a grading scale for each adverse event listed. A copy of the NCI CTCAE v 4.03 can be 
downloaded from the Cancer Therapy Evaluation Program (CTEP) home page 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm 
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). 
4. Severity of the event as determined by NCI CTCAE, Version 4.03 grading scale. 
5. Relationship of the AE to study therapy. Refer to NCI Guidelines for Investigators 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguideli
nes.pdf which are categorized as follows: 


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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 13.3 Serious 
Adverse Events. 
7. Whether the AE is Suspected and/or Unexpected. Refer to FDA Title 21 part 312. 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32  
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. 
 
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 provides information about these expedited reporting 
requirements. 
 
Events of Clinical Interest 
Not applicable.  
 
STATISTICAL CONSIDERATIONS 
 
Overview 
The primary objective of this single-arm, open label, phase II study is to determine the 
pathologic objective response rate (CR + PR) in patients treated with pembrolizumab, 
paclitaxel and carboplatin for advanced stage III or IV EOC. Pathologic objective 
response will be assessed at time of IDS. 
 


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Secondary objectives of this study include (1) determine treatment-related toxicity and 
(2) PFS in patients with advanced Stage III or IV EOC treated with pembrolizumab, 
paclitaxel and carboplatin. 
 
In addition, the study exploratory objectives are as follows: (1) determine if an 
immunologic profile (defined as an increased intra-tumor infiltration of perforin+ 
CD8+ T lymphocytes) may be a useful predictive biomarker of response and PFS; (2) 
define changes in tumor and blood biomarkers such as but not limited to, CD3, CD4, 
CD8, PD-L1, PD-1, FOXP3) after treatment and its correlation with pathological and 
radiological response to therapy. 
 
Analysis of primary and secondary endpoints will be based on all evaluable patients as 
defined in Section 14.2. Sample size justification of 40 patients is provided in Section 
14.3. 
In addition, Section 15.2 provides early stopping guidelines for monitoring toxicity and 
pathologic response on a continuous basis throughout the course of the trial. The 
stopping boundaries were determined using Bayesian posterior probability 
methodology; thus, they 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.51, 52 The early stopping 
guidelines are offered for the Data Safety and Monitoring Committee (DSMC) 
consideration in its review of accumulating study data assessing AEs and treatment 
response. The number of interim analyses is unknown, but they occurred at times 
requested by the DSMC. The DSMC may recommend to stop enrollment to a study if at 
an interim analysis there is evidence of harm that is, evidence of high rate of 
unacceptable toxicity or low response rate (lack of efficacy). 
 
Definitions and Study Endpoints 
Evaluable for safety and toxicity: Study eligible patients who receive at least one dose 
of pembrolizumab in combination with paclitaxel and carboplatin. 
Evaluable for pathologic objective response: Study eligible patients who receive at 
least one dose of pembrolizumab in combination with paclitaxel and carboplatin and 
have tissue collected at baseline and at IDS. 
Exclusions: Any patient who is enrolled on study but does not receive any dose of 
proposed NACT (pembrolizumab in combination with paclitaxel and carboplatin) will 
be excluded from all efficacy analyses. Any patient who initiates treatment and is later 
found to be ineligible for study (e.g., protocol violation) will be withdrawn from study 
but will be followed for toxicity and disease progression; the experience of such 
patients will be characterized separately from that of evaluable patients. Reasons for 
exclusion of enrolled patients from the analysis set for safety will be characterized. 
Main Endpoints (see more details in sections 3 and 14): 


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Pathologic objective response rate (pORR):  the proportion of patients with best 
overall response of pathologic complete or partial responses; that is, pORR = (pCR + 
pPR)/n. 
Progression-free survival (PFS): Measured from date of start of treatment to the 
earliest occurrence of any of the following events: documented disease progression or 
death from any cause. Patients who are alive and progression-free will be censored at 
the date of last documented progression-free status which is the date of last tumor 
assessment according to RECIST v1.1.47 
 
Patient Enrollment, Follow-Up, and Sample Size Justification 
In this single-arm phase II study, we plan to enroll a maximum of 40 evaluable 
patients. Based on our institution’s enrollment capacity, we anticipate successful 
enrollment of 40 patients in approximately 36 months with an estimated 1-2 patients 
per month. The expected study duration is 4 years including a desirable minimum 
follow up of 2 years. Of note, as described in Section 15, enrollment to study will stop 
early with less than 40 patients if there is evidence of high rate of unacceptable toxicity 
at any interim monitoring as determined by the SCCC DSMC. 
The planned sample size of 40 evaluable patients provides reasonable precision as 
illustrated by considering the width of the 95% confidence interval (CI) estimate for the 
rate of pathologic objective response, pORR = (pCR + pPR)/n. Based on available 
literature, we estimate that the pORR for carboplatin and paclitaxel is about 4-6%.3,32 
We expect that the addition of pembrolizumab to paclitaxel and carboplatin will 
improve pORR to 10-15%. Table 14.3.1 illustrates point estimates and corresponding 
precisions for possible outcomes in the expected range for the true pathologic objective 
response rate (pORR). 
Table 14.3.1. Precision on potential study findings for pORR with 40 
evaluable patients 
Number of pCR + pPR 
pORR 
95% CI 
5 
12.5% 
4.2 – 26.8% 
6 
15% 
5.7 – 29.8% 
7 
17.5% 
7.3 – 32.8% 
8 
20% 
9.1 – 35.6% 
9 
22.5% 
10.8 – 38.5% 
95% CI: 95% confidence interval using binomial method. 
In terms of study power, our study size of 40 patients provides 74% power to detect a 
difference of 10% between pORRs of 5% and 15% under the null and alternative 
hypotheses respectively using a one-sided binomial test at a target 5% significance 
level. The actual significance level achieved by this test is 4.8%. Our study with 40 
patient provides 85% power to detect a difference of 12.5%, comparing pathologic 


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objective response rates 5% versus 17.5% for null and alternative hypotheses, 
respectively. 53 
Note: We plan one interim analysis after enrollment of 20 evaluable patients to assess 
futility. See Section 14.2.2. This power calculation does not take into account this 
planned interim analysis and the unknown number of interim analysis of pathologic 
response, which are determined by the DSMC. In addition, the DSMC may also 
recommend to stop enrollment to the study if at an interim analysis there is evidence of 
harm that is, evidence of high rate of unacceptable toxicity. 
 
Planned Statistical Analysis 
Statistical analysis will be based on evaluable patients as defined in Section 14.2. 
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 NCI CTCAE version 4.03. 
Pathologic objective response rate, pORR = (pCR + pPR)/n, and the rates of individual 
categories pCR and pPR as defined in section 14.0, will be reported with corresponding 
95% confidence intervals (95% CIs) using the binomial method.54 
The Kaplan-Meier method will be used to estimate and plot PFS.55 Point estimates with 
corresponding 95% CI for the proportion of progression-free and surviving patients will 
be given for selected times, such as 6 and 12, 18, and 24 months. Median time to 
progression and median survival time, if attained, will also be reported. 
Logistic regression will be utilized to assess the effect of patient prognostic factors on 
the pORR and endpoints.56 To the extent that it is possible with small sample size, 
comparison of PFS by important subgroups will be made using the log-rank test, and 
Cox proportional hazard regression will be employed for univariate and multivariable 
analysis of PFS. 57 Potential prognostic factors also include endpoints addressing 
exploratory objectives; for example, change in in perforin+CD8+ tumor infiltrating T 
cells measured in tissue or blood at laparoscopy and at debulking surgery and change in 
tumor/blood biomarker (such as but not limited to CD3, CD4, CD8, PD-L1, PD-1, 
FOXP3). 
Methods for analysis of longitudinal data, such as repeated measures analysis of 
variance (ANOVA), linear models, generalized mixed models, and profile plots will be 
employed to assess differences over time and to compare subgroups defined by key 
patient characteristics. 58 Genetic panel testing will be descriptive and evaluated in all 
patients as per institutional practice. 
 


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 DATA REPORTING 
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 and Safety Monitoring 
The SCCC DSMC will monitor this clinical trial according to the SCCC’s data and 
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 efficacy. The guidelines appearing in the Section 17.2 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. 
 Stopping Rules 
We propose the following guidelines for 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. 51, 52 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 rate. 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. 
 
 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. 
 
If a treatment-related (possible, probable, or definite) death occurs, enrollment will be 
suspended and continuation of the study will be reassessed by the DSMC. 
 
For the purposes of safety monitoring, we define unacceptable toxicity to be any 
treatment-related (possible, probable, or definite) grade 3 or higher toxicity due to 
pembrolizumab. For instance, SJS or TEN would be considered unacceptable and would 
be assigned treatment-related attribution either possible, probable or definite. Toxicity 
due to chemotherapy alone occurs commonly including grades 3/4 (neutropenia, anemia, 


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etc.) and is acceptable. Unacceptable toxicity is expected to occur in no more than 25% 
of patients. If there is evidence that the true rate of unacceptable toxicity exceeds 25%, 
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 25%. The table below shows specific instances where this guideline is met, 
suggesting early termination due to evidence of excessive unacceptable toxicity. 
Table 15.2.1.1. Stopping boundaries for toxicity 
(Stop if the number of unacceptable toxicity in N evaluable patients is more than or equal to X.) 
X: Number (%) of patients with 
unacceptable toxicity* 
N: total evaluable patients 
assessed  
for toxicity 
Observed  
unacceptable toxicity  
 rate ≥ 
3 
4 to 7 
42.9% 
4 
8 to 10 
40.0% 
5 
11 to 13 
38.5% 
6 
14 to 17 
35.3% 
7 
18 to 20 
35.0% 
8 
21 to 23 
34.8% 
9 
24 to 27 
33.3% 
10 
28 to 31 
32.3% 
11 
32 to 34 
32.4% 
12 
35 to 38 
31.6% 
13 
39 to 39 
33.3% 
*: Possible, probable, or definite treatment-related grade 3 toxicity. 
 
To illustrate the stopping guidelines, suppose that 10 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 50%, resulting in a posterior probability of >90% that the true underlying rate 
exceeds 25%, thereby suggesting early termination. 
 
Posterior probabilities for the above table are calculated under a weak prior beta 
distribution with parameters 1 =0.5 and 2 =1.5, which corresponds to an expected 
unacceptable-toxicity rate of 25% based on very limited information roughly equal to 
having studied 2 patients. This prior distribution implies also a priori chance of 39.1% 
that true rate of unacceptable toxicity is 25% or greater. 
 
 Early Stopping Due to Lack of Efficacy. 
We plan one interim analysis to assess futility. Available literature indicates that the 
pORR = pCR + pPR) for carboplatin and paclitaxel is about 4-6%, and we expect that the 
addition of pembrolizumab to paclitaxel and carboplatin will improve pORR to 10-15%. 
Based on conservative stopping rule of ≥90% posterior probability that pORR is less than 
4%, the study will be terminated early when there are no pORR observed among the first 
20 evaluable patients. This posterior probability was calculated under a weak prior beta 
distribution with parameters 1 = 0.3 and 2 = 1.7, which corresponds to an expected 


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response rate of 15%, and roughly equal to having studied 2 patients. This prior 
distribution implies a priori chance of 46.2% that true response rate is 4% or less.  
 
 
STUDY AUDITING AND MONITORING 
This study will be audited and/or monitored (as applicable) according to the University of 
Miami requirements. See also http://researchedu.med.miami.edu/regulatory-compliance-
services  and http://research.med.miami.edu/clinical-research/crors. 
 
 INVESTIGATOR RESPONSIBILITIES 
 
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. 
 
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. 
 
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). For subjects not qualified or able to give legal consent, consent 
must be obtained from a parent, legal guardian, or custodian. The investigator or 
designee must explain to the subject before enrollment into the study that for 
evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study Sponsor-Investigator, 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. 
 
Source Documentation and Investigator Files 


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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, ECG, electroencephalogram 
(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.  
 
Recording and Processing of Data 
If using hard copies of CRFs, study center personnel will complete individual CRFs in 
black 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. 
 
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. 
 
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. 
Essential documents are those documents with individually and collectively permit 
evaluation of the conduct of a trial and the quality of the data produced. This study will 


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create, utilize and file all essential documents following Good Clinical Practice (GCP) 
and the institution’s standard operating procedures.
 
 


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recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 1999; 
17(11): 3461-7. doi: 10.1200/JCO.1999.17.11.3461. Erratum in: J Clin Oncol 2000; 18(13): 
2644. Erratum in: J Clin Oncol 2007; 25(9): 1154. Erratum in: J Clin Oncol 2013; 31(13): 
1702. 
49. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, 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. J Clin 
Oncol 2008; 26(7): 1148-59.  
50. Vergote I, Rustin GJ, Eisenhauer EA, Kristensen GB, Pujade-Lauraine E, Parmar MK, et al. 
Re: new guidelines to evaluate the response to treatment in solid tumors [ovarian cancer]. 
Gynecologic Cancer Intergroup. J Natl Cancer Inst 2000; 92(18): 1534-5. 
51. Spiegelhalter DJ, Freedman LS, Parmar MK.  Bayesian approaches to randomized trials 
(with discussion). J Royal Stat Soc Ser A 1994; 157:357-416. 


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52. Fayers PM, Ashby D, Parmar MKB. Tutorial in biostatistics: Bayesian data monitoring in 
clinical trials. Stat Med 1997;16:1413 - 30. 
53. Hintze, J. (2014). PASS 13. NCSS, LLC. Kaysville, Utah, USA. www.ncss.com. 
54. Hosmer DW and Lemeshow S. Applied Logistic Regression, 2nd ed. Wiley, New York, 
2000. 
55. Armitage P, Berry G, and Matthews J N.  Statistical Methods in Medical Research, Fourth 
Edition.  Oxford: Blackwell Scientific, 2001. 
56. Machin D, Cheung YB, and Parmar MKB.  Survival Analysis: A Practical Approach.  
Second Edition, Cambridge, UK: John  Wiley & Sons, 2006. 
57. Brown H, Prescott.  Applied Mixed Models in Medicine.  New York: Wiley, 1999. 
58. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument 
for use in international clinical trials in oncology. J Natl Cancer Inst. 1993 Mar; 85(5):365-
76. 
 
 
 
 
 


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APPENDIX A: EXPEDITED ADVERSE EVENT (AE) REPORTING REQUIREMENTS 
For all AEs that meet criteria for expedited reporting, the 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 and any Safety Reports 
released by the Sponsor as applicable. 
 
I. 
FDA Expedited Reporting 
A. 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. 
B. 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/UCM0483
34.pdf 
1. 
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. 
2. 
All fatal or life-threatening AEs must be directly reported to the FDA 
within 7 calendar days of being made known to the PI. 
C. 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 
II. 
IRB Expedited Reporting 
A. All Investigators should also be aware of local Institutional requirements for AE 
reporting. For more information regarding the IRB policy, please refer to the 
University of Miami’s Human Subjects Research Office (HSRO)’s Investigator 
Manual: https://hsro.uresearch.miami.edu/_assets/pdf/hrp-103---investigator-manual--
-rev022717.pdf  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 
B. 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. 


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C. 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. 
D. All unanticipated deaths must be reported to the IRB within 24 hours of being 
made known to the PI. 
III. 
Merck Expedited Reporting 
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 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, and whether or not related to Merck 
product must be reported within 24 hours to the Sponsor-Investigator and within 2 
working days to Merck Global Safety. 
C. All reports of overdose with and without an 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. 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-Investigator and to Merck. 
E. SAE reports and any other relevant safety information are to be forwarded to 
the Merck Global Safety facsimile number:  +1-215-993-1220 
F. 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. All subjects with SAE must 
be followed up for outcome. 
 
 


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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. 
 
 


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APPENDIX C: NYHA CLASSIFICATION OF HEART DISEASE 
New York Heart Association (NYHA) classification of heart disease; 
https://manual.jointcommission.org/releases/TJC2016A/DataElem0439.html  
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. 
 
 
 


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APPENDIX D: BIOMARKER, CORRELATIVE AND SPECIAL STUDIES 
Samples will be processed and stored at the University of Miami’s (UM) Biospecimen Shared 
Resource (BSSR). Biomarker analysis (PDL-1) will be performed by QualTek Molecular 
Laboratories. Additional biomarker analysis will be performed as deemed by Abdulrahman 
Sinno, MD. 
 
1. Email Notification 
Abdulrahman Sinno, MD (PI) should be contacted via email to notify her of all specimen 
submissions for banking. The subject line should read “NACT+Pembro_EOC_Biospecimen 
Banking”. 
PI: ak.sinno@med.miami.edu to 
Tissue Banking Facility: bssr@med.miami.edu 
 
2. Blood samples collection 
Collection of blood will be performed pre-treatment, on treatment (before pembrolizumab 
infusion) and post-treatment. 
Plasma and blood monocytes will be obtained, aliquoted and stored following the Standard 
Operating Procedures (SOP) for handling the blood samples. 
 
3. Tissue samples collection 
Collection of tissue samples will be performed pre-treatment (laparoscopy or needle core biopsy) 
and at IDS. 
For each time point, two 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. 
A sample of normal tissue will be also collected preferable at pre-treatment (laparoscopy or 
needle core biopsy). Alternatively, this sample can be collected at IDS. 
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 
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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 BSSR. 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 investigator who will have 
access to samples and data being kept in the bank is Abdulrahman Sinno, MD. 
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. 
Specimen Storage Conditions 
• 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 Information 
Biospecimen Shared Resource 
Rosenstiel Medical Science Building 
1600 NW 10th Avenue, Suite 4051 
Miami, FL 33136 
Phone: 305-243-6777 
Email: bssr@med.miami.edu 
 
5. Biomarker Analysis 
PDL1 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. 
5.1 Sample Requirements 
 
1. 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 75mm x 25mm x 1mm (other slide sizes cannot be accommodated). In 
the event this requirement cannot be met, please contact QualTek to discuss alternative 
options. 
 
2. 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 
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3. 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. 
4. 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. 
5. 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. 
 
6. 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. 
 


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5.2 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 (75mm x 25 mm x 1mm) 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. 
 
 


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5.3 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. 


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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. 
13. Ship Standard Overnight Monday through Thursday, do not ship Friday, Saturday or 
Sunday. 
5.4 Investigator Studies Supply List for FFPE Sectioned Slides Shipping to QualTek 
The following supplies, or their equivalent, will be provided by QualTek: 
Positively charged microscope slides used for 
sectioning of slides (5 per patient) 
Fisher ProbeOn Plus 25mm x 75mm x 1mm 
Capillary Gap Microscope Slides catalog 22-230-
900 
http://www.fishersci.com 
 
Plastic slide holders (1 per patient, each hold 
maximum of 5 slides) 
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 
 
 
 
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 
 


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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) 
 
 
Cold Packs (12 oz. Ice Packs, 1 for the Mailer, 2 for 
the Small Shipper, 4 for the Large Shipper) 
Bubble wrap 
Catalog s-683 
http://www.uline.com 
 
 
Miscellaneous 
Labels for the slide holders 
FedEx Pre‑Printed Air bills 
Site Supply Inventory 
Sample Manifest Template (Excel Spreadsheet 
provided electronically to site contact) 
 
 
 
 
 
 


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5.5 (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) 
 
5.6 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. 
 
 


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APPENDIX E: CYP1A2, CYP2C8, CYP2C19, CYP3A4 SUBSTRATES, INHIBITORS & 
INDUCERS * 
SUBSTRATE(S) 
1A2 
2C8 
2C19 
3A4,5,7 
Amitriptyline 
caffeine 
clomipramine 
clozapine 
cyclobenzaprine 
duloxetine 
→
→
zolmitriptan 
[paclitaxel] 
torsemide 
amodiaquine 
cerivastatin 
repaglinide 
sorafinib 
Anti-epileptics: 
diazepam→Nor 
phenytoin(O) 
S-mephenytoin 
phenobarbitone 
 
amitriptyline 
carisoprodol 
citalopram 
chloramphenicol 
clomipramine 
chlopidogrel 
cyclophosphamide 
hexobarbital 
imipramine N-
DeME 
→
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: 
Inhibitors: 
atorvastatin 
cerivastatin 
lovastatin 
NOT pravastatin 
NOT rosuvastatin 
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 
lidocaine 
methadone 
nateglinide 
nevirapine 
ondansetron 
pimozide 
propranolol 
quetiapine 
quinine 
risperidone 
romidepsin 
NOT rosuvastatin 
salmeterol 
sildenafil 
sirolimus 
sorafenib 
tamoxifen 
taxol 
telaprevir 


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SUBSTRATE(S) 
1A2 
2C8 
2C19 
3A4,5,7 
simvastatin 
terfenadine 
torisel 
trazodone 
vemurafenib 
vincristine 
zaleplon 
INHIBITORS 
1A2 
2C8 
2C19 
3A4,5,7 
fluvoxamine 
furafylline 
interferon 
methoxsalen 
mibefradil 
ticlopidine 
gemfibrozil 
trimethoprim 
glitazones 
montelukast 
quercetin 
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 
norfloxacin 
norfluoxetine 
star fruit 
telaprevir 
voriconazole 
INDUCERS 
1A2 
2C8 
2C19 
3A4, 5, 7 
broccoli 
brussel sprouts 
carbanazepine 
char-grilled meat 
insulin 
methylcholanthrene 
modafinil 
rifampin 
carbamazepine 
nevirapine 
phenobarbital 
rifampin 
secobarbital 
St. John’s Wort 
HIV Antivirals: 
efavirenz 
nevirapine 
barbiturates 
carbamazepine 
glucocorticoids 
modafinil 


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INDUCERS 
1A2 
2C8 
2C19 
3A4, 5, 7 
nafcillin 
beta-naphthoflavone 
omeprazole 
rifampin 
tobacco 
oxcarbazepine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin 
rifampin 
St. John's wort 
troglitazone 
*Reference): http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
 
 


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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 


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acceptable by local regulatory agencies and ERCs/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. 
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 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-Investigator and to Merck without 
delay and within 24 hours to the Sponsor-Investigator and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn). 
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor-Investigator. 
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.