Clinical trial NCT02728830
Conditions: Gynecologic Neoplasms Epithelial Ovarian Cancer Uterine Endometrial Cancer Fallopian Tube Cancer Peritoneal Cancer
Keywords: gynecologic cancers mullerian cancers tumoral immunoprofile
Sponsor: AA Secord
Start date: 2016-06-01; Completion date: 2022-01-31
Enrollment: 39 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The ultimate goal of the study is to identify potential biomarkers, immune gene expression signatures, and co-stimulatory pathways that may be used to understand the effect of immune checkpoint inhibitors on gynecologic cancers.

Detailed description:
Epithelial gynecologic malignancies are tumors of müllerian origin, which include ovarian, endometrial, fallopian tube, and primary peritoneal cancers, and account for \>70,000 new diagnoses and \>22,000 deaths per year in the United States alone. Treatment typically consists of a thorough cytoreductive and staging surgery in combination with platinum/taxane chemotherapy. Newer approaches adding anti-angiogenic therapies to chemotherapy have resulted in moderate improvements in recurrence free survival. However, despite these aggressive treatments, the majority of women with advanced stage at diagnosis will experience relapse. Unfortunately, relapsed disease is incurable and women ultimately die of their disease despite maximal efforts at cancer control using subsequent chemotherapy or targeted agents. There has been significant interest in incorporating immune checkpoint therapies in the treatment of gynecologic malignancies, especially given the durable remissions associated with these therapies in the treatment of melanoma and early indications of durable responses in recurrent ovarian cancer. At this time, little is known about whether or how to combine chemotherapy, anti-angiogenic therapies, and immunologic therapies for maximal benefit. Understanding the tumor microenvironment, particularly immune and angiogenic factors that contribute to tumor survival, as well as the changes that occur in response to immunotherapy is critical to identify favorable biomarker profiles which could lead to improved prognostic outcomes and inform the development and sequencing of therapies to maximize benefit.

Arms: arm 1: Subjects will receive one dose of 200mg pembrolizumab by IV 14-21 days prior to surgery. Subjects will undergo standard surgical cytoreductive surgery as deemed appropriate by their gynecologic oncologist, followed by standard adjuvant chemotherapy for their cancer as deemed appropriate by their treating physician.

If subject's disease does not get worse following standard of care chemotherapy, they will receive pembrolizumab in the maintenance setting every three weeks for up to a year.

If subject's disease returns after completing a year of pembrolizumab and they have not had adverse reactions to pembrolizumab they may be eligible to continue receiving pembrolizumab for an additional year in the second course phase.
Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: Pembrolizumab 200mg IV

Protocol documents:
Prot_SAP_000.pdf: 
 
Original version: 
October 8, 2015 
 
Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
 
 1 
 
 
 A Pilot Study Investigating the Effect of Pembrolizumab on the 
Tumoral Immunoprofile of Gynecologic Cancers of Müllerian Origin  
 
 
 
Sponsor: 
PI – Duke Cancer 
Institute 
Funding Source: 
Merck & Co. 
Protocol 
Source: 
PI - Duke Cancer 
Institute  
Duke IRB#: 
Pro00068544 
IND Number 
129933 
EudraCT 
NUMBER  
Studies in Europe only 
 
Principal Investigator 
Angeles Alvarez Secord, MD 
30 Duke Medicine Circle, 
Room 25172 
Durham, NC 27710 
919-684-6998 
919-684-5336 
secor002@mc.duke.edu 
 
Sub-Investigators 
Andrew Berchuck, MD 
andrew.berchuck@duke.edu 
 
Laura Havrilesky, MD 
laura.havrilesky@duke.edu 
Sub-Investigators (cont.) 
Paula S. Lee, MD 
paula.s.lee@duke.edu 
 
Brittany Davidson, MD 
brittany.davidson@duke.edu  
 
Kimberly Nolte, PA-C 
kimberly.nolte@duke.edu 
  
Sarah Collins, RN, MSN, ARNP 
sarah.cohlmeyer@duke.edu 
 
Stéphanie Gaillard, MD PhD 
stephanie.gaillard@jhmi.edu 
Sub-Investigators (cont.) 
Rebecca Previs, MD 
rebecca.previs@duke.edu 
 
Lead Study Coordinator 
William Andrews, RN 
william.s.andrews@duke.edu 
 
Research Nurse 
Kara Hagler, RN 
kara.hagler@duke.edu 
 
Regulatory Coordinator 
Megan Houpe, BA, CCRP 
megan.houpe@duke.edu 
 
 
 
 
 
 
 
 


 
Original version: 
October 8, 2015 
 
Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
 
 2 
 
 
 
1.0 
TRIAL SUMMARY .............................................................................................................5 
2.0 
TRIAL DESIGN ..................................................................................................................5 
2.1 
TRIAL DESIGN ........................................................................................................................... 5 
2.2 
TRIAL DIAGRAM ........................................................................................................................ 6 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) ......................................................................................7 
3.1 
PRIMARY OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................................... 7 
3.2 
EXPLORATORY OBJECTIVE............................................................................................................ 7 
4.0 
BACKGROUND & RATIONALE............................................................................................7 
4.1 
BACKGROUND ........................................................................................................................... 7 
4.1.1 
Pharmaceutical and Therapeutic Background .................................................................. 7 
4.1.2 
Preclinical and Clinical Trial Data ..................................................................................... 9 
4.2 
RATIONALE ............................................................................................................................... 9 
4.2.1 
Rationale for the Trial and Selected Subject Population .................................................. 9 
4.2.2 
Rationale for Dose Selection/Regimen/Modification ..................................................... 11 
4.2.3 
Rationale for Endpoints .................................................................................................. 12 
5.0 
METHODOLOGY ............................................................................................................. 15 
5.1 
ENTRY CRITERIA ...................................................................................................................... 15 
5.1.1 
Diagnosis/Condition for Entry into the Trial ................................................................... 15 
5.1.2 
Subject Inclusion Criteria ................................................................................................ 15 
5.1.3 
Subject Exclusion Criteria ................................................................................................ 17 
5.1.4 
Patient Entry and Registration........................................................................................ 19 
5.2.1 
Dose Selection/Modification ........................................................................................... 20 
5.2.2 
Timing of Dose Administration ....................................................................................... 23 
5.2.3 
Trial Blinding/Masking .................................................................................................... 23 
5.3 
CRITERIA FOR ENTRY INTO MAINTENANCE PHASE ......................................................................... 23 
5.4 
STRATIFICATION ...................................................................................................................... 23 
5.5 
CONCOMITANT MEDICATIONS/VACCINATIONS (ALLOWED & PROHIBITED) ........................................ 24 
5.5.1 
Acceptable Concomitant Medications ............................................................................ 24 
5.5.2 
Prohibited Concomitant Medications ............................................................................. 24 
5.6 
RESCUE MEDICATIONS & SUPPORTIVE CARE ................................................................................ 25 
5.6.1 
Supportive Care Guidelines ............................................................................................. 25 
5.7 
DIET/ACTIVITY/OTHER CONSIDERATIONS .................................................................................... 26 
5.7.1 
Diet .................................................................................................................................. 26 
5.7.2 
Contraception ................................................................................................................. 27 
5.7.3 
Use in Pregnancy ............................................................................................................ 27 
5.7.4 
Use in Nursing Women ................................................................................................... 28 
5.8 
SUBJECT WITHDRAWAL/DISCONTINUATION CRITERIA .................................................................... 28 
5.8.1 
Discontinuation of Study Therapy ................................................................................... 29 
5.9 
SUBJECT REPLACEMENT STRATEGY ............................................................................................. 29 


 
Original version: 
October 8, 2015 
 
Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
 
 3 
 
5.10 
CLINICAL CRITERIA FOR EARLY TRIAL TERMINATION ....................................................................... 29 
6.0 
TRIAL FLOW CHART ........................................................................................................ 30 
6.1 
STUDY FLOW CHART ................................................................................................................ 30 
6.2 
SECOND PHASE FLOW CHART .................................................................................................... 32 
7.0 
TRIAL PROCEDURES ........................................................................................................ 34 
7.1 
TRIAL PROCEDURES .................................................................................................................. 34 
7.1.1 
Administrative Procedures .............................................................................................. 34 
7.1.2 
Clinical Procedures/Assessments .................................................................................... 36 
7.1.3 
Laboratory Procedures/Assessments .............................................................................. 38 
7.1.4 
Immunohistochemistry for PD-L1 expression on tumor cells .......................................... 40 
7.1.5 
Other Procedures ............................................................................................................ 40 
7.1.6 
Visit Requirements .......................................................................................................... 40 
7.2 
ASSESSING AND RECORDING ADVERSE EVENTS ............................................................................. 43 
7.2.1 
Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor 
and to Merck ................................................................................................................................ 44 
7.2.2 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck............................. 45 
7.2.3 
Immediate Reporting of Adverse Events to the Sponsor and to Merck .......................... 45 
7.2.4 
Evaluating Adverse Events .............................................................................................. 47 
7.2.5 
Sponsor Responsibility for Reporting Adverse Events ..................................................... 51 
8.0 
STATISTICAL ANALYSIS PLAN .......................................................................................... 51 
8.1 
STATISTICAL ANALYSIS PLAN SUMMARY ...................................................................................... 51 
8.2 
STATISTICAL ANALYSIS PLAN ...................................................................................................... 51 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ........................... 51 
9.1 
INVESTIGATIONAL PRODUCT ...................................................................................................... 51 
9.2 
PACKAGING AND LABELING INFORMATION ................................................................................... 52 
9.3 
CLINICAL SUPPLIES DISCLOSURE ................................................................................................. 52 
9.4 
STORAGE AND HANDLING REQUIREMENTS ................................................................................... 52 
9.5 
RETURNS AND RECONCILIATION ................................................................................................. 52 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ................................................................ 53 
10.1 
CONFIDENTIALITY .................................................................................................................... 53 
10.2 
COMPLIANCE WITH FINANCIAL DISCLOSURE REQUIREMENTS ........................................................... 53 
10.3 
COMPLIANCE WITH LAW, AUDIT AND DEBARMENT ....................................................................... 53 
10.4 
COMPLIANCE WITH TRIAL REGISTRATION AND RESULTS POSTING REQUIREMENTS .............................. 53 
10.5 
QUALITY MANAGEMENT SYSTEM ............................................................................................... 53 
10.6 
DATA MANAGEMENT ............................................................................................................... 54 
11.0 
APPENDICES .................................................................................................................. 55 
11.1 
ECOG PERFORMANCE STATUS .................................................................................................. 55 
11.2 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V4.0 (CTCAE) ........................................ 55 
11.3 
EVENTS OF CLINICAL INTEREST GUIDANCE DOCUMENT .................................................................. 55 
11.4 
STANDARD OPERATING PROCEDURES FOR BLOOD, ASCITES, AND TISSUE SPECIMEN COLLECTION ......... 55 
11.5 
ELIGIBILITY CHECKLIST .............................................................................................................. 56 


 
Original version: 
October 8, 2015 
 
Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
 
 4 
 
11.6 
REGISTRATION FORM ............................................................................................................... 58 
11.7 
INVESTIGATOR SIGNATURE PAGE ................................................................................................ 59 
12.0 
REFERENCES .................................................................................................................. 60 


 
Original version: 
October 8, 2015 
 
Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
 
 5 
 
1.0 TRIAL SUMMARY 
Abbreviated Title 
Change in immunoprofile after Pembrolizumab dose in gynecologic 
cancers 
Trial Phase 
0 
Clinical Indication 
Newly diagnosed gynecologic cancers of müllerian origin 
Trial Type 
Biomarker study 
Type of control 
None 
Route of administration 
IV 
Trial Blinding 
Unblinded 
Treatment Groups  
1 
Number of trial subjects 
15 
Estimated enrollment period 
18 months 
Estimated duration of trial 
2 years 
Duration of Participation 
18 months 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
 
Patients with a gynecologic tumor of müllerian origin and no prior therapy for their current 
diagnosis will be eligible for the study. Patients will receive one dose of pembrolizumab at 
least 7 days prior to post-treatment surgery or biopsy.  Patients will undergo standard surgical 
cytoreductive surgery as deemed appropriate by their gynecologic oncologist, followed by 
standard chemotherapy for their cancer as deemed appropriate by their treating physician.  
Follow-up after completion of therapy will be per institutional standard practice.  
Patients already enrolled prior to amendment 5 will have the option of receiving maintenance 
pembrolizumab following completion of chemotherapy. Patients enrolled subsequent to the 
amendment will be required to receive maintenance pembrolizumab if they meet eligibility for 
pembrolizumab maintenance. Patients who experience radiographic disease progression after 
completion of maintenance pembrolizumab may be eligible for up to one year of additional 


 
Original version: 
October 8, 2015 
 
Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
 
 6 
 
treatment with pembrolizumab via the Second Course Phase at the discretion of the investigator 
if no cancer treatment was administered since the last dose of pembrolizumab, the subject 
meets the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is open.   
 
2.2 
Trial Diagram 
 
 


 
Original version: 
October 8, 2015 
 
Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
 
 7 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Efficacy Objective:  To assess the change in tumor immune infiltrates after 
administration of pembrolizumab. 
Hypothesis:  Tumor immune infiltrates will increase after administration of 
pembrolizumab. 
Safety Objective: To evaluate the feasibility and toxicity profile of pembrolizumab 
when given to patients with newly diagnosed gynecologic cancers of müllerian origin 
prior to standard therapy and as maintenance therapy after completion of 
chemotherapy.  
Hypothesis:  Pembrolizumab will be well tolerated when given prior to standard 
chemotherapy +/- surgery and as maintenance after completion of chemotherapy in 
patients with gynecologic cancers of müllerian origin.  
3.2 
Exploratory Objective 
(1) Objective:  To characterize changes in the tumoral and circulating blood 
immunoprofile after administration of pembrolizumab.  Levels of immune and 
inflammatory mediators, profile of tumor immune infiltrates, and the expression of 
PD-L1 in pre-administration samples will be compared to post-administration 
surgical resection (including ascites) or biopsy samples. 
(2) Objective: For patients who enroll on the second course phase: To evaluate 
changes in the tumoral and circulating blood immunoprofile at time of recurrence.  
Levels of immune and inflammatory mediators, profile of tumor immune infiltrates, 
and the expression of PD-L1 in samples at time of recurrence will be compared to 
pre-administration and surgical or biopsy samples. 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475. 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 


 
Original version: 
October 8, 2015 
 
Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
 
 8 
 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of 
murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar 
to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins.  PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors.  Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to 
PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed at 
low levels on various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune 
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety 
of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL).  
This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
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.  KeytrudaTM (pembrolizumab) has recently been approved in the United 


 
Original version: 
October 8, 2015 
 
Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
 
 9 
 
States for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Epithelial gynecologic malignancies are tumors of müllerian origin, which include ovarian, 
endometrial, fallopian tube, and primary peritoneal cancers, and account for >70,000 new 
diagnoses and >22,000 deaths per year in the United States alone1. Treatment typically consists 
of a thorough cytoreductive and staging surgery in combination with platinum/taxane 
chemotherapy.  Newer approaches adding anti-angiogenic therapies to chemotherapy have 
resulted in moderate improvements in recurrence free survival.  However, despite these 
aggressive treatments, the majority of women with advanced stage at diagnosis will experience 
relapse.  Unfortunately, relapsed disease is incurable and women ultimately die of their disease 
despite maximal efforts at cancer control using subsequent chemotherapy or targeted agents. 
There has been significant interest in incorporating immune checkpoint therapies in the 
treatment of gynecologic malignancies, especially given the durable remissions associated 
with these therapies in the treatment of melanoma and early indications of durable responses 
in recurrent ovarian cancer2,3.  At this time, little is known about whether or how to combine 
chemotherapy, anti-angiogenic therapies, and immunologic therapies for maximal benefit. 
Understanding the tumor microenvironment, particularly immune and angiogenic factors that 
contribute to tumor survival, as well as the changes that occur in response to immunotherapy 
is critical to identify favorable biomarker profiles which could lead to improved prognostic 
outcomes and inform the development and sequencing of therapies to maximize benefit. 
In this study, we propose to use immunohistochemical and molecular approaches to expand 
our current understanding of the effects of tumor immune checkpoint inhibition on cancers of 
müllerian origin.  The ultimate goal of the study is to identify potential biomarkers, immune 
gene expression signatures, and co-stimulatory pathways that may be used to develop future 
clinical trials.  Following the pathologic diagnosis of a cancer of müllerian origin, baseline 
blood and tumor samples would be obtained.  Women would receive a single dose of 
Pembrolizumab then treated conventionally with surgical therapy including total abdominal 
hysterectomy, bilateral salpingo-oophorectomy, and lymph node sampling as indicated.  This 
design affords the opportunity to obtain a significant post-administration tumor sample 
(including ascites) for analysis. In cases where surgery is not performed, a post-treatment 
biopsy specimen should be obtained. While the short-term administration of Pembrolizumab 
may have a therapeutic benefit, all women will go on to receive standard therapy which may 
include chemotherapy +/- surgery, if indicated. 


 
Original version: 
October 8, 2015 
 
Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
 
 10 
 
Amendment 5: Encompassed two major changes to the protocol: the addition of maintenance 
therapy and the allowance of a Second Course Phase of therapy with pembrolizumab for 
subjects who experience radiographic disease progression after completion of initial treatment. 
The rationale for the inclusion of maintenance therapy after completion of chemotherapy in 
this study is predicated on scientific, practical, and ethical considerations. Several current 
studies are evaluating the combination of chemotherapy with pembrolizumab followed by 
pembrolizumab maintenance. However, while the combination is feasible, it is unclear that 
giving concurrent chemotherapy and pembrolizumab is necessary; maintenance therapy 
following initial chemotherapy may be sufficient. Thus, in this amendment in addition to the 
primary objectives of evaluating the safety and immune profile after a pre-surgical dose of 
pembrolizumab, we propose to evaluate whether there are any safety concerns with 
administering pembrolizumab as maintenance therapy after receiving an initial dose prior to 
surgery and after completion of chemotherapy. As part of this, we will evaluate the circulating 
immune profile after completion of chemotherapy and during pembrolizumab maintenance 
therapy to determine the immune effect of therapy.  
This change should also obviate a practical/ethical concern we have encountered with this 
study thus far. As there are currently other studies combining chemotherapy and 
immunotherapy for this patient population, physicians and patients have been reluctant to 
consider this protocol as the patient would only receive one dose of pembrolizumab. This study 
was not originally designed with a therapeutic intent, however exposure to the single dose of 
pembrolizumab in this study would make patients ineligible for any other anti-PD-1 study. It 
stands to reason that one dose is unlikely to provide substantial therapeutic benefit, thus the 
allowance of maintenance therapy with pembrolizumab in this amendment would provide 
reasonable exposure to pembrolizumab to maintain anti-tumor response and is in keeping with 
currently FDA-approved approach to maintenance adjuvant therapy with ipilimumab in 
malignant melanoma. 
The second major change of amendment 5 is the allowance of a Second Course Phase of 
therapy with pembrolizumab for subjects who experience radiographic disease progression 
after completion of initial treatment. This approach is in keeping with current pembrolizumab 
protocols that allow for a Second Course Phase if radiographic progression is observed after 
discontinuation for complete response. Biopsy samples will be obtained from patients who opt 
for the Second Course Phase to evaluate the immunoprofile in recurrent disease. 
Amendment 6: Allows for patients to participate if they have disease that is amenable to post-
treatment biopsy 
Amendment 8: Allows for collection of additional tumor specimen and blood collection at the 
time of interval debulking surgery for exploratory translational research analysis.  


 
Original version: 
October 8, 2015 
 
Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
 
 11 
 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
Pembrolizumab (MK-3475): 200mg once at least 7 days prior to surgery or biopsy will be used 
to assess changes in immune markers pre- and post-study drug administration. 
An open-label Phase I trial (Protocol 001) has been conducted to evaluate the safety and 
clinical activity of single agent MK-3475 in locally advanced or metastatic carcinoma, 
melanoma, or non-small cell lung carcinoma (NCT01295827).  The dose escalation portion 
of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 
2 weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were well 
tolerated and no dose-limiting toxicities were observed.  This first in human study of MK-
3475 showed evidence of target engagement and objective evidence of tumor size reduction 
at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  10.0 mg/kg Q2W, the highest dose 
tested in P001, will be the dose and schedule utilized in Cohorts A, B, C and D of this 
protocol to test for initial tumor activity.  Recent data from other clinical studies within the 
MK-3475 program has shown that a lower dose of MK-3475 and a less frequent schedule 
may be sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W on P001 showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).   
 
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement is 
durable (>21 days).  This early PK and pharmacodynamic data provides scientific rationale 
for testing a Q2W and Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients enrolled on P001. Within the resulting population PK model, 
clearance and volume parameters of MK-3475 were found to be dependent on body weight. 
The relationship between clearance and body weight, with an allometric exponent of 0.59, is 
within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  MK-3475 has been found to have 
a wide therapeutic range based on the melanoma indication.  The differences in exposure for 
a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are 
anticipated to remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 
in the melanoma indication. The exposure margins are based on the notion of similar efficacy 
and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W 
(i.e. 5-fold higher dose and exposure). The population PK evaluation revealed that there was 
no significant impact of tumor burden on exposure. In addition, exposure was similar 
between the NSCLC and melanoma indications. Therefore, there are no anticipated changes 
in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 


 
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2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established 
in melanoma that are well tolerated and safe.  
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. 
For the maintenance portion of the study, subjects will receive 200mg IV every 3 weeks. This 
is the dose used in ongoing studies evaluating maintenance therapy. 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
In this biomarker study the main focus is to identify potential biomarkers, immune gene 
expression signatures, and co-stimulatory pathways that may be used to develop future 
clinical trials. We have established the following efficacy and safety endpoints.  
Because of the small sample size in this pilot study, statistical analyses will be 
descriptive. 
(1) Efficacy Endpoint: Fold change in tumor immune infiltrates after administration of 
pembrolizumab. 
(2) Safety Endpoint: Frequency and severity of adverse events associated with 
pembrolizumab when given to patients with newly diagnosed gynecologic cancers of 
müllerian origin prior to standard surgical therapy, and as maintenance therapy after 
completion of chemotherapy, as assessed by CTCAE.  
Immune checkpoint inhibitors have not been given to patients with gynecologic cancer 
prior to standard surgical therapy. While immune checkpoint inhibitors have been 
safely given in patients with recurrent gynecologic cancers and in a neoadjuvant setting 
in other cancers, establishing the safety profile of pembrolizumab for patients newly 
diagnosed with gynecologic malignancies is essential.  


 
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4.2.3.2 Biomarker Research 
(1) Changes in the tumoral and circulating blood immunoprofile after administration of 
pembrolizumab.  Levels of immune and inflammatory mediators, profile of tumor 
immune infiltrates, and the expression of PD-L1 in pre-administration samples will be 
compared to post-administration surgical resection (and ascites) and biopsy samples.  
Further biomarker analysis will be performed in a subset of patients who undergo 
neoadjuvant chemotherapy followed by standard-of-care interval debulking. In this 
subset, tumor and blood specimens will be collected from the day of surgery +/- 1 day. 
Immune markers may predict response to immunotherapy agents, however the early 
changes that occur in response to PD-1 inhibition have not been assessed. It is our 
hypothesis that characteristics of the immunomodulatory cells in the blood or tumor 
may be associated with clinical response of gynecologic malignancies to 
pembrolizumab. The identification of the markers expressed in gynecologic 
malignancies, and the change in immunophenotype in response to pembrolizumab, will 
inform the development of future clinical trials. 
The specific phenotypic markers comprising the Immune Profiling Panels (Table 1) 
were selected based upon key cellular subsets proven important in the assessment of 
immune checkpoint blockade therapeutic strategies for various human cancers, 
including melanoma, NSCLC, and renal cell carcinoma. These panels are currently in 
use to evaluate effects of immune checkpoint blockade in several clinical trials. Within 
the Tumor Reactive Panel, maturational subsets of CD4+ and CD8+ T cells (defined 
by CD197 and/or CD45RA expression) will be monitored for co-expression of 
‘regulation’ and ‘exhaustion’ markers such as CTLA-4, TIM3, PD-1, and LAG3. The 
coexpression of the latter 3 markers identifies tumor-reactive TILs4. We will also 
examine the expression of T cell activation markers HLA-DR and ICOS previously 
shown to be upregulated in patients responding to ipilimumab therapy, identifying them 
as potential pharmacodynamic biomarkers5,6. Lastly, we will track proliferating T cell 
subsets expressing the intracellular marker Ki67.   


 
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Table 1 Immune Profile Panels 
 
The Treg and MDSC panel monitors levels of immunosuppressive cells shown to 
predict response to ipilimumab6.  For these studies, Tregs will be defined as 
CD3+/CD4+/CD25hi/FoxP3+/CD127low-neg, and MDSC will be defined as lineage 
negative/CD14+/HLA-DRlow-neg.  Additionally, intracellular expression of CD152 
and FoxP3 will be monitored on Treg cells.  
A multiplex ELISA approach has been developed to analyze over 25 tumor 
angiogenesis, growth factors, and inflammatory cytokines in less than 0.5 ml of plasma 
or ascites. Coefficients of variation for most analytes are <20%.  This platform has been 
successfully used to analyze samples from several phase I to III studies. Markers of 
inflammation will be analyzed in our Phase I biomarker lab, which serves as a core lab 
for these analyses for the US Alliance Cooperative Group. Samples will be evaluated 
for soluble angiogenic factors (including but not limited to bFGF, HGF, PlGF, VEGF 
A-D, ANG1-2, PDGF, IGFBP1-3, sVEGFR1-3, sTie2), matrix-derived angiogenic 
factors (including but not limited to MMP2, MMP9, TGFβ1-2, osteopontin, 
sEndoglin), markers of coagulation (e.g. CRP, d-dimer, VWF, tissue factor), and 
markers of vascular activation and inflammation (including but not limited to IFNγ, 
IL1β, IL6, sILR6R, sGP130, IL4, IL7, IL10, IL12, IL17A, IL17E, and IL23). 


 
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The actual analytes tested may be adapted based on current knowledge at the time of 
collection. 
5.0  METHODOLOGY 
5.1 
Entry Criteria 
Before patient screening begins, each site must submit the following documents to Duke 
University, Division of Gynecologic Oncology Clinical Trials via mail or email (Attn: 
Regulatory Department, Protocol Pembro Merck): 
• 
IRB approval. 
• 
IRB-approved informed consent. 
• 
IRB Membership list or FWA assurance letter. 
• 
Study-specific signed original FDA Form 1572 for institution PI. 
• 
Current CV (signed and dated within one year) for institution PI and sub-investigators 
listed on FDA Form 1572. 
• 
Medical license for institution PI and sub-investigators listed on the FDA Form 1572. 
• 
Lab license, certificates, and required Normal Lab Values (NLV) for labs listed on 
FDA Form 1572. 
• 
Signed original Signature Page for PI. 
• 
Signed original Financial Disclosure Form for all investigators listed on FDA Form 
1572. 
• 
Delegation of Authority log. 
• 
Human Subject Protection Certificates for investigators and personnel who will be 
seeing and consenting study participants. 
 
Please allow 7-10 days for processing of regulatory documents before screening the first 
patient. All copies of the above should be filed into a study-specific regulatory binder at your 
institution. 
The initial supply of study drug cannot be shipped until all the regulatory documents have been 
reviewed and approved. Duke University may require copies of the regulatory documentation 
prior to any shipment of drug. 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Patients newly diagnosed with a gynecologic tumor of müllerian origin, specifically epithelial 
ovarian, fallopian tube, primary peritoneal, or uterine endometrial cancer. 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 


 
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1. Have histologically or cytologically confirmed gynecologic tumor of müllerian origin, 
specifically epithelial ovarian, fallopian tube, primary peritoneal, or uterine 
endometrial cancer. 
2. Have disease amenable to surgical resection or biopsy. 
3. Be willing and able to provide written informed consent/assent for the trial. 
4. Be ≥ 18 years of age on day of signing informed consent. 
5. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor 
lesion or ascites or pleural effusions via paracentesis or thoracentesis. Subjects for 
whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety 
concern) may submit an archived specimen only upon agreement of the investigator. 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
7. Demonstrate adequate organ function as defined in Table 2, all screening labs should 
be performed within 10 days of study drug administration.   
Table 2  Adequate Organ Function Laboratory Values 
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 dependency or EPO 
dependency (within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or 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 
AST (SGOT) and ALT (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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8. Female subjects of childbearing potential should have a negative serum pregnancy test 
within 72 hours prior to receiving the first dose of study medication.     
9. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity until planned 
hystecterectomy/oopherectomy (Reference Section 5.7.2).  Subjects of childbearing 
potential are those who have not been surgically sterilized or have not been free from 
menses for > 1 year.  
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving a study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the study drug administration. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to study drug 
administration. 
 
3. Has a known history of active TB (Bacillus Tuberculosis) 
 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier. 
6. Has received prior chemotherapy, targeted small molecule therapy, or radiation therapy 
for the current gynecologic malignancy.  
- 
Note:  Subjects who have received treatment for a prior unrelated malignancy 
must have recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to 
a previously administered agent. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   


 
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7. 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 that has undergone potentially curative therapy, or in situ cervical cancer. 
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks 
prior to  study drug administration and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to  study drug administration.  This exception does not 
include carcinomatous meningitis which is excluded regardless of clinical stability.   
9. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
10. Has known history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
11. Has an active infection requiring systemic therapy. 
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
14. Is pregnant or breastfeeding. 
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
18. Has received a live vaccine within 30 days of planned start of study therapy. 


 
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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. 
5.1.4 Patient Entry and Registration 
When a suitable candidate has been obtained for protocol entry, the following steps should be 
taken: 
• 
An approved consent form must be signed by the patient or guardian. The consent must 
contain language permitting the release of personal health information. Current FDA 
and institutional regulations concerning informed consent will be followed 
• 
All eligibility requirements indicated must be satisfied 
• 
Eligibility checklist data should be gathered and faxed to (919) 681-7689 
• 
Subject entry will take place after the fax is received and verification of the Eligibility 
Checklist data completed.  
• 
The institution will enter the patient’s name into a log book to verify the patient’s entry 
The study drug and dose to be used in this trial is outlined below. 
Table 3  Trial Treatment 
 
Drug 
Dose/ 
Potency 
Dose 
Frequency 
Route  
Regimen/ 
Treatment 
Period 
Use 
Pre-surgical 
or biopsy 
dose 
Pembrolizumab 
200 mg  
Once  
IV 
infusion 
Day 1  
Experimental 
Maintenance 
Pembrolizumab 
200mg 
Every 3 
weeks up 
to 1 year 
IV 
infusion 
Maintenance 
post-
chemotherapy 
(MC1-MC18)*   
Experimental 
Study drug administration should begin as close as possible to the date of enrollment on study. 
* Patients who experience dose delays of maintenance pembrolizumab will receive up to 12 
months of therapy, which may be less than 18 cycles of pembrolizumab maintenance therapy 


 
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5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.   
5.2.1.2 Dose Modifications and Interruptions  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after or several 
months after the last dose of pembrolizumab. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 4 below. No dose 
modifications are allowed.  
Table 4 Dose Modification and Toxicity Management Guidelines for Immune-Related AEs 
Associated with Pembrolizumab 
General Instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10mg prednisone or equivalent per day 
within 12 weeks 
3. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2 
Withhold 
• Administer corticosteroids 
(initial dose of 1-2mg/kg 
prednisone or equivalent) 
followed by taper 
• Monitor participants for signs and 
symptoms of pneumonitis 
• Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment 
• Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
discontinue 
Diarrhea/Colitis 
Grade 2 or 3 
 
Withhold 
• Administer corticosteroids 
(initial dose of 1-2mg/kg 
prednisone or equivalent) 
followed by taper 
 
• Monitor participants for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel perforation 
(ie, peritoneal signs and ileus) 
Grade 4 
Permanently 
discontinue 


 
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General Instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10mg prednisone or equivalent per day 
within 12 weeks 
3. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other therapies 
Monitor and follow-up 
• Participants with ≥ Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis 
• Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion 
AST, ALT, or 
Increased 
Bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids 
(initial dose of 0.5-1mg/kg 
prednisone or equivalent) 
followed by taper 
• Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme 
value returned to baseline or is 
stable 
 
3-4 
Permanently 
discontinue 
• Administer corticosteroids 
(initial dose of 1-2mg/kg 
prednisone or equivalent) 
followed by taper  
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of β-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM 
• Administer anti-hyperglycemic 
in participants with 
hyperglycemia 
• Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated 
• Monitor for signs and symptoms 
of hypophysitis (including 
hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
Hyperthyroidism  Grade 2 
Continue 
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 
 
• Monitor for signs and symptoms 
of thyroid disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 


 
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General Instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10mg prednisone or equivalent per day 
within 12 weeks 
3. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other therapies 
Monitor and follow-up 
Hypothyroidism 
Grade 2-4 
Continue 
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of 
care 
• Monitor for signs and symptoms 
of thyroid disorders 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold 
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper 
 
• Monitor for changes of renal 
function 
 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinue 
All Other 
Immune-Related 
AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
• Based on type and severity of 
AE administer corticosteroids 
 
• Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the 
type of event. 
Events that 
require 
discontinuation 
include and not 
limited to: 
Guillan-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 
1. 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab 
may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic 
control (in case of T1DM).   
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 


 
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and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
 
5.2.2 Timing of Dose Administration 
Study drug will be administered on an outpatient basis. The Pharmacy Manual contains 
specific instructions for the preparation of the pembrolizumab infusion fluid and administration 
of infusion solution. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion once.  Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible.  However, 
given the variability of infusion pumps from site to site, for reporting sites may follow their 
institutional standard guidelines. 
Day 1: Study drug is planned to be administered at least 7 days prior to standard surgery or 
research biopsy. Study drug should be administered after all procedures/assessments have been 
completed as detailed on the Trial Flow Chart (Section 6.0).   
Maintenance Phase: Study drug should be administered after all procedures/assessments have 
been completed as detailed on the Trial Flow Chart (Section 6.0).   
 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
 
5.3 
Criteria for Entry into Maintenance Phase 
 Demonstrate adequate hematologic, renal, and hepatic function as defined in Table 2 in 
Section 2.1.2. 
5.4 
Stratification 
There is no powered stratification for enrollment. Post-hoc analyses will be performed based 
upon histology of tumor, whether patient received steroids, and exploratory biomarkers. 


 
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5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (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 received within 28 days before and 30 days after study drug 
administration should be recorded.  Concomitant medications administered after 30 days after  
study drug administration should be recorded for SAEs and ECIs as defined in Section 7.2. 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Study 
Drug Administration Phase (up until and including time of surgery or biopsy)  of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.   
• Live vaccines within 30 days prior to study drug administration and while participating 
in the trial.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid 
vaccine.  


 
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• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Follow-up Phase. 
5.6 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined in Table 4 in section 5.2.1.2 and in 
greater detail in the ECI guidance document. Where appropriate, these guidelines include the 
use of oral or intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids.   Note 
that several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. For each disorder, attempts should be made to rule out other causes 
such as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. The treatment guidelines are intended to be applied when the investigator 
determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document).  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
 
5.6.1.1 Management of Infusion Reactions: Signs and symptoms usually develop during 
or shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
Table 5 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 


 
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Table 5 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but 
is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator. 
If symptoms resolve within one hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held until symptoms 
resolve and the subject should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further trial treatment 
administration. 
Subject may be premedicated 1.5h (± 
30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po (or 
equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but 
is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further 
trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug administration. 
 
 
 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 


 
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5.7.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study.  The two birth control methods can be either two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 
start using birth control from study Visit 1 throughout the study period up to planned 
hysterectomy/oopherectomy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy 
and Lactation to the Sponsor and to Merck.  If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered into 
the study. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on study, 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 and to Merck without delay and within 24 hours to 
the Sponsor and within 2 working days to Merck if the outcome is a serious adverse experience 
(e.g., death, abortion, congenital anomaly, or other disabling or life-threatening complication 
to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.    


 
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5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
• Unacceptable adverse experiences as described in Section 5.2.1.2. 
• Intercurrent illness that prevents administration of treatment. 
• Investigator’s decision to withdraw the subject. 
• The subject has a confirmed positive serum pregnancy test. 
• Noncompliance with trial treatment or procedure requirements. 
• The subject is lost to follow-up. 
• Administrative reasons. 
The Safety Follow-up visit and Post-Administration monitoring procedures are listed in 
Section 6 (Protocol Flow Chart) and Section 7.1.5 (Visit Requirements).  After study drug 
administration, each subject will be followed for 30 days for adverse event monitoring (serious 
adverse events will be collected for at least 90 days after study drug administration as described 
in Section 7.2.3.1).  Subjects who discontinue for reasons other than progressive disease will 
have post-administration follow-up for disease status until disease progression, initiating a 
non-study cancer treatment, withdrawing consent or becoming lost to follow-up.  After 
documented disease progression each subject will be followed by telephone for overall survival 
until death, withdrawal of consent, or the end of the study, whichever occurs first. 


 
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5.8.1 Discontinuation of Study Therapy 
Maintenance therapy will be discontinued after 1 year for subjects who do not discontinue for 
unacceptable adverse experiences as in Section 5.2.1.2 or progression of disease during the 
treatment phase of the study. Subjects who subsequently experience radiographic disease 
progression may be eligible for up to one year of additional treatment with pembrolizumab via 
the Second Course Phase at the discretion of the investigator if no cancer treatment was 
administered since the last dose of pembrolizumab, the subject meets the safety parameters 
listed in the Inclusion/Exclusion criteria, and the trial is open.  Subjects will resume therapy at 
the same dose and schedule at the time of initial discontinuation.  Additional details are 
provided in Section 7.1.6.6. 
5.9 
Subject Replacement Strategy 
In the event a patient is deemed ineligible or is not assessable for the primary endpoint 
assessment, the patient may be replaced at the discretion of the study PI in consultation with 
Merck. 
5.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. The study will be stopped if adequate tissue is not obtained in more than 2/3 of paired 
samples with a maximum accrual of 20 patients. 
2. Quality or quantity of data recording is inaccurate or incomplete 
3. Poor adherence to protocol and regulatory requirements 
4. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
5. Plans to modify or discontinue the development of the study drug 
 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 
 
[THIS SPACE INTENTIONALLY LEFT BLANK] 


 
Original version: 
October 8, 2015 
 
Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
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30 
 
6.0 TRIAL FLOW CHART 
 
6.1 
Study Flow Chart 
Trial Period: 
Screening 
Phase 
Pre-surgery or Biopsy Administration a 
Maintenance (M)k 
Post-
Administration 
SAE Monitoring 
Survival 
Follow-upc  
Title: 
 
Day
1 
Phone f/u 
post-dose 
Surgery 
or 
Biopsy 
Interval 
Surgery 
or 
Biopsyp  
Safety 
Follow-up 
M-C1 
M-C2 
to C18q 
Safety 
Follow-up 
 
 
Scheduling Window (Days): 
-10 to -1 
  
± 3 
≥7 days 
post-
Day1 
During 
SOC 
chemo 
30 ± 7 
post-Day1 
≤ 3 mo 
after last 
chemoh,l 
Q3wks  
-1+3D 
30 ± 7 
post- 
study drug 
90 days following 
last dose of 
pembrolizumab 
every 16 
weeks  
± 4 weeks 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant Medications 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
Post-study anticancer therapy 
 
 
 
 
 
X 
 
 
X 
 
X 
Survival Status 
 
 
 
 
 
X 
 
 
X 
 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
 
 
Xg 
Xb 
 
X 
X 
X 
X 
X 
 
Physical Examinationd 
X 
Xo 
 
 
 
X 
X 
Xi 
X 
 
 
Vital Signs and Weight 
X 
Xo 
 
 
 
X 
X 
Xm 
X 
 
 
ECOG Performance Status 
X 
Xo 
 
 
 
X 
 
 
X 
 
 
Administration of 
Pembrolizumab 
 
X 
 
 
 
 
X 
X 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – β-HCG 
 
Xa 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
X 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
 
 
 
 
X 
Xl 
X 
X 
 
 
CA125 
X 
 
 
 
 
X 
Xl 
X 
X 
 
 
Comprehensive Serum 
Chemistry  
X 
 
 
 
 
X 
Xl 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
FT3, FT4 and TSH 
X 
 
 
 
 
X 
Xl 
X 
X 
 
 


 
Original version: 
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Amended version 1:   
  April 12, 2016 
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31 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Newly Obtained Tissue or Fluid 
Collection (or archival if 
permitted at discretion of 
investigator)e 
X 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood 
Collection 
X 
 
 
Xb 
Xp 
Xf 
Xj 
Xj 
 
 
 
Surgical or Biopsy Specimen 
Collectione 
 
 
 
X 
Xp 
 
Xn 
Xn 
 
 
 
a Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication.  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.   
b Correlative studies blood collection and adverse events review may be performed up to 3 days prior to surgery or biopsy. 
c Survival follow-up may be performed by chart review or phone survey within 16 weeks, ± 4 weeks. 
d Full physical exam is to be performed during screening; directed physical exams may be performed in subsequent visits. 
e Tissue or fluid will be collected and processed according to the laboratory manual and sent to Qualtek for PD-L1 IHC and to the Weinhold lab for immune profiling. 
f Collection of a blood sample (30ml) at the next scheduled visit after completion of chemotherapy. If this coincides with start of maintenance phase, only one blood sample (30ml) 
need be collected.  
g Check of adverse events by phone ≥3 days after study drug but prior to surgery or biopsy to assess for adverse effects and/or changes to medications. 
h Patients who enrolled prior to Amendment 5 have the option to start maintenance phase within a 6 month window from last chemotherapy if they choose.  
i MD visits and physical exams will be required every other cycle.  
j Collection of blood for correlative studies during maintenance phase must occur prior to M-C1 and at least once prior to subsequent cycles.  
k Patients who have radiographic progression after completion of maintenance phase may be eligible for up to one year of additional treatment with pembrolizumab via the Second 
Course Phase at the discretion of the investigator if no cancer treatment was administered since the last dose of pembrolizumab, the subject meets the eligibility requirements for 
Second Course Phase, and the trial is open. Tissue biopsy and blood samples are required prior to start of second course phase. See Section 7.1.6.6. 
l There is a 10 day window for labs prior to start of Maintenance Phase or Second Course Phase.  
m Weight is only required every other cycle 
n Tissue collection is required at time recurrence 
o Screening procedures may be used if collected within 10 days of C1D1 
p Interval biopsy and correlative studies are optional and done only if clinically indicated at any time during standard of care treatment; subjects must opt-in or opt-out of 
collection 
q Patients who experience dose delays of maintenance pembrolizumab will receive up to 12 months of therapy, which may be less than 18 cycles of pembrolizumab maintenance 
therapy 
 


 
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  April 12, 2016 
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32 
 
6.2 
Second Phase Flow Chart 
Patients who have radiographic progression after completion of maintenance phase may be eligible for up to one year of additional 
treatment with pembrolizumab via the Second Course Phase at the discretion of the investigator if no cancer treatment was administered 
since the last dose of pembrolizumab, the subject meets the eligibility requirements for Second Course Phase, and the trial is open. 
Tissue biopsy and blood samples are required prior to start of second course phase. See Section 7.1.6.6. 
Trial Period: 
Second Course Phase (SC) 
Post-Administration SAE 
Monitoring 
Survival Follow-upc 
Title: 
SC-C1l 
SC-C2 to C18 
Safety Follow-up 
Scheduling Window (Days): 
Radiographic 
recurrencel 
Q3wks  
-1+3D 
30 ± 7 post- study 
drug 
90 days following last dose of 
pembrolizumab 
every 16 weeks 
Administrative Procedures 
Informed Consent 
 
 
  
 
  
Inclusion/Exclusion Criteria 
 
 
  
 
  
Demographics and Medical History 
 
 
  
 
  
Prior and Concomitant Medication Review 
X 
X 
 X 
 
  
Post-study anticancer therapy status 
 
 
X 
 
X 
Survival Status 
 
 
X 
 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
  
Physical Examinationd 
X 
Xi 
X 
 
  
Vital Signs and Weight 
X 
X 
X 
 
  
ECOG Performance Status 
 
 
X 
 
  
Administration of Pembrolizumab 
X 
X 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
PT/INR and aPTT 
 
 
  
 
  
CBC with Differential 
Xl 
X 
X 
 
  
CA125 
Xl 
X 
X 
 
 
Comprehensive Serum Chemistry Panel 
Xl 
X 
X 
 
  
Urinalysis 
 
 
  
 
  
FT3, FT4 and TSH 
Xl 
X 
X 
 
  
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Newly Obtained Tissue or Fluid Collection  
Xm 
 
 
 
  
Correlative Studies Blood Collection 
Xm 
 
 
 
  
Surgical and Biopsy Specimen Collectione 
 
 
 
 
  
c Survival follow-up may be performed by chart review or phone survey. 
d Full physical exam is to be performed during screening; directed physical exams may be performed in subsequent visits. 


 
Original version: 
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Amended version 1:   
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33 
 
e Tissue or fluid will be collected and processed according to the laboratory manual and sent to Qualtek for PD-L1 IHC and to the Weinhold lab for immune profiling. 
i MD visits and physical exams will be required every other cycle.  
l There is a 10 day window for labs prior to start of Maintenance Phase or Second Course Phase.  
m Patients who have radiographic progression after completion of maintenance phase may be eligible for up to one year of additional treatment with pembrolizumab via the Second 
Course Phase at the discretion of the investigator if no cancer treatment was administered since the last dose of pembrolizumab, the subject meets the eligibility requirements for 
Second Course Phase, and the trial is open. Tissue biopsy and blood samples are required prior to start of second course phase. 


 
 
Original version: 
October 8, 2015 
 
Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
34 
 
7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   


 
 
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35 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 


 
 
Original version: 
October 8, 2015 
 
Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
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36 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
study drug administration.  If a subject initiates a new anti-cancer therapy, other than planned 
chemotherapy, within 30 days after study drug administration, the Safety Follow-up visit must 
occur before the first dose of the new therapy.  Once new anti-cancer therapy, other than 
planned chemotherapy, has been initiated the subject will move into survival follow-up.  
7.1.1.6 Assignment of Screening Number 
As they are enrolled in the study, subjects will be assigned a unique consecutive number. 
7.1.1.7 Assignment of Randomization Number 
Not applicable 
7.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) 
The investigator or qualified designee will administer study drug only to subjects enrolled in 
the study in accordance with the protocol. The study drug must not be used for reasons other 
than that described in the protocol. Subjects will be supervised at the time of study drug 
administration. 
A requirement for enrollment on study is a fresh biopsy (or collection of ascites fluid or pleural 
effusions via paracentesis or thoracentesis). Subjects whose sample is found to be inadequate 
for study purposes (e.g. could not be obtained or insufficient) may continue on study at the 
discretion of the investigator. 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0 (see Section 11.2). Adverse events will not 
be collected during standard of care treatment. Toxicities will be characterized in terms 
regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  
For subjects receiving pembrolizumab all AEs of unknown etiology associated with 
pembrolizumab exposure should be evaluated to determine if it is possibly an event of clinical 


 
 
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interest (ECI) of a potentially immunologic etiology (termed immune-related adverse events, 
or irAEs).   
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to study 
drug administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of study drug as specified in the Trial Flow Chart (Section 6.0).  Vital signs 
should include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be 
measured at screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, 
prior to each administration of study drug and at end of treatment visit as specified in the Trial 
Flow Chart.   
7.1.2.6 Tumor Imaging and Assessment of Disease 
Tumor imaging and/or disease assessment will occur per NCCN guidelines during treatment 
on this protocol.  
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
All samples will be collected through the Duke Biospecimen Repository and Processing Core 
(BRPC). A biopsy (or one of the following: endometrial curettage, paracentesis for ascites 
fluid, or thoracentesis for pleural effusions) and baseline correlative studies blood collection 
will be performed within 10 days prior to study drug administration on Day 1. After 
administration on day 1, peripheral blood will be collected within 3 days prior to surgery or 
biopsy, prior to start of maintenance therapy, and at least once during maintenance therapy 


 
 
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(prior to infusion) Tumor samples and ascites/pleural effusions will be collected at the time of 
surgery or biopsy, and at time of recurrence. Samples will be collected, delivered, and stored 
according to standard operating procedures, detailed in separate lab manual. 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. 
7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 6.   


 
 
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Table 6  Laboratory Tests 
Hematology 
Comprehensive Serum Chemistries 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Free thriiodothyronine (FT3) 
Absolute Neutrophil Count 
Carbon Dioxide (CO2 or 
biocarbonate) 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Creatinine 
 
 
 
Glucose 
 
CA-125 
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   


 
 
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Laboratory tests for screening, entry into the Maintenance Phase, or entry into the Second 
Course Phase should be performed within 10 days prior to study drug administration. After 
Maintenance Cycle 1 (M-C1) or Second Course Phase Cycle 1 (SC-C1), pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of study drug 
administration.  
7.1.3.2 Pharmacodynamic Evaluations 
7.1.3.2.1 Blood Collection for Serum Pembrolizumab 
Not applicable. 
7.1.3.2.2 Blood Collection for Anti-Pembrolizumab Antibodies  
Not applicable. 
7.1.4 Immunohistochemistry for PD-L1 expression on tumor cells 
Immunohistochemistry for PD-L1 expression will be performed on the pre-treatment biopsy 
tissue or collected fluid, post-treatment surgical and biopsy specimens, and recurrence biopsy 
tissue. Sample collection, storage and shipment will be performed by the Duke BRPC as per 
instructions in the Qualtek MISP Sample Handling Manual. 
7.1.5 Other Procedures 
Not applicable. 
7.1.5.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.   
7.1.5.2 Blinding/Unblinding 
Not applicable. 
7.1.6 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 


 
 
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7.1.6.1 Screening 
Screening will only be performed after an initial pre-eligibility determination is made using 
those requirements that are part of the medical history (disease and treatment history, recent 
labs or scans, etc.), do not require specific testing, where it appears the patient may be eligible 
for study, and after an informed consent is made. 
Screening studies and labs are performed in accordance with the sections listed above. 
7.1.6.2 Pre-Surgery/Biopsy Administration Period 
The treatment period will consist of the time from study drug administration until the time of 
surgery or biopsy. A single dose of pembrolizumab will be administered on this study. The 
subject will be contacted at least once by phone ≥3 days after dose administration and prior to 
surgery or biopsy to assess for adverse effects and/or any changes in medications. 
7.1.6.3 Maintenance Phase 
Subjects who complete chemotherapy per local guidelines without unacceptable adverse 
experience (Section 5.2.1.2) attributable to Pre-Surgery/Biopsy Administration of 
pembrolizumab or progression of disease may be eligible for up to one year of maintenance 
pembrolizumab therapy. Maintenance therapy may be initiated if the subject meets the 
following conditions: 
• No radiographic evidence of disease progression after chemotherapy 
AND 
• Has a performance status of 0 or 1 on the ECOG Performance Scale 
• Demonstrates adequate organ function as detailed in Section 5.1.2 
• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of 
the trial or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator. 
Subjects who receive treatment during the maintenance phase will receive therapy according 
to Section 5.2.1.1  Maintenance treatment will be administered for up to one year. Patients who 
experience dose delays of maintenance pembrolizumab will receive up to 12 months of therapy 
which may be less than 18 cycles of pembrolizumab maintenance therapy. 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 


 
 
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7.1.6.4 Safety Follow-up Visits 
Safety Follow-Up Visits will occur after completion of each phase of treatment (i.e. Pre-
surgery/biopsy Administration, Maintenance Phase, and Second Course Phase, if applicable). 
The Safety Follow-Up Visits should be conducted approximately 30 ± 7 days after last study 
drug administration for each phase, as outlined in Section 6.0 - Trial Flow Chart.  All AEs that 
occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with an AE of Grade 
> 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning of a new 
anti-neoplastic therapy (other than planned adjuvant chemotherapy), whichever occurs first. 
SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.  Subjects who are eligible for retreatment with 
pembrolizumab (as described in Section 7.1.5.5) may have three safety follow-up visits, one 
after the Pre-Surgery/biopsy Administration Period, one after the Maintenance Phase, and one 
after the Second Course Phase. 
7.1.6.4.1  Post-Administration SAE Monitoring 
SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.  
7.1.6.5 Survival Follow-up 
After completion of post-administration monitoring, the subject moves into the survival 
follow-up phase and should be contacted by telephone every 16 weeks (+/- 4 weeks) to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever occurs 
first.  
7.1.6.6 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab after completion of the maintenance phase without 
unacceptable adverse experience or progression may be eligible for up to one year of additional 
pembrolizumab therapy if they progress after stopping study treatment.  This retreatment is 
termed the Second Course Phase of this study and is only available if the study remains open 
and the subject meets the following conditions: 
• Stopped initial treatment with pembrolizumab after completion of maintenance phase 
without disease progression or intolerability 
AND 


 
 
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• Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
• Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
• Has a performance status of 0 or 1 on the ECOG Performance Scale 
• Demonstrates adequate organ function as detailed in Section 5.1.2 
• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of 
the trial or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year. 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 


 
 
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Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator. 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. No adverse events will be collected while subjects are receiving standard 
of care chemotherapy The reporting timeframe for adverse events meeting any serious criteria 
is described in section 7.2.3.1. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided 
if clinically indicated. In the event of overdose, the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor’s designated safety reporting system, the Duke Safety Desk by fax (919-681-9357) 
or by secure email (dcccsafe@dm.duke.edu). The Duke Safety Desk will report to Merck 
Global Safety within 2 working days hours. (Attn: Worldwide Product Safety; FAX 215 993-
1220) 


 
 
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7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial treatment period. All subjects who become 
pregnant must be followed to the completion/termination of the pregnancy.  Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, 
fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events).  If the pregnancy continues to term, the outcome (health of infant) 
must also be reported. 
Such events must be reported within 24 hours to the Sponsor’s designated safety reporting 
system, the Duke Safety Desk by fax (919-681-9357) or by secure email 
(dcccsafe@dm.duke.edu). The Duke Safety Desk will report to Merck Global Safety within 2 
working days. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is an other important medical event  
Refer to Table 7 for additional details regarding each of the above criteria. 
Any serious adverse event, or follow up to a serious adverse event, 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 at least 90 days following administration of study drug, except 
when subjects are solely receiving standard of care chemotherapy, or the initiation of new anti-
cancer therapy (other than planned chemotherapy), whichever is earlier, whether or not related 
to Merck product, must be reported within 24 hours to the Sponsor’s designated safety 
reporting system, the Duke Safety Desk, by fax (919-681-9357) or by secure email 


 
 
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(dcccsafe@dm.duke.edu). The Duke Safety Desk will report to Merck Global Safety within 2 
working days.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, 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’s designated safety reporting system, the Duke Safety Desk, by 
fax (919-681-9357) or by secure email (dcccsafe@dm.duke.edu). The Duke Safety Desk will 
report to Merck Global Safety. 
SAE reports and any other relevant safety information will be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 by the Duke Safety Desk 
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 the Duke Safety Desk, which 
will send a copy to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to the Sponsor’s designated safety reporting system, the Duke Safety 
Desk by fax (919-681-9357) or by secure email (dcccsafe@dm.duke.edu). The Duke Safety 
Desk will report to Merck Global Safety within 2 working days. (Attn: Worldwide Product 
Safety; FAX 215 993-1220) Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 


 
 
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upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent). 
1. Additional adverse events: 
 
Events of Clinical Interest can be found in section 5.4.5 and tables 32 and 33 of the 
Pembrolizumab Investigator’s Brochure.   
 
ECIs (both non-serious and serious adverse events) identified in these sections from the 
date of study drug administration through at least 90 days following study drug 
administration, except when subjects are solely receiving standard of care chemotherapy, 
or 30 days after the initiation of a new anticancer therapy (not including planned 
chemotherapy), whichever is earlier, need to be reported within 24 hours to the Sponsor’s 
designated safety reporting system, the Duke Safety Desk by fax (919-681-9357) or by 
secure email (dcccsafe@dm.duke.edu). The Duke Safety Desk will report to Merck Global 
Safety within 2 working days. (Attn: Worldwide Product Safety; FAX 215 993-1220), 
regardless of attribution to study treatment, consistent with standard SAE reporting 
guidelines. 
 
Subjects should be assessed for possible ECIs prior to each dose of pembrolizumab.  Lab 
results should be evaluated and subjects should be asked for signs and symptoms 
suggestive of an immune-related event.  Subjects who develop an ECI thought to be 
immune-related should have additional testing to rule out other etiologic causes.  If lab 
results or symptoms indicate a possible immune-related ECI, then additional testing should 
be performed to rule out other etiologic causes.  If no other cause is found, then it is 
assumed to be immune-related. 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to 
the NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse 
event which changes CTCAE grade over the course of a given episode will have each 
change of grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
 


 
 
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Table 7 Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to:  
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 


 
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50 
 
 
 
 
 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology 
or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not reasonable 
OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 


 
Original version: 
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Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
51 
 
7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
We expect to enroll 15 patients with epithelial gynecologic malignancies over a period of 18 
months from the time of approval of Amendment 5 (22 Dec 2017).  Since this is a pilot study 
with a limited sample size, statistical analyses will be descriptive.  The information gained 
from this study will help inform the development of future studies.  
8.2 
Statistical Analysis Plan 
Analysis of toxicity data: The number of participants with adverse events will be determined 
and each observed toxicity will be tabulated by type, grade, and frequency.   
Biomarker statistics: Descriptive statistics will be used to summarize baseline, post-
administration, and change from pre-to post-administration for each biomarker. Ninety-five 
percent confidence intervals will be constructed to describe the change in the levels of each 
marker between pre- and post-administration. Correlation coefficients will be calculated and 
graphical displays of biomarker data will be generated to determine correlation between 
biomarkers.  Waterfall plots will be used to illustrate changes from baseline. Coefficients of 
variation will be used to assess the dispersion of each analyte. PFS and OS will be estimated 
for analyte levels and changes (both will be dichotomized). 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 8 . 
 
 


 
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Table 8 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 


 
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Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
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53 
 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
All data for patients and this trial are subject to all applicable federal, state, local, and 
institutional policies that may be applicable during the conduct of the trial. 
10.2 Compliance with Financial Disclosure Requirements 
The investigator and study team members will follow federal and institutional regulatory 
standards, including compliance with required financial disclosure reporting. 
10.3 Compliance with Law, Audit and Debarment 
All investigators and sites must be in agreement to allow reasonable access by study designated 
personnel to all study data and study related patient data necessary in order to allow the proper 
conduct and demonstrate compliance with applicable laws, regulations and statutes. Any 
investigator or site under investigation or receiving disbarment should notify the sponsor of 
this study as soon as possible, but no later than 5 days.  
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.     
10.5 Quality Management System 
The Duke Cancer Institute (DCI) Monitoring Team will conduct monitoring visits to ensure 
subject safety and to ensure that the protocol is conducted, recorded, and reported in 
accordance with the protocol, standard operating procedures, good clinical practice, and 
applicable regulatory requirements.  As specified in the DCI Data and Safety Monitoring Plan, 
the DCI Monitoring Team will conduct routine monitoring after the third subject is enrolled, 
followed by annual monitoring of 1 – 3 subjects until the study is closed to enrollment and 
subjects are no longer receiving study interventions that are more than minimal risk.  External 
site monitoring will be performed in accordance with the External Site Monitoring Plan, 
which accompanies this protocol. Please refer to this document for specifics regarding 
monitoring procedures. 


 
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  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
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54 
 
Additional monitoring may be prompted by findings from monitoring visits, unexpected 
frequency of serious and/or unexpected toxicities, or other concerns and may be initiated upon 
request of DUHS and DCI leadership, the DCI Cancer Protocol Committee, the Safety 
Oversight Committee (SOC), the sponsor, the Principal Investigator, or the IRB.  All study 
documents must be made available upon request to the DCI Monitoring Team and other 
authorized regulatory authorities, including but not limited to the National Institute of Health, 
National Cancer Institute, and the FDA.  Every reasonable effort will be made to maintain 
confidentiality during study monitoring. 
The Duke School of Medicine Clinical Trials Quality Assurance (CTQA) office may conduct 
audits to evaluate compliance with the protocol and the principles of GCP.  The PI agrees to 
allow the CTQA auditor(s) direct access to all relevant documents and to allocate his/her time 
and the time of the study team to the CTQA auditor(s) in order to discuss findings and any 
relevant issues. 
CTQA audits are designed to protect the rights and well-being of human research subjects. 
CTQA audits may be routine or directed (for cause). Routine audits are selected based upon 
risk metrics generally geared towards high subject enrollment, studies with limited oversight 
or monitoring, Investigator initiated Investigational Drugs or Devices, federally-funded 
studies, high degree of risk (based upon adverse events, type of study, or vulnerable 
populations), Phase I studies, or studies that involve Medicare populations. Directed audits 
occur at the directive of the IRB or an authorized Institutional Official. 
CTQA audits examine research studies/clinical trials methodology, processes and systems to 
assess whether the research is conducted according to the protocol approved by the DUHS 
IRB. The primary purpose of the audit/review is to verify that the standards for safety of human 
subjects in clinical trials and the quality of data produced by the clinical trial research are met. 
The audit/review will serve as a quality assurance measure, internal to the institution. 
Additional goals of such audits are to detect both random and systemic errors occurring during 
the conduct of clinical research and to emphasize “best practices” in the research/clinical trials 
environment. 
10.6 Data Management 
Data will be collected and reported through a Medidata RAVE database that will be designed 
specifically for this study. Data will be analyzed and reported after the trial has completed 
accrual. All subsequent data collected will be analyzed and reported in a follow-up clinical 
report. 
 
 


 
Original version: 
October 8, 2015 
 
Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
55 
 
 
11.0 APPENDICES 
11.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
11.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
11.3 Events of Clinical Interest Guidance Document 
Refer to section 5.4.5 and Tables 32 and 33 in the Pembrolizumab Investigator’s Brochure. 
11.4 Standard Operating Procedures for Blood, Ascites, and Tissue Specimen 
Collection 
For instructions regarding specimen processing please refer to the Specimen Processing 
Manual and the QualTek Sample Handling Manual. 


 
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Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
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56 
 
11.5 
Eligibility Checklist 
 
 
 
 
 
 
Study #: Pro00068544                                                                                           Subject ID #: 
Inclusion Criteria 
Yes 
No 
N/A 
Patient has histologically or cytologically confirmed gynecologic tumor of müllerian origin, specifically 
epithelial ovarian, fallopian tube, primary peritoneal, or uterine endometrial cancer 
  
  
  
Patient has disease amenable to surgical resection 
  
  
  
Patient is willing and able to provide written informed consent for the trial 
  
  
  
Patient is ≥ 18 years of age on day of signing informed consent 
  
  
  
Patient is willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion or 
ascites or plural effusions via paracentesis or thoracentesis. 
  
  
  
• Patients for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern)   
   may submit an archived specimen only upon agreement of the investigator 
 
 
 
Patient has an ECOG Performance status of 0 or 1. 
  
  
  
Patient has adequate bone marrow function:  
  
  
  
• Absolute Neutrophil Count ≥ 1,500/mcl  
  
  
  
• Platelets ≥ 100,000/mcl.  
  
  
  
• Hemoglobin ≥ 9.0 g/dL or ≥5.6 mmol/L without transfusion dependency or EPO dependency (within 7 days 
of assessment) 
  
  
  
Patient has adequate renal function: 
  
  
  
• Creatinine ≤ 1.5 x institutional upper limit of normal OR 
  
  
  
• Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl)      
   ≥60mL X ULN 
 
 
 
Patient has adequate hepatic function: 
  
  
  
• Bilirubin ≤ 1.5 X ULN OR 
• Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 X ULN 
  
  
  
• ALT/AST ≤ 2.5 x ULN  If patient has liver metastases: ALT/AST ≤ 5 x ULN. 
  
  
  
• Albumin ≥ 2.5 mg/dL 
  
  
  
Patient has adequate blood coagulation: 
  
  
  
• International Normalized Ratio (INR) or Prothrombin Time (PT)  ≤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 
  
  
  
• 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 
  
  
  
If patient is of child-bearing potential: negative serum pregnancy test within 72 hours prior to  receiving 
the first dose of study medication. 
  
  
  
If patient is of childbearing potential: should be willing to use 2 methods of birth control or be surgically 
sterile, or abstain from heterosexual activity until planned hysterectomy/oophorectomy. Subjects of 
childbearing potential are those who have not been surgically sterilized or have not been free from 
menses for > 1 year 
  
  
  


 
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Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
57 
 
Study #: Pro00068544                                                                      Subject ID #: 
 
Exclusion Criteria 
Yes 
No 
N/A 
Patient is currently participating and receiving a study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 4 weeks of the 
study drug administration 
  
  
  
Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form 
of immunosuppressive therapy within 7 days prior to study drug administration 
  
  
  
Patient has a known history of active TB (Bacillus Tuberculosis). 
  
  
  
Patient has hypersensitivity to pembrolizumab or any of its excipients 
  
  
  
Patient has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1, 
or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered 
more than 4 weeks earlier 
  
  
  
Patient has received prior chemotherapy, targeted small molecule therapy, or radiation therapy for the 
current gynecologic malignancy  
  
  
  
• Patients who have received treatment for a prior untreated malignancy must have recovered (i.e., ≤ Grade 1 
or at baseline) from adverse events due to a previously administered agent 
 
 
 
• If patient received major surgery, they must have recovered adequately from the toxicity and/or 
complications from the intervention prior to starting therapy 
 
 
 
Patient 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 that has undergone 
potentially curative therapy, or in situ cervical cancer 
  
  
  
Patient has 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 four weeks prior to study drug administration and any 
neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids for at least 7 days prior to study drug administration. This 
exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. 
  
  
  
Patient has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic treatment. 
  
  
  
Patient has known history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis  
  
  
  
Patient has active infection requiring systemic therapy. 
  
  
  
Patient has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full duration 
of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating 
investigator 
  
  
  
Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial 
  
  
  
Patient is pregnant or breastfeeding 
  
  
  
Patient has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
  
  
  
Patient has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) 
  
  
  
Patient has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] 
is detected). 
  
  
  
Patient has received a live vaccine within 30 days of planned start of study therapy 
  
  
  
• Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; 
however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed 
 
 
 
Subject eligibility verbally reviewed with PI/delegated physician and subject was deemed eligible on: _________________________________ 
                                                                                                                                                                                            Date and Time 
______________________________________________ 
Signature of Coordinator/Research Nurse                                                                                                                                                                          
PI/Delegated physician agrees that the above statement is true and the subject was eligible: 
 
______________________________________________                                                 _______________________________ 
Signature of Investigator/Sub-Investigator                                                                                         Date 


 
Original version: 
October 8, 2015 
 
Amended version 5:         September 18, 2017 
Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
58 
 
11.6 
Registration Form 
 
 
 
 Subject Registration Form 
Section 1:  SUBJECT INFORMATION 
 
First Name: ________________________ Middle Initial: ____ Last Name: _____________________________ 
Sex: 
 Male 
 Female   Date of Birth: ____ / ____ / _______   Duke MRN (if applicable): _______________ 
Date Consent Signed: ____ /____ / _______        Version Date of Site Consent: ____ /____ / _______ 
Type of Cancer Diagnosis:  ____________________________ Protocol Name: ___________________________ 
RACE: 
 White 
 Black or African American 
 Native Hawaiian or other Pacific Islander 
 Asian 
 American Indian or Alaska Native 
 Not Reported 
 Unknown 
 
ETHNICITY: 
 Hispanic or Latino 
 Non Hispanic or Latino 
 Not Reported 
 Unknown 
 
 
Section 2:  SITE INFORMATION 
 
Site Name: ______________________________________ Site Fax #: __________________________________     
Study Coordinator Name: __________________________ Phone #: _____________ Pager #: ______________ 
Study Coordinator Email: _____________________________________________________________________ 
Treating MD Name: _______________________________ Phone #: _____________ Pager #: ______________ 
Treating MD Email: __________________________________________________________________________ 
Section 3:  ELIGIBILITY 
 
    Subject meets all eligibility criteria.  (Please note:  If subject meets all eligibility criteria, please provide completed  
             eligibility checklist along with supporting source documentation to the Duke Team.) 
 
           Date of expected Cycle 1 Day 1:  ____ / ____ / _______ 
 
    Subject does not meet all eligibility criteria. 
 
          If subject does not meet eligibility, please explain below. 
         _______________________________________________________________________________________ 
 
Study Coordinator Signature: _________________________________________ Date: ____________________ 
Section 4:  TO BE COMPLETED BY DUKE STUDY TEAM 
------------------------------------------------------------------------------------------------------------------------------------------ 
 
Subject Study 
Number 
 
 
Cohort 
Number 
 
N/A 
 
 


 
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  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
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59 
 
11.7 
Investigator Signature Page 
Investigator Signature Page 
 
 
Product:  Pembrolizumab (Keytruda) 
 
Protocol: A PILOT STUDY INVESTIGATING THE EFFECT OF PEMBROLIZUMAB ON 
THE TUMORAL IMMUNOPROFILE OF GYNECOLOGIC CANCERS OF MÜLLERIAN 
ORIGIN 
 
Investigator’s Agreement 
 
I have read the attached protocol entitled “A PILOT STUDY INVESTIGATING THE 
EFFECT OF PEMBROLIZUMAB ON THE TUMORAL IMMUNOPROFILE OF 
GYNECOLOGIC CANCERS OF MÜLLERIAN ORIGIN”, and agree to abide by all 
provisions set forth therein. 
 
I agree to comply with the International Conference on Harmonization Tripartite Guideline 
on Good Clinical Practice and applicable FDA regulations/guidelines set forth in 21 CFR 
Parts 11, 50, and 56. 
 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation. 
 
 
______________________________    
Signature 
 
 
 
                                                                             
______________________________  
 
 
_______________________ 
Name of Principal Investigator 
 
 
 
 Date (DD Month YYYY) 


 
Original version: 
October 8, 2015 
 
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Amended version 1:   
  April 12, 2016 
                Amended version 6:         March 29, 2018 
Amended version 2:                  July 25, 2016 
 Amended version 7:         August 28, 2018 
Amended version 3:                  November 11, 2016                   Amended version 8:         December 27, 2018  
Amended version 4:                  February 27, 2017                    Amended version 9:           October 17, 2019 
60 
 
12.0 REFERENCES 
1. Siegel, R, Naishadham, D et al. Cancer statistics, 2013. CA Cancer J. Clin. (2013) 63, 11- 
30. 
2. Topalian, SL, Sznol, M et al. Survival, durable tumor remission, and long-term safety in 
patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. (2014) 32, 
1020-1030. 
3. Hamanishi, J, Mandai, M et al. in SGO 2015 Annual Meeting on Women's Cancer. 
4. Gros, A, Robbins, PF et al. PD-1 identifies the patient-specific CD8(+) tumor-reactive 
repertoire infiltrating human tumors. J. Clin. Invest. (2014) 124, 2246-2259. 
5. Weber, JS, Hamid, O et al. Ipilimumab increases activated T cells and enhances humoral 
immunity in patients with advanced melanoma. J. Immunother. (2012) 35, 89-97. 
6. Tarhini, AA, Edington, H et al. Immune monitoring of the circulation and the tumor 
microenvironment in patients with regionally advanced melanoma receiving 
neoadjuvant ipilimumab. PLoS One (2014) 9, e87705.