Clinical trial NCT02635360
Conditions: Cervical Cancer
Keywords: advanced cervical cancer pembrolizumab chemoradiation immunotherapy
Sponsor: Linda R Duska
Start date: 2017-02-09; Completion date: 2022-12-14
Enrollment: 94 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and effectiveness of immunotherapy in combination with chemotherapy and radiation (chemoradiation) for the treatment of advanced cervical cancer. Pembrolizumab, a type of immunotherapy called a checkpoint inhibitor, will be administered after or during chemoradiation.

Detailed description:
Primary: (1) To estimate the immunologic effects, as assessed in the tumor \& PBMC, of both sequential and concurrent administration of pembrolizumab to CRT. Change between pre and post measurements of HPV E2, E7 specific CD8+ T cells, regulatory FoxP3+ T cells (Tregs) and the ratio of CD8+ T cells to Tregs are the immune measurements of primary interest. (2) To determine the safety of concurrent chemoradiation in combination with pembrolizumab for the treatment of locally advanced cervical cancer. Secondary: (1) To estimate rates of complete metabolic response on PET/CT imaging obtained 12 weeks after CRT.

(2) To estimate rates of distant metastasis as the first site of recurrence for patients.

(3) To estimate the influence of concurrent and consolidative MK-3475 on levels of plasminogen activator inhibitor-1 (PAI-1), a marker of immunosuppressive TGF-B.

(4) To estimate the influence of concurrent and consolidative MK-3475 on levels of IDO, an enzyme that depletes tryptophan, which is essential for T-cell function.

(5) To estimate the influence of concurrent and consolidative MK-3475 on levels of MHC class I (CD8+ T cell ligand) and MICA (NK ligand), as measured by MHC.

(6) To estimate the progression free survival (PFS) in subjects with locally advanced cervical cancer treated with sequential and concurrent administration of pembrolizumab in relation to CRT.

(7) To estimate the overall survival (OS) in subjects with locally advanced cervical cancer treated with sequential and concurrent administration of pembrolizumab in relation to CRT.

Arms: arm 1: Subjects will receive standard chemotherapy weekly and 4-6 fractions of brachytherapy radiation for 5-6 weeks. After chemoradiation is complete, subjects will receive the study drug, pembrolizumab. arm 2: Subjects will receive standard chemotherapy weekly and 4-6 fractions of brachytherapy radiation for 5-6 weeks. While subjects are receiving chemotherapy and radiation, they will also receive the study drug, pembrolizumab.
Interventions: intervention 1: Pembrolizumab intervention 2: Brachytherapy intervention 3: Cisplatin
Intervention descriptions: intervention 1: 200 mg of study drug is given through intravenous (IV) administration once every 21 days for 3 months. intervention 2: Radiation is done for standard clinical care purposes. intervention 3: 40 mg of chemotherapy drug will be given weekly for 5-6 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
Title: Pembrolizumab and Chemoradiation Treatment for Advanced 
Cervical Cancer
NCT02635360
Document Date: March 6, 2018


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Study Title 
A randomized Phase II study of chemoradiation and pembrolizumab for locally 
advanced cervical cancer 
Test Article 
Pembrolizumab (MK-3475) 
Protocol Number 
UVA-LACC-PD201 
Phase of Study 
Phase II 
Sponsor-
Investigator 
Linda Duska, MD 
Drug Source:   
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc 
GCP Statement 
This study is to be performed in full compliance with acceptable Good Clinical 
Practices (GCP) and applicable regulations. All required study documentation 
will be archived as required by regulatory authorities. 
Confidentiality 
This document is confidential and the property of the University of Virginia. No 
part of it may be transmitted, reproduced, published, or used by other persons 
without prior written authorization from the study Sponsor-Investigator. 
Study Chair 
Linda Duska, M.D. 
Professor, Obstetrics and Gynecology, Division of Gynecologic Oncology 
University of Virginia Health System 
Box 800712 
Charlottesville, VA  22908 
Tel: (434) 924-5100 
Fax: (434) 982-1570 
lduska@virginia.edu 
Biostatistician 
Gina Petroni, PhD 
Professor, Division of Translation Research and Applied Statistics 
Department of Public Health Sciences 
University of Virginia School of Medicine 




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TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY ..................................................................................................................... 6 
2.0 
TRIAL DESIGN .......................................................................................................................... 7 
2.1 
Trial Design ........................................................................................................................... 7 
3.0 
OBJECTIVES & HYPOTHESES ............................................................................................. 10 
3.1 
Primary Objectives .............................................................................................................. 10 
3.2 
Secondary Objectives ......................................................................................................... 10 
4.0 
BACKGROUND & RATIONALE .............................................................................................. 11 
4.1 
Disease Background ........................................................................................................... 11 
4.2 
Pembrolizumab ................................................................................................................... 11 
4.3 
Rationale ............................................................................................................................. 13 
5.0 
METHODOLOGY .................................................................................................................... 16 
5.1 
Entry Criteria ....................................................................................................................... 16 
5.2 
Trial Treatments .................................................................................................................. 18 
5.3 
Dose Selection/Modification ................................................................................................ 19 
5.4 
Concomitant Medications/Vaccinations .............................................................................. 27 
5.5 
Rescue Medications & Supportive Care ............................................................................. 28 
5.6 
Diet/Activity/Other Considerations ...................................................................................... 31 
5.7 
Subject Participation and Withdrawal/Discontinuation Criteria ........................................... 32 
6.0 
TRIAL FLOW CHART .............................................................................................................. 35 
6.1 
Study Flow Chart ................................................................................................................. 35 
6.2 
TRIAL PROCEDURES ........................................................................................................ 39 
6.3 
Trial Procedures .................................................................................................................. 39 
6.4 
Assessing and Recording Adverse Events ......................................................................... 45 
7.0 
STATISTICAL CONSIDERATIONS ........................................................................................ 54 
7.1 
Evaluation Criteria ............................................................................................................... 54 
7.2 
Sample size/ and accrual .................................................................................................... 55 
7.3 
Randomization .................................................................................................................... 55 
7.4 
Safety and Futility Monitoring .............................................................................................. 55 
7.5 
Analyses .............................................................................................................................. 57 
8.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ................. 58 
8.1 
Investigational Product ........................................................................................................ 58 
8.2 
Packaging and Labeling Information ................................................................................... 58 
8.3 
Clinical Supplies Disclosure ................................................................................................ 58 
8.4 
Storage and Handling Requirements .................................................................................. 58 
8.5 
Returns and Reconciliation ................................................................................................. 58 


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9.0 
ADMINISTRATIVE AND REGULATORY DETAILS ................................................................ 59 
9.1 
Institutional Review Board (IRB) Approval and Consent .................................................... 59 
9.2 
Adherence to the Protocol................................................................................................... 59 
9.3 
Record Retention ................................................................................................................ 60 
9.4 
Obligations of Investigators ................................................................................................. 60 
9.5 
Compliance with Trial Registration and Results Posting Requirements ............................. 61 
10.0 
REFERENCES ........................................................................................................................ 62 
11.0 
APPENDICES.......................................................................................................................... 64 
11.1 
ECOG Performance Status ................................................................................................. 65 
11.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) .................................... 66 
 
 
 


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List of Abbreviations 
Abbreviation or 
specialist term 
Explanation 
AE 
Adverse Event 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code Of Federal Regulations 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRT 
Chemoradiation Treatment 
CTCAE 
Common Terminology Criteria For Adverse Events 
DSMC 
University of Virginia Cancer Center Data and Safety 
Monitoring Committee 
ECG 
Electrocardiogram 
FDA 
Food And Drug Administration 
GCP 
Good Clinical Practices 
HCG 
Beta-Human Chorionic Gonadotropin 
HR 
Heart Rate 
I/E 
Inclusion Exclusion Criteria 
ICH 
International Conference On Harmonization 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
iULN 
Institutional Upper Limit Of Normal 
IV 
Intravenous 
OS 
Overall Survival 
PFS 
Progression Free Survival 
RR 
Clinical response rate  
pCR 
Pathological complete response 
aPTT 
Activated Partial Thromboplastin Time  
PT 
Prothrombin Time  
SAE 
Serious Adverse Event 
US 
United States 
UVA 
University of Virginia 
WOCBP 
Women of Childbearing Potential 
 
 


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1.0 TRIAL SUMMARY 
Abbreviated Title 
Chemoradiation (CRT) with pembrolizumab in Cervical Cancer 
Trial Phase 
Phase 2 
Clinical Indication 
Locally advanced cervical cancer (stages IB-IVA, all histologies) 
Trial Type 
Randomized 
Type of control 
Active comparator and historical data 
Route of administration 
IV 
Trial Blinding 
Unblinded (open label) 
Treatment Groups  
2 arms 
Number of trial subjects 
88 evaluable 
Estimated enrollment period 24 months 
Estimated duration of trial 
3 years to analysis of primary endpoint 
Duration of Participation 
20 weeks active treatment plus 5 years survival follow-up 
 
 
 
 


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2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a randomized, Phase II, open-label multi-center study in which 88 eligible subjects with locally 
advanced cervical cancer will be treated with standard chemoradiation treatment (CRT) plus the PD-
L1 monoclonal antibody pembrolizumab. The primary objectives in the study will be to estimate the 
safety and immune response to pembrolizumab given either sequentially or concurrently with CRT. 
Secondary objectives will evaluate the metabolic response and rates of distant metastases following 
treatment with pembrolizumab given sequentially or concurrently with CRT. The study design also 
affords the opportunity to characterize the effect of treatment on immune response pathways by 
estimating the effects of treatment on specific immune markers. 
At baseline, subjects will undergo a full medical history and physical examination, vital signs, 
performance status, and general laboratory evaluations. Baseline imaging assessments will include 
PET/CT and MRI (MRI is required, unless there are contraindications or at the discretion of the 
investigator). Eligible subjects (n=88) will be randomized 1:1 to two treatment sequences to receive 
pembrolizumab after completion of CRT (Arm 1) or to receive pembrolizumab concurrent to CRT 
(Arm 2). Subjects in both arms will receive identical regimen, as follows:  
 
Chemotherapy: Weekly Cisplatin (40 mg/m2) for 5 or 6 weeks  
 
Radiation: Standard dose IMRT with 4-6 fractions of high-dose-rate (HDR) brachytherapy 
using standard doses and methods 
 
Pembrolizumab: 200 mg, 3 cycles (every 21 days) 
Subjects will be evaluated for safety by monitoring for adverse events. All subjects will have a 
PET/CT approximately 12 weeks following completion of all CRT to evaluate for response. Tumor and 
blood samples will be collected at baseline, during CRT and post-treatment for analysis of immune 
response markers.  All subjects will be followed for disease-free survival and overall survival for up to 
5 years. 


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Figure 1. Study Design 
 
 
 
 
Primary Carcinoma 
of the Cervix 
•
Squamous 
•
Adenosqua
mous 
•
Adenocarci
noma 
Standard Clinical 
Staging 
IB, II, III, IVA, or IB1 with 
positive pelvic and/or 
para-aortic lymph nodes 
Standard radiologic evaluation 
PET/CT and MRI pelvis 
  
Tissue biopsy and peripheral 
blood collection 
Arm 1 
Standard ChemoRT (CDDP) 
CDDP 40 mg/m2 weekly for 5 or 6 
weeks 
Concurrent with XRT 
(EBRT plus brachytherapy) 
  
3 cycles of consolidative MK-3475: 
200 mg every 21 days beginning 
week 9 for 3 total cycles 
Arm 2 
ChemoRT (CDDP plus MK-3475) 
CDDP 40 mg/m2 weekly for 5 or 6 
weeks 
MK-3475 200 mg every 21 days 
beginning on day 1 of CDDP for 3 
total cycles 
  
Concurrent with XRT 
(EBRT plus brachytherapy) 
Tissue biopsy 
and peripheral 
blood collection 
at 6 weeks and 
12 weeks post-
CRT 
PET/CT at 12 
weeks post-CRT 


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Figure 2. Study Schema 
 
 


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3.0 OBJECTIVES & HYPOTHESES 
3.1 
Primary Objectives  
(1) To estimate the immunologic effects, as assessed in the tumor & PBMC, of both sequential 
and concurrent administration of pembrolizumab to CRT. Change between pre and post 
measurements of HPV E2, E7 specific CD8+ T cells, regulatory FoxP3+ T cells (Tregs) and 
the ratio of CD8+ T cells to Tregs are the immune measurements of primary interest. 
(2) To determine the safety of concurrent chemoradiation in combination with pembrolizumab for 
the treatment of locally advanced cervical cancer. 
3.2 
Secondary Objectives  
(1) To estimate rates of complete metabolic response on PET/CT imaging obtained 12 weeks 
after CRT. 
(2) To estimate rates of distant metastasis as the first site of recurrence for patients. 
(3) To estimate the influence of concurrent and consolidative MK-3475 on levels of plasminogen 
activator inhibitor-1 (PAI-1), a marker of immunosuppressive TGF-B. 
(4) To estimate the influence of concurrent and consolidative MK-3475 on levels of IDO, an 
enzyme that depletes tryptophan, which is essential for T-cell function. 
(5) To estimate the influence of concurrent and consolidative MK-3475 on levels of MHC class I 
(CD8+ T cell ligand) and MICA (NK ligand), as measured by MHC. 
(6) To estimate the progression free survival (PFS) in subjects with locally advanced cervical 
cancer treated with sequential and concurrent administration of pembrolizumab in relation to 
CRT. 
(7) To estimate the overall survival (OS) in subjects with locally advanced cervical cancer treated 
with sequential and concurrent administration of pembrolizumab in relation to CRT. 
 
 


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4.0 BACKGROUND & RATIONALE 
4.1 
Disease Background 
Cervical cancer is the fourth most common cancer among women worldwide, with an estimated 
528,000 new cases and 266,000 deaths in 2012.[1] The standard of care (SOC) for patients with 
locally advanced cervical cancer (LACC) is concurrent chemoradiation therapy (CRT) with weekly 
cisplatin.[2] Five-year disease OS after contemporary CRT for Stages IB-IVA cervical cancer is only 
66%.[2] 
Human Papillomavirus (HPV) DNA is detected in virtually all cervical cancers, and HPV specific CD4+ 
and CD8+ T cells are found in cervical tumors.[3] The failure of the immune system to eradicate HPV 
DNA integration is due to cancer cells’ acquisition of cytotoxic T cells, including down-regulation of 
HLA class I, down-regulation of MHC class I chain-related molecule A (MICA), production of immune-
suppressive cytokines, and induction of FoxP3+ immunosuppressive regulatory T cells.[4] Low ratios 
of CD8+ T cells: regulatory T cells (Tregs) are associated with poorer survival for cervical cancer 
patients,[4] suggesting that strategies to enhance immune response would be effective. 
Compelling evidence indicates that B7 molecules (i.e., B7-1/CD80, B7-2/CD86, B7-H1/PDL1, B7-
H2/LICOS, B7-DC, B7-H3 and B7-H4) and their ligands (i.e., CTLA-4, CD28, PD-1, ICOS) not only 
provide crucial positive signals to stimulate and support T-cell activation, but also offer negative 
signals that control and suppress potentially protective T-cell responses against spontaneously 
arising and virally-induced human tumors.[5] Expression of these molecules on the surface of cervical 
tumor cells, tumor associated macrophages, and/or dendritic cells (DC), may attenuate or abrogate 
the ability of the immune system to eliminate strongly antigenic (i.e., virus-infected) tumors such as 
cervical cancer.[5] Because these negative signals in human solid tumors have been shown to be 
largely provided by programmed death, blockade of PD- 1/PD-L1 co-inhibitory pathways by novel 
monoclonal antibodies may represent an innovative and effective approach to reverse immune 
suppression while inducing tumor-specific immunity in cervical cancer patients. 
PD-1 and PD-L1 expression on cervical T cells and DCs, respectively, has been recently reported to 
be associated with high risk-HPV positivity and to be increased in parallel with increasing CIN 
grade.[6] Increased expression of PD-1 and PD-L1 correlates with impaired cell-mediated immunity in 
high-risk HPV related CIN.[7] Finally, in cervical cancer, PD-1 is expressed by the majority of 
infiltrating CD8 T cells, suggesting that blocking of PD-1 could have therapeutic potential.[7] Taken 
together, this evidence validates the importance of the PD-1-PD-L1 pathway for the treatment of 
patients harboring virally-infected tumors such as cervical cancer. 
4.2 
Pembrolizumab 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information on 
pembrolizumab. 
 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation 
has been known for decades. Accumulating evidence shows a correlation between tumor-infiltrating 
lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies. In particular, 


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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 Stated for the 
treatment of patients with unresectable or metastatic melanoma and disease progression following 
ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 


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4.3 
Rationale 
 Rationale for the Trial and Selected Subject Population 
We hypothesize that CRT in LACC will be beneficial to the immunostimulatory activity of 
pembrolizumab compared to single agent use. This hypothesis is based on evidence that platinum-
based DNA intercalators and irradiation are highly effective at inducing a form of apoptosis known as 
immunological cell death (ICD),[8] which can lead to auto-vaccination that is promoted by blocking 
checkpoint molecules such as PD-1. We anticipate that ICD will not only curtail the 
immunosuppressive activity of T cells, but will also increase the source of antigen and improve the 
context of antigen presentation (by activating dendritic cells) that could lead to greater immune cell 
activation in the cervical cancer environment. However, cisplatin is deleterious to activated effector T 
cells (our unpublished data), and irradiation and chemotherapy can recruit myeloid cells and 
regulatory cells with immunosuppressive function.[9, 10] Therefore, the sequencing of SOC with PD-1 
blockade deserves considerable attention, with the intent of defining optimal treatment regimens and 
the development of prognostic and predictive biomarkers. These observations suggest that PD-1 
blockade is a potential therapeutic strategy to increase immune responses against cervical cancer. 
Pembrolizumab (MK-3475) is an PD-1 antibody approved for use in melanoma,[11] and the proposed 
study focuses on evaluating the influence of the addition of pembrolizumab to standard CRT, and 
sequencing of pembrolizumab with CRT, on CD8+ infiltrating T cells in subjects with locally advanced 
cervical cancer. 
Secondary objectives of the study will estimate clinical endpoints to obtain preliminary data regarding 
the potential clinical effect of the combination. We will estimate the rate of complete metabolic 
response as measured by PET/CT at 12 weeks, as well as the rate of distant (versus local) 
recurrence.  
There is no data available to predict the optimal time point to incorporate immunotherapy into a 
treatment course. Therefore, this study will evaluate biological endpoints and responses to 
immunotherapy given at the time of chemotherapy and following completion of chemotherapy.  
 
 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  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).  No MTD has been 
identified to date. 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 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.   


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A population pharmacokinetic analysis has been performed using serum concentration time data from 
476 patients. Within the resulting population PK model, clearance and volume parameters of 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 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. 
4.3.2.1 
Biomarker Research 
The overall rationale for this study is that the addition of pembrolizumab to the standard of care 
chemoradiation treatment may improve survival for cervical cancer patients by modifying the immune 
response against the tumor. It is anticipated that pembrolizumab treatment will favorably improve the 
ratio of effector CD8+ T cells: regulatory T cells in the tumor microenvironment.   Biopsies and blood 
samples to collect peripheral blood mononuclear cells (PBMC) will be collected pre, during and post 
treatments in both arms. We will determine whether the inclusion of pembrolizumab: 1) alters the 
quantity and quality of tumor lymphocytic infiltration; 2) increases the systemic immune response 
against tumor-associated antigens. 
Tumor lymphocyte infiltration: PD-1 blockade (pembrolizumab) can support CD8+ T cell function in 
the periphery, either by promoting TCR signaling or biochemical pathways that support effector 
activity, or potentially by influencing regulatory T cell development and function. Thus, pembrolizumab 


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has the potential to synergize with CRT to augment CD8+ T cell responses. Tumor biopsies will be 
evaluated by IHC and flow cytometry and by transcriptional analysis to provide a broad 
characterization of the effect of treatment on lymphocyte and myeloid cell composition and immune 
function.  
These studies will provide a direct assessment of the capability of PD-1 blockade to augment T cell 
responses initiated by CRT-induced ICD and DC activation. Our current trial design will allow us to 
detect acute effects of these study drugs on the immunological composition of the tumors, but not 
their independent effect on long term immune responses initiated in CRT-treated subjects. Our goal is 
to generate preliminary data addressing whether the addition of pembrolizumab to CRT promotes the 
modulation of cellular subsets that are likely to be involved in controlling tumor outgrowth and whether 
concomitant treatment alters patterns of adaptive resistance (checkpoint molecules; 
immunosuppressive cellular populations; inhibitory cytokines) compared to CRT alone. With respect 
to immunological outcomes, our expectation is that the addition of pembrolizumab will augment the 
magnitude and the function of intratumoral and systemic tumor-specific CD8+ T cells (as judged by 
HPV reactivity), and will lead to increased expression of HLA, MICA and PDL1 compared to CRT 
alone. We will learn whether pembrolizumab can modulate NK and Treg frequencies in tumors in 
addition to peripheral blood. Furthermore, we anticipate that CRT will initially deplete tumor infiltrating 
lymphocytes, but that the consolidation regimen of pembrolizumab post CRT will increase the 
acuteness and magnitude of the response driven by CRT. 
Systemic response: Flow cytometry will be used to examine blood for an increase in HLA-DR (a 
marker of recent T cell activation) expressing CD8+ T cells. ELIspot assays, using overlapping 
peptide libraries constructed for HPV E2, E5, E6 and E7, will be used to determine whether treatment 
induces/increases CD8+ T cell responses to defined cervical cancer antigens. 
Human Papillomavirus (HPV) and tumor immunogenicity: DNA is detected in virtually all cervical 
cancers, and HPV specific CD4+ and CD8+ T cells are found in cervical tumors.[3] The failure of the 
immune system to eradicate HPV DNA integration is due to cancer cells’ acquisition of resistance to 
cytotoxic T cells, including down-regulation of HLA class I, down-regulation of MHC class I chain-
related molecule A (MICA), production of immune-suppressive cytokines, and induction of FoxP3+ 
immunosuppressive regulatory T cells.[4] The presence of CD8+ T cells specific for HPV-antigens in 
cervical cancer subjects is limited, considering the potential immunogenicity of these antigens. Tumor 
infiltration by lymphocytes could be limited by antigen availability and weak T cell activation; 
deficiencies in lymphocyte trafficking into tumor; or poor survival and proliferation in the tumor site. In 
preclinical models, both cisplatin and irradiation have profound influences on the cellular and cytokine 
components of the tumor; they can lead to the death of immunosuppressive cell subsets, the release 
of damage associated molecular patterns that can activate DC resulting in increased T cell activation 
and presence of lymphocytes within tumors. Whether this occurs in human disease has not been 
assessed. However, irradiation can induce many negative feedback mechanisms, and has the 
capacity to induce PD-L1 expression either directly, or as a part of adaptive resistance to the effector 
activity of infiltrating lymphocytes. Furthermore, it is unknown whether low-dose cisplatin will 
eradicate both regulatory and effector T cells in the tumor site, and whether any HPV-specific CD8+ T 
cell response can be elicited subsequent to SOC treatment and whether these cells express PD-1 
and other inhibitory molecules.  


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5.0 METHODOLOGY 
5.1 
Entry Criteria 
 Diagnosis/Condition for Entry into the Trial 
1. Histologically confirmed cervical cancer 
a. Histologically confirmed invasive squamous cell carcinoma, adenocarcinoma, or 
adenosquamous carcinoma of the uterine cervix, stages IB, IIA, IIB, IIIB, and IVA. 
Stage IB1 with positive pelvic or para-aortic nodes based on imaging is also eligible. 
b. No evidence of distant metastases (based on PET/CT done within 6 weeks of start of 
treatment).  
c. Recurrent cervical cancer is not eligible. 
 
 Subject Inclusion Criteria 
2. Be willing and able to provide written informed consent for the trial. 
3. Be  18 years of age on day of signing informed consent. 
4. Have a performance status of 0-2 on the ECOG Performance Scale. 
5. Demonstrate adequate organ function as defined in Table 1, all screening labs should be 
performed within 14 days of treatment initiation.   
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
 
 
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)  
 
 
≤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 
 


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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 
aCreatinine clearance should be calculated per institutional standard. 
6. Female subject 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.   
7. Subjects of childbearing potential should be willing to use 2 methods of birth control or be 
surgically sterile, or abstain from heterosexual activity for the course of the study through 120 
days after the last dose of study medication, or until they are no longer of child bearing potential.    
 
 Subject Exclusion Criteria 
Medical History: 
1. Has history of malignancy within the prior 5 years. Exceptions include basal cell carcinoma of 
the skin or squamous cell carcinoma of the skin that has undergone potentially curative 
therapy. 
2. Has a diagnosis of immunodeficiency 
3. Has a known history of: i) Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies); ii) 
Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative]); iii) active TB 
(Bacillus Tuberculosis); or iv) inflammatory bowel disease. 
4. Hypersensitivity to pembrolizumab or any of its excipients 
5. 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.  
6. Has known history of, or any evidence of active, non-infectious pneumonitis. 
7. Has an active infection requiring systemic therapy. 
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 the first dose of trial 
treatment and any neurologic symptoms have returned to baseline), have no evidence of new 
or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial 
treatment.  This exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability.   


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9. 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.   
10. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
11. A serious uncontrolled medical disorder that in the opinion of the Investigator would impair 
the ability of the subject to receive protocol therapy. 
Medication History: 
12. Has had prior radiation for other diagnoses to the expected treatment field. 
13. Has had prior radiation, chemotherapy, targeted therapy, or investigational therapy for 
cervical cancer. 
- 
Note:  If subject received major surgery for reason other than cervical cancer, they 
must have recovered adequately from the toxicity and/or complications from the 
intervention prior to starting treatment.   
14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
15. Within 7 days prior to the planned start of study treatment: 
a) Is receiving systemic steroid therapy or any other form of immunosuppressive 
therapy 
16. Within 30 days prior to the planned start of study treatment: 
a) Has received a live vaccine. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, 
and typhoid vaccine. 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. 
b) Has participated in a study of an investigational agent and received study therapy or 
used an investigational device. 
Subject Characteristics: 
17. Is unable or unwilling to participate in a study related procedure. 
18. Is pregnant or breastfeeding, or expecting to conceive children within the projected duration 
of the trial, starting with the pre-screening or screening visit through 120 days after the last 
dose of pembrolizumab. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2. 


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Table 2.  Trial Treatment 
 
Agent 
 
Dose 
 
Route 
 
Schedule 
Use 
Pembrolizumab 
200 mg 
IV 
Infusion given every 21 (± 3) 
days for 3 cycles 
Experimental 
Cisplatin 
40 
mg/m2  
in 1L 
(max 70 
mg) 
IV 
One hour infusion, once 
weekly for 5-6 weeks 
 
Standard of care 
Radiation 
45 Gy  
+/- boost 
doses 
IMRT to primary 
tumor and nodal 
volumes 
25 fractions over a 5-8 week 
interval 
Standard of care 
(Parametrial or nodal 
boosts of 5.4-14.4 Gy 
can be delivered as 
indicated.) 
Variations permitted to 
reflect institutional 
standards 
25-30 Gy 
high-dose-rate 
(HDR) 
brachytherapy 
4-6 fractions of 5-6 Gy per 
fraction  
Standard of care 
Variations permitted as 
described to reflect 
institutional standards 
 
5.3 
Dose Selection/Modification 
 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.   
 Dose Modification  
Dose modifications in response to treatment-related adverse events are permitted in order to keep 
the participant on study drug. Details on the modifications for each study intervention are provided in 
the sections below. In general: 
i. Dose modifications for reasons other than treatment related adverse events are not allowed on 
this protocol. Relationship to treatment should be determined as outline in Table 7.  
ii. Whenever treatment is held pending resolution of toxicity to grade 1 or 0, this criterion may also 
be met if the toxicity resolves to pre-study baseline grade (if toxicity was present at baseline). 
iii. Study drugs and radiation may be held together or separately. Investigator discretion is 
permitted to determine which drug is the source for a given toxicity and to adjust the dosage of 
pembrolizumab, cisplatin, or radiation therapies accordingly. If study drugs are held for 
hematological toxicity, radiation therapy may be continued at the investigator’s discretion in 
order to minimize treatment delays. 


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5.3.2.1 
Pembrolizumab Dose Modification  
Modification of the dose of pembrolizumab is not allowed on this study. The dose of pembrolizumab 
can be delayed or withheld due to adverse events. Adverse events (both non-serious and serious) 
associated with pembrolizumab exposure may represent an immunologic etiology. Pembrolizumab 
must be withheld for drug-related toxicities and severe or life-threatening AEs as per Error! 
Reference source not found. below. See Section 5.5.1 and Events of Clinical Interest Guidance 
Document for supportive care guidelines, including use of corticosteroids. 
Pembrolizumab should be administered once every 21 days for 3 cycles. If a delay in dosing is 
required per the guidelines in Error! Reference source not found., then the dose may be delayed 
for up to 7 days. In case the toxicity does not resolve to Grade 0-1 or baseline within 7 days, the 
dosing on either the second or third cycle may be withheld. If the second cycle dose cannot be 
administered due to unresolved toxicity, then the third dose of pembrolizumab should occur on the 
scheduled day 1 of the third cycle (if the toxicity has resolved to Grade 0-1 or baseline). If the third 
dose cannot be administered due to unresolved toxicity within 7 days, then the subject may continue 
on study without additional pembrolizumab (may continue to receive cisplatin and RT). In general, 
please follow the following pembrolizumab-specific guidelines: 
i. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to 
taper over at least 4 weeks. This criterion may also be met if the toxicity resolves to pre-study 
baseline grade (if toxicity was present at baseline). 
ii. 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. 
iii. For situations where pembrolizumab has been withheld and the toxicity has not resolved within 
7 days, the dose may be skipped. Otherwise, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 (or baseline, as described in “i”) and corticosteroid has been 
tapered.  
Table 3. Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with 
Pembrolizumab  
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 1-2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
 
 
Monitor participants for signs and 
symptoms of pneumonitis 
 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment 
 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 
2 
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
 Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
 
 
Monitor participants for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 


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Grade 4 
Permanently 
discontinue 
 
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 
elevation or 
Increased bilirubin 
Grade 2 
Withhold 
 Administer 
corticosteroids (initial 
dose of 0.5- 1 mg/kg 
prednisone or 
equivalent) followed 
by taper 
 
Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme value 
returned to baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
 Administer 
corticosteroids (initial 
dose of 1-2 mg/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 -
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 
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 changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 


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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:  
Gullain-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) 
 
5.3.2.2 
Dose Modifications of Other Treatments 
5.3.2.3 
Radiation Dose Modifications  
Radiation treatment may be delayed due to toxicities for 1- 7 consecutive days in patients in either 
treatment arm. Additionally, the start of brachytherapy can be delayed 1-14 days from completion of 
external beam RT if needed. All radiation treatments must be delivered within a total of 8 weeks, 
therefore treatment breaks should be kept to a minimum. 
If radiation treatment is held, then cisplatin dose should be held until radiation treatment is resumed. 
5.3.2.4 
Cisplatin Dose Modifications  
Toxicity due to cisplatin administration may be managed by symptomatic treatment, dose 
interruptions and adjustment of cisplatin dose. Recommended dose reductions are provided in Table 
3. Dose should only be reduced once and future dosing should continue at the reduced dose.  If the 
reduced dose cannot be tolerated the subject may continue on study without cisplatin (may continue 
to receive pembrolizumab and RT).  
Table 3. Cisplatin Dose Modifications 
DOSE LEVEL  
CISPLATIN  
Dose Level 1  
40 mg/m2 (max = 70 mg*)  
Dose Level -1  
30 mg/m2 (max = 52.5 mg*)  
* Max doses apply to those with BSA > 1.75 m2 
 


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5.3.2.4.1 
Recommendations for Cisplatin Dose Modifications  
Gastrointestinal Adverse Effects  
 
For nausea and vomiting, anti-emetics should be used prophylactically.  
 
For Grade 4 nausea and vomiting, reduce Cisplatin by one dose level.  
Renal/Genitourinary Adverse Effects  
 
If creatinine rises to greater than 2.0 mg/dl, hold cisplatin therapy. If creatinine does not 
recover after a one-week delay, discontinue cisplatin for remainder of regimen.  
 
Selective renal tubular defects are sometimes observed:  
o 
Hypocalcemia with hypomagnesemia and hypokalemia are common and potentially 
severe.  
o 
Replacement of magnesium, calcium and potassium are usually effective.  
o 
Severe tubular effects, although rare, may require chronic replacement therapy.  
o 
Diagnostic tests for alternative mechanisms of hypocalcemia (e.g. GI or metabolic) 
should be considered.  
Neurologic Adverse Effects  
 
Grade 1 - No change  
 
Grade 2 - Reduce Cisplatin by one dose level  
 
Grade 3-4 – Hold cisplatin.  Reduce Cisplatin by one dose level after recovery to ≤ Grade 2 
Blood/Bone Marrow (Hematologic) Adverse Effects  
 
Cisplatin should be withheld from patients with an ANC less than 1,000 or platelet count less 
than 50,000. Therapy should be delayed week-by-week until these levels are exceeded. Any 
interruption in cisplatin for longer than one week due to toxicity requires a dose reduction of 
one level.  
 
External radiation should continue while drug is withheld. 
 
 Timing of Dose Administration 
The below sections describe the recommended timing of study specific treatments. Treatments may 
be delayed up to 3 days (without this being considered to be a protocol violation) for major life events 
(e.g., serious illness in a family member, major holiday, vacation which is unable to be re-scheduled). 
5.3.3.1 
Cisplatin 
Cisplatin chemotherapy will consist of weekly administrations of 40 mg/m2 of cisplatin administered in 
1 L of IV fluid (according to local protocol) delivered in 1 hour IV infusion (per institutional guidelines) 
The maximum dose of cisplatin administered should not exceed 70 mg. Cisplatin will be given on a 
day that IMRT is scheduled and must be given prior to radiation therapy that day. Cisplatin should be 
given on a Monday, Tuesday or Wednesday. Cisplatin infusion should proceed after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 6.0). 


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5.3.3.2 
Pembrolizumab 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible.  However, given 
the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted 
(i.e., infusion time is 30 minutes: -5 min/+10 min). 
Pembrolizumab should be administered on day of treatment after all pretreatment 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 6.0). Trial 
treatment may be administered up to 3 days before or after the scheduled treatment date due to 
administrative reasons. 
Pembrolizumab treatment to subjects in Arm 2 should be given prior to any other chemoradiation 
treatment (i.e. prior to radiation therapy). It is recommended that subjects receive pembrolizumab on 
the same day as cisplatin. The pembrolizumab infusion can be administered concurrent to the pre-
hydration for the cisplatin treatment. 
All trial treatments will be administered on an outpatient basis. 
5.3.3.3 
Radiation Treatments 
Radiation therapy details will be identical for both Arms 1 and 2. This trial will include external beam 
radiation therapy (EBRT), including intensity modulated radiation therapy (IMRT), and image-guided 
brachytherapy with three-dimensional (3-D) treatment planning. IMRT is included as it may reduce 
the acute normal tissue toxicity from cervical cancer radiotherapy[14], and 3-D planned brachytherapy 
has been shown to improve local tumor control and reduce toxicity compared to two-dimensional 
planning.[15] Standard doses of external beam radiation therapy and brachytherapy will be delivered, 
and this radiation therapy section is written with the purpose of including the range of treatment 
approaches used by each participating institution, as long as the cumulative doses are within the 
target range. Each institution may follow their specific institutional policies for IMRT, including 
pseudo-split-field IMRT.[16]  Parametrial boosts and nodal boosts may be delivered using either 
sequential or concomitant-integrated boost methods. Investigators may use both simultaneous and 
integrated boosts to comply with local institutional policies.[17] All IMRT and brachytherapy 
treatments must be delivered within a total of 8 weeks. 
5.3.3.3.1 
External Beam Radiation Therapy 
IMRT planning is encouraged in this study. However, three-dimensional conformal radiation therapy 
is permitted instead of IMRT if cumulative organ-at-risk (OAR) constraints are respected. The EBRT 
plan will deliver at least 45 Gy, with treatment sites including the primary tumor and nodal volumes. 
Consensus guidelines are suggested to define target volume definition for IMRT.[18] This may be 
accompanied by parametrial or nodal boosts of 5.4-18 Gy as indicated (up to total dose of 63 Gy by 
EBRT).  Three-dimensional conformal radiation therapy is permitted instead of IMRT if cumulative 
organ-at-risk (OAR) constraints are respected.  
Simulation and Immobilization 


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CT simulation is required for the study to permit target delineation and dose calculation. Patients may 
be simulated in the supine or prone position based on institutional practice. If a four-field, 3D 
conformal plan is used rather than IMRT, prone positioning with a belly board is recommended.  
Target Volume ad Organ-At-Risk Definitions 
Target volumes and OARs must be defined on CT scan, and co-registered complementary imaging 
(i.e., MRI and/or PET imaging) can be used based on institutional practice. OAR volumes should 
include the entire organ (rather than just the wall of the organ) for ease of reporting. The radiation 
therapy case report forms will use the following nomenclature, so consistent labeling is suggested. 
Investigators may choose to label structures differently according to institutional standards, and the 
target volume and OAR labeling are suggestions, not protocol requirements. , When completing the 
case report forms, investigators are asked to simply report the requested data for their target volume 
that is most similar to the structures described below. The case report form will request the data using 
the following labels: 
Target Volumes 
Description 
GTV (gross tumor volume) or 
HR-CTV (high risk CTV) 
Gross tumor alone (GTV) or gross tumor and highest 
risk area at time of brachytherapy (HR-CTV) 
GTVnodal 
Gross tumor volume for lymph node as identified on 
imaging or exam. Dose to the nodal volume receiving 
highest boost dose will be requested. 
CTVnodal 
Clinical target volume for regional lymph nodes. 
Prescription dose to at-risk nodal regions will be 
requested. 
OARs 
Description 
Bladder 
Entire organ contoured on CT. Cumulative dose from 
EBRT+brachytherapy will be requested. 
Sigmoid 
Entire organ contoured on CT. Cumulative dose from 
EBRT+brachytherapy will be requested. 
Rectum 
Contoured from ischial tuberosities to sigmoid flexure. 
Entire organ contoured. Cumulative dose from 
EBRT+brachytherapy will be requested. 
Bowel 
May be contoured as bag of bowel or individual loops 
of bowel. Cumulative dose from EBRT alone will be 
requested. 
CT = computed tomography; CTV = clinical target volume; EBRT = external beam radiation therapy; 
GTV = gross tumor volume 
Treatment Planning 
IMRT or 3D conformal RT planning will be used to deliver a total dose of at least 45 Gy to the nodal 
CTV. Depending on institutional practice, pseudo-split-field IMRT or integrated boost approaches can 
be used with goal of meeting the planning objectives stated in the table below. The following 


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objectives are based on a recent RTOG protocol (NCT01672892), published series,[16, 17, 19] and 
guidelines.[20, 21] 
Target Volumes 
Planning Objectives 
GTV or HR-CTV 
D90 EQD2 ≥ 80 Gy (representing dose from 
brachytherapy + EBRT) 
GTVnodal 
≥ 59 Gy from EBRT 
CTVnodal 
≥ 45 Gy from EBRT 
OARs 
Planning Objectives 
Bladder 
D2cc ≤ 90 Gy EQD2 (representing dose from 
brachytherapy + EBRT) 
Sigmoid 
D2cc ≤ 75 Gy EQD2 (representing dose from 
brachytherapy + EBRT) 
Rectum 
D2cc ≤ 75 Gy EQD2 (representing dose from 
brachytherapy + EBRT) 
Bowel 
D5cc ≤ 55 Gy EQD2 (representing dose from EBRT 
only); no more than 30% receives 40 Gy 
D2cc = dose encompassing the highest exposed 2 cc; D5cc = dose encompassing the most exposed 
5 cc; EQD2 = equivalent dose in 2 Gy fractions; HR-CTV = high risk clinical target volume 
(recommended to comply with GEC-ESTRO definition[21]); EBRT = external beam RT; OARs = 
organs at risk 
Treatment Delivery 
Daily imaging is recommended during EBRT to permit verification of target alignment. Imaging and 
alignment method is to follow institutional practice, and can consist of orthogonal plain films, kV 
matching or CT imaging. 
5.3.3.3.2 
Brachytherapy 
Brachytherapy will consist of 4-6 fractions of 5-7 Gy per fraction delivered with high-dose-rate (HDR) 
brachytherapy, based on institutional practice.  Brachytherapy is not to be delivered on the same day 
as cisplatin chemotherapy.  
Either CT-based or MRI-based treatment planning will be permitted for brachytherapy. The minimum 
EQD2Gy for the highest dose encompassing 90% (D90) of the high-risk clinical target volume (HR-
CTV) or gross tumor volume (GTV) is 80 Gy, consistent with ABS guidelines.[20] It is recommended 
that the HR-CTV D90 is ≥ 100% of the prescription dose and the HR-CTV volume encompassing 
100% of the target volume (V100) is ≥ 90%.  
Cumulative doses to rectum, bladder, sigmoid and bowel will be followed to limit doses below 
threshold values for dose to the hottest 2 cc (D2cc) as calculated by equivalent dose in 2 Gy fractions 
(EQD2Gy) using a modified version of the American Brachytherapy Society (ABS) worksheet. The 
EQD2Gy limits will be 90 Gy for bladder and 75 Gy for rectum and sigmoid. This is consistent with 
ABS guidelines.[20] 


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Brachytherapy Target Volume Definitions 
It is recommended that the brachytherapy treatment planning include delineation of the GTV or HR-
CTV, per institutional practice, as well as the rectum, sigmoid, bladder and bowel. 
Dose Reporting 
Case report forms will request these doses for each fraction of brachytherapy: estimated D90 and 
V100 for the HR-CTV or GTV, Point A, and D2cc for sigmoid, rectum, bladder and bowel. Cumulative 
EQD2Gy doses for D90 of the HRCTV and D2cc for the sigmoid, rectum, bladder and bowel will be 
requested. 
5.4 
Concomitant Medications/Vaccinations 
Medications or vaccinations specifically prohibited in the exclusion criteria and listed in Section 5.4.2 
are not allowed during the Screening and Treatment Phase of this trial. There are no prohibited 
therapies during the Post-Treatment Follow-up Phase. 
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 Sponsor-Investigator. The final 
decision on any supportive therapy or vaccination rests with the investigator and/or the subject's 
primary physician.  
 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.  
 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase 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 not specified in this protocol 
 
Live vaccines  
 
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-Investigator. 


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5.5 
Rescue Medications & Supportive Care 
 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator. Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below and in greater detail in the ECI guidance document. 
Where appropriate, these guidelines include the use of oral or intravenous treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids. Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. For each disorder, attempts should be 
made to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are recommended 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). Refer to Section 5.3.2 for guidelines regarding dosing delays and 
modifications.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. These procedures should be performed at the 
discretion of the investigator and are not mandated by the protocol. Suggested conditional 
procedures, as appropriate, can be found in the ECI guidance document. 
 
Pneumonitis:  
o 
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
o 
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
For Grade 3-4 events, or recurrent Grade 2 events, permanently discontinue 
Pembrolizumab. 
o 
Monitor participants for signs and symptoms of pneumonitis 
o 
Evaluate participants with suspected pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
o 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 
 
Myocarditis: 
o 
Ensure adequate evaluation to confirm etiology and/or exclude other causes  
o 
Administer corticosteroids based on severity of event 
 
 
Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   


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If diarrhea/colitis occurs prior to initiation of pembrolizumab or can be attributed to the CRT 
treatment, then subjects should be advised to drink liberal quantities of clear fluids and will 
receive standard management for diarrhea with loperamide, low residue diet and Lomotil if 
needed.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted 
via IV infusion.  For Grade 2 or higher diarrhea where colitis is suspected, consider GI 
consultation and endoscopy to confirm or rule out colitis. 
If diarrhea/colitis occurs after subject has received any administration of pembrolizumab, then 
it is critically important to evaluate the subject for immune-related diarrhea/colitis. The 
diarrhea/colitis is likely to be immune-related if it has any of the following characteristics: 
o 
Bloody or mucous stools 
o 
Cramping 
o 
occurs at a timepoint not typical for chemoRT (i.e., in first 2 weeks of treatment or 
after completion of external beam RT)  
If the event meets these criteria, then it should be treated as follows: 
o 
All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.   
o 
For Grade 2 diarrhea/colitis that is felt to be possibly, probably, or likely related to 
investigational agent, administer oral corticosteroids consistent with the guidelines in 
the pembrolizumab lab. Current recommendation is to start at an initial dose of 1 to 2 
mg/kg/day prednisone or equivalent. 
o 
For Grade 3 or 4 diarrhea/colitis that is felt to be possibly, probably, or likely related 
to investigational agent and that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids.   
o 
Withhold pembrolizumab administration for moderate (Grade 2) or severe (Grade 3) 
colitis, and permanently discontinue pembrolizumab administration for life-threatening 
(Grade 4) colitis. 
o 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 
 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
 
o 
For T1DM or Grade 3-4 Hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes mellitus and 
anti-hyperglycemic in participants for Grade 3-4 hyperglycemia with evidence 
of Beta-cell failure.  
 
Monitor participants for hyperglycemia or other signs and symptoms of 
diabetes. 
 
Evaluate subjects with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
 
Hypophysitis: 


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Protocol/Amendment No.:  UVA-LACC-PD201, Version 4.0, 06 March 2018 
 
 
 
 
o 
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
o 
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
o 
Monitor for signs and symptoms of hypophysitis (including hypopituitarism and 
adrenal insufficiency) 
 
 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor subjects for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
 
o 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine 
or liothyroinine, is indicated per standard of care. 
o 
Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
 
 
Hepatic: 
o 
For Grade 2-4 events, monitor with liver function tests (weekly or more frequently 
until returned to baseline values or is stable. 
 
Treat with IV or oral corticosteroids 
o 
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
 
Renal Failure or Nephritis: 
o 
For Grade 2-4 events, treat with corticosteroids (prednisone 1-2 mg/kg or equivalent) 
followed by taper. 
o 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
o 
Monitor changes in renal function 
 
 
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 4. 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. 
 
5.6 
Diet/Activity/Other Considerations 
 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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 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) sterilized surgically 
or as a result of radiation treatments, 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 120 days after the last 
dose of study therapy, or until they are no longer of childbearing potential.  
The following are considered adequate barrier methods of contraception: diaphragm, condom (by the 
partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal contraceptives will 
include any registered and marketed contraceptive agent that contains an estrogen and/or a 
progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to the fetus 
(unborn baby) if pregnancy were to occur during the study. In order to participate in the study they 
must adhere to the contraception requirement (described above) for the duration of the study and 
during the follow-up period. If there is any question that a subject will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. 
 Use in Pregnancy 
If a subject becomes pregnant while on treatment with pembrolizumab, the subject will immediately 
be removed from the study. The site will contact the subject at least monthly and document the 
subject’s status until the pregnancy has been completed or terminated. The outcome of the 
pregnancy will be reported to the Sponsor-Investigator. 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), this should be reported within 24 hours to the Sponsor-
Investigator.   
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor-Investigator.  
 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, subjects 
who are breast-feeding are not eligible for enrollment. 
5.7 
Subject Participation and Withdrawal/Discontinuation Criteria 
A subject is considered On-Study from the time eligibility is confirmed through the follow-up interval. 
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-Investigator if enrollment into the trial is inappropriate, 


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the trial plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in the sections below. 
 Duration of Treatment 
Subjects will continue to receive study treatment (defined as chemoradiation and pembrolizumab) 
until: 
 
Subject has completed all study treatments  
 
Disease progression 
 
Unacceptable adverse event(s)  
 
Subject withdraws consent for further treatment 
 
Female subject has a confirmed positive serum pregnancy test 
 
Subject receives a non-study treatment (not protocol-specified) for their cancer 
 
Subject non-compliance 
 
General or specific changes in the subject’s condition render the subject unacceptable for 
further treatment in the judgment of the investigator 
If any of the above events occurs, the subject will be considered off treatment and in follow-up. 
Subjects will be followed for 5 years for PFS and OS, or until the trial is terminated per Section 5.7.4.  
 Discontinuation/Withdrawal from Study 
Subjects may withdraw or be discontinued from the study at any time for any of the following reasons: 
 
Subject decides to withdraw from the study 
 
Subject is unable or unwilling to complete the follow-up procedures 
 
The subject is lost to follow-up 
 
Death 
The primary reason for discontinuation or withdrawal should be entered into OnCore.  All subjects 
that discontinue or withdraw from the study will continue to receive standard of care treatment. 
Subjects who have withdrawn consent for the study will not be followed for any reason.   
A subject’s participation is considered completed when the subject has completed the 5 year follow-
up interval.  
 Subject Status Definitions 
Enrolled: All subjects who sign an informed consent will be considered enrolled on the study. All 
subjects consented on the study must be entered into OnCore. 
Screen Failure: A subject who is withdrawn or discontinues from the study prior to receiving any 
treatment is considered a post enrollment screen failure. Post enrollment screen failures are not 
considered a study accrual and will be replaced. Note: The UVa IRB-HSR defines any individual that 
has signed an informed consent as an enrollment in this study and so screen failures should be 
reported to the IRB with enrollment numbers. 


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On-Study: A subject is considered on-study on the date when the study team has confirmed the 
subject has met all of the inclusion and none of the exclusion criteria, and the treating 
physician/surgeon or study PI has signed off on the confirmation. 
Randomized: A subject that has been randomized to an arm is considered a randomized subject. 
On-Treatment: A subject is considered on-treatment on the date that CRT is initiated  
Off-Treatment: A subject is considered off-treatment on the date that they have met any of the criteria 
listed in Section 5.7.1 
On Follow-up: A subject is considered on follow-up on the date that they have met any of the criteria 
listed in Section 5.7.1.    
Off-Study: A subject is considered off-study if they are removed from the study for any of the reasons 
listed in Section 5.7.2, or if they have completed the follow-up interval. 
 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of a decision by Merck to no longer supply study drug, ample notification will be provided 
so that appropriate adjustments to subject treatment can be made. 
 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor-Investigator, investigator and subject will know the 
treatment administered. 


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Protocol/Amendment No.:  UVA-LACC-PD201, Version 4.0, 06 March 2018 
 
 
 
 
 
 
6.0 TRIAL FLOW CHART 
 
6.1 
Study Flow Chart  
 Arm 1 
Trial Period: 
Pre- 
Study 
Treatment  
Post-treatment 
Survival 
Follow-
Up1 
Visit: Screening 
CRT 
Pembro 
EOT  visit2 Imaging  
Scheduling Interval: -42d-1d 
W1-W8 
W9-W15 
35 ± 5d 
12w ± 10d 
post-CRT 
Administrative Procedures 
Informed Consent/ IE 
X 
 
 
 
 
 
Demographics/Medical 
History 
X 
 
 
 
 
 
Concomitant Medication 
Review 
X 
 
 
 
 
 
Disease Status 
 
 
 
 
 
X 
Survival Status 
 
 
 
 
 
X 
Study Treatments 
Cisplatin 
 
X 
 
 
 
 
Radiation 
 
X 
 
 
 
 
MK-3475 administration 
 
 
X
3 
 
 
 
Specimen Collection 
Tissue Collection
4 
X 
X
5 
 
 
X 
 
Research Blood Collection 
X 
X5 
 
 
X 
 
Clinical Procedures/ Laboratory Assessments 
Pregnancy Test (Urine or 
Serum)
6 
X 
 
 
 
 
 
Review Adverse Events 
X 
X 
X 
X 
 
 
                                                 
1 All subjects should be followed for 5 years following treatment to monitor disease status and overall survival. 
There are no per protocol assessments, all subjects should be monitored according to the standard of care of 
the treating physicians. 
2 Each subject should return to the clinic for a visit 30-40 days following the last study treatment (of either 
pembrolizumab or chemoradiation) for assessment of adverse events 
3 Pembrolizumab treatment should be scheduled for every 21 days (± 3 days) starting on Week 9.  
4 Fresh tissue biopsies are required. If archival tissue is available these may also be submitted to supplement fresh 
tissue collected at baseline. 
5 Tissue and blood specimen collected during CRT interval should be obtained at  5 ± 2 weeks 
6 Women of childbearing potential must have a negative pregnancy test within 72 hours of first dose of study 
treatment. 


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Protocol/Amendment No.:  UVA-LACC-PD201, Version 4.0, 06 March 2018 
 
 
 
 
 
 
Trial Period: 
Pre- 
Study 
Treatment  
Post-treatment 
Survival 
Follow-
Up1 
Visit: Screening 
CRT 
Pembro 
EOT  visit2 Imaging  
Scheduling Interval: -42d-1d 
W1-W8 
W9-W15 
35 ± 5d 
12w ± 10d 
post-CRT 
Physical 
Examination/ECOG 
X7 
X8 
X8 
X 
X7 
 
Vital Signs 
X 
X 
X 
X 
 
 
PT/INR and aPTT14 
X 
 
 
 
 
 
CBC with Differential14 
X 
X
9,10,11 
X11,12 
X 
 
 
Serum Chemistry Panel14 
X 
X9,10,11 
X11,12  
X 
 
 
Thyroid panel14 
X 
 
X11,13 
X 
 
 
Tumor Imaging/Disease Assessments 
MRI15 
X 
 
 
 
 
 
PET/CT16 
X 
 
 
 
X 
 
 
 
                                                 
7 Physical exam at screening and at the time of the post-treatment imaging should include a clinical tumor 
assessment 
8 Physical exams should be done at a minimum every 3 weeks during study treatment interval 
9 Prior to first day of treatment (Day 1 Week 1), laboratory tests do not need to be repeated if screening labs were 
performed within 14 days prior to treatment date. 
10General safety labs (CBC and Basic Serum Chemistry) should be performed once weekly during 
chemoradiation to evaluate for toxicities.  
11 Labs required prior to treatments do not need to be repeated if labs have been performed within 72 hours     prior 
to dose.  
12 General safety labs (CBC and Complete Chemistry Panel including liver function tests) should be performed 
prior to pembrolizumab administration on day of dosing to evaluate for toxicities (if not done in previous 72 
hours). 
13Thyroid function tests should include, at a minimum, TSH.  If TSH is abnormal, T3 and T4 must be evaluated.  
Thyroid function tests should be performed prior to pembrolizumab administration on day of dosing (if not done 
in previous 72 hours). 
14Screening labs must be obtained within 14 days of start of treatment. 
15Pelvic MRI is required within 4 weeks of start of treatment unless there are contraindications or at the discretion 
of investigator. 
16PET/CT (skull base to thighs) should be performed within 6 weeks of start of treatment and repeated at 12 weeks 
+/- 10 days after completion of CRT. 


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Protocol/Amendment No.:  UVA-LACC-PD201, Version 4.0, 06 March 2018 
 
 
 
 
 
 
 Arm 2 
Trial Period: 
Pre- 
Study 
Treatment 
Post-treatment 
Survival 
Follow-
Up1 
Visit: Screening 
CRT + 
MK-3475 EOT visit2 
Imaging 
Scheduling Interval: -42d-1d 
W1-W9 
(35 ± 5d) 12w ± 10d 
post-CRT 
Administrative Procedures 
Informed Consent/ IE 
X 
 
 
 
 
Demographics/Medical 
History 
X 
 
 
 
 
Concomitant Medication 
Review 
X 
 
 
 
 
Disease Status 
 
 
 
 
X 
Survival Status 
 
 
 
 
X 
Study Treatments 
Cisplatin 
 
X 
 
 
 
Radiation 
 
X 
 
 
 
MK-3475 administration  
 
X
3 
 
 
 
Specimen Collection 
Tissue Collection
4 
X 
X
5 
 
X 
 
Research Blood Collection 
X 
X5 
 
X 
 
Clinical Procedures/ Laboratory Assessments 
Pregnancy Test (Urine or 
Serum)
6 
X 
 
 
 
 
Review Adverse Events 
X 
X 
X 
 
 
Physical 
Examination/ECOG 
X7 
X8 
X 
X7 
 
Vital Signs 
X 
X 
X 
 
 
                                                 
1 All subjects should be followed for 5 years following treatment to monitor disease status and overall survival. 
There are no per protocol assessments, all subjects should be monitored according to the standard of care of 
the treating physicians. 
2 Each subject should return to the clinic for a visit 30-40 days following the last study treatment (of either 
pembrolizumab or chemoradiation) for assessment of adverse events 
3 Pembrolizumab treatment should be scheduled for every 21 days (± 3 days) starting on Day 1.  
4 Fresh tissue biopsies are required. If archival tissue is available these may also be submitted to supplement fresh 
tissue collected at baseline. 
5 Tissue and blood specimen collected during CRT interval should be obtained at  5 ± 2 weeks 
6 Women of childbearing potential must have a negative pregnancy test within 72 hours of first dose of study 
treatment. 
7 Physical exam at screening and at the time of the post-treatment imaging should include a clinical tumor 
assessment 
8 Physical exams should be done at a minimum every 3 weeks during study treatment interval 


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Protocol/Amendment No.:  UVA-LACC-PD201, Version 4.0, 06 March 2018 
 
 
 
 
 
 
Trial Period: 
Pre- 
Study 
Treatment 
Post-treatment 
Survival 
Follow-
Up1 
Visit: Screening 
CRT + 
MK-3475 EOT visit2 
Imaging 
Scheduling Interval: -42d-1d 
W1-W9 
(35 ± 5d) 12w ± 10d 
post-CRT 
PT/INR and aPTT13 
X 
 
 
 
 
CBC with Differential13 
X 
X
9,10,11 
X 
 
 
Serum Chemistry Panel13 
X 
X9,10,11 
X 
 
 
Thyroid panel13 
X 
X9,11,12 
X 
 
 
Tumor Imaging/Disease Assessments 
MRI14 
X 
 
 
 
 
PET/CT15 
X 
 
 
X 
 
 
 
 
                                                 
9 Prior to first day of treatment (Day 1 Week 1), laboratory tests do not need to be repeated if screening labs were 
performed within 14 days prior to treatment date. 
10 General safety labs (CBC and serum chemistry) should be performed once weekly during chemoradiation and 
should also be performed prior to pembrolizumab administration on day of dosing to evaluate for toxicities (if 
not done in previous 72 hours). A basic serum chemistry panel is sufficient during chemoradiation, however, a 
complete chemistry panel including liver function tests should be performed within 72 hours of pembrolizumab 
treatments.  
11 Labs required prior to treatments do not need to be repeated if labs have been performed within 72 hours prior 
to dose 
12 Thyroid function tests should include, at a minimum, TSH.  If TSH is abnormal, T3 and T4 must be evaluated. 
Thyroid tests should be completed within 72 hours prior to pembrolizumab administration. 
13Screening labs must be obtained within 14 days of start of treatment. 
14 Pelvic MRI is required within 4 weeks of start of treatment unless there are contraindications or at the discretion 
of investigator. 
15 PET/CT (skull base to thighs) should be performed within 6 weeks of start of treatment, and repeated at 12 
weeks ± 10 days after completion of CRT. 


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Protocol/Amendment No.:  UVA-LACC-PD201, Version 4.0, 06 March 2018 
 
 
 
 
 
 
6.2 
TRIAL PROCEDURES 
6.3 
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-Investigator 
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. 
 
Administrative Procedures 
6.3.1.1 
Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to participating in 
a clinical trial. 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 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.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor-Investigator requirements. 
6.3.1.2 
Registration  
Subjects who are consented to the study must be registered in OnCore in accordance with the 
University of Virginia Cancer Center OnCore SOP, which can be found on the OnCore Resources 
page (see the Oncore Help tab). General guidelines are provided below for reference, but the 
procedure should follow the OnCore SOP in case of any discrepancy. 
All subjects who have signed an informed consent should have the following information entered into 
OnCore: 


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 
demographics 
 
date of signed informed consent 
Subject eligibility must be confirmed by the site principal investigator (PI) and the eligibility packet 
should include at a minimum the informed consent and eligibility worksheet. All sites will submit an 
eligibility packet for each eligible subject to the study manager for review.  The study manager will 
inform the site if the subject can be put on-study and instruct the site to then enter the following 
information into OnCore: 
 
subject number (provided by the study manager) 
 
on-study date 
 
disease site 
 
registering investigator 
 Randomization or Treatment Allocation 
The subject will be randomized by the study manager at UVa using custom randomization software 
developed at UVa. The software incorporates the randomization scheme generated by the study 
statistician and assigns the subject to one of the two protocol arms. 
6.3.2.1 
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.   
6.3.2.2 
Prior and Concomitant Medications Review 
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.  
6.3.2.3 
Disease Details and Treatments 
6.3.2.3.1 
Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status.  
6.3.2.3.2 
Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
 Clinical Procedures/Assessments 
6.3.3.1 
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 according to NCI CTCAE Version 4.0.  Toxicities will be 


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characterized in terms regarding seriousness, causality, toxicity grading, and action taken with regard 
to trial treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated with 
pembrolizumab exposure should be evaluated to determine if it is possibly an event of clinical interest 
(ECI) of a potentially immunologic etiology (termed immune-related adverse events, or irAEs); see 
separate ECI guidance document regarding the identification, evaluation and management of 
potential irAEs.   
Please refer to Section 6.4 for detailed information regarding the assessment and recording of AEs.   
6.3.3.2 
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.   
At subsequent visits requiring a physical exam per the Trial Flow Chart, the investigator or qualified 
designee will perform a directed physical exam as clinically indicated. On treatment days the physical 
exam should be performed prior to trial treatment administration.  The physical exam conducted at 
the time of the post-treatment imaging should include, at a minimum, a clinical tumor assessment. 
6.3.3.3 
Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration of 
each dose of trial treatment and at treatment discontinuation 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. 
6.3.3.4 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each dose of trial treatment and discontinuation of trial treatment as specified in the 
Trial Flow Chart.   
 Laboratory Procedures/Assessments 
Labs required prior to treatments do not need to be repeated if labs have been performed within 72 
hours prior to dose. Screening labs must be performed within 14 days prior to treatment initiation; 
prior to first day of treatment (Day 1 Week 1) laboratory tests do not need to be repeated if screening 
labs were completed in the 14 day window. Results must be reviewed by the investigator or qualified 
designee and found to be acceptable prior to each dose of trial treatment. Laboratory tests for 
hematology, chemistry, urinalysis, and others are specified in Table 5.   
 


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Table 5. Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Urine pregnancy test † 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
 
PT (INR) 
Platelet count 
Alanine aminotransferase (ALT) 
 
aPTT 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
 
Total triiodothyronine (T3) 
Red Blood Cell Count 
Carbon Dioxide ‡ 
 
Free thyroxine (T4) 
Absolute Neutrophil Count 
  (CO2 or biocarbonate) 
 
Thyroid stimulating hormone (TSH) 
Absolute Lymphocyte Count 
Calcium 
 
Blood for correlative studies 
 
Chloride 
 
 
 
Glucose 
 
 
 
Phosphorus 
 
 
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
  
 
Total protein 
 
  
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 
 


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6.3.4.1 
Tumor Imaging and Assessment of Disease 
Baseline imaging should be obtained within 6 weeks of the start of treatment and should include MRI 
and PET/CT. A pelvic MRI is required only at the Pre-Study Assessments unless there are 
contraindications or at the discretion of investigator.  
PET/CT should be inclusive of the skull base to the thigh area (“eyes to thighs”) and should be 
performed during the Pre-Study Assessments for initial staging. PET/CT should be repeated at 12 
weeks ± 10 days after completion of CRT for evaluation of disease.     
6.3.4.2 
Tumor Tissue Collection and Correlative Studies Blood Sampling 
Blood and tumor tissue should be collected from subjects at the intervals specified in the Trial Flow 
Chart and sent to the University of Virginia for analysis. All blood and tissue will be stored for 
research.  
 
Tissue Markers: Tissue samples will be evaluated for tumor infiltrating lymphocytes using flow 
cytometry (FC) and standard immunohistochemical (IHC) staining techniques. Flow cytometry will be 
performed using standard techniques as described previously. For immunohistochemistry, tissue 
microarrays will be prepared using tissue cores from representative tumor areas from the FFPE 
tissue blocks. The tissue microarray will be incubated with specific antibodies, and positive and 
negative controls. Staining will be quantitated in quadruplicate by a pathologist blinded to the sample 
identity. Total cell count will be expressed in cells/mm2 and density will be expressed as a number of 
cells per high power field (hpf). Staining will be determined in the five most abundant areas, using the 
average over the five to determine the percentage. 
 
In addition, gene expression arrays on the resected tumor samples will be performed as a part of this 
study and may assist in identifying the activation of these receptors and factors.  
 
Circulating Biomarkers: Collected blood will be processed to isolate peripheral blood lymphocytes.  
ELIspot analyses will be performed on PBMCs isolated from blood samples at each timepoint. 
 
The planned initial analyses of the samples include the markers specified in this protocol; however 
actual analyses conducted may vary slightly as new information and technology develop. 
6.3.4.2.1 
Tumor Samples 
Tumor tissue samples must be collected at the intervals specified in the Trial Flow Chart, adhering to 
the following guidelines: 
1. Pre-study Tissue sample: Fresh tissue must be collected from an office biopsy performed 
within the 4 weeks prior to start of treatment. If this biopsy yields insufficient tumor tissue, an 
archival sample may be requested. 
2. CRT Treatment Sample:  Fresh tissue must be collected during CRT treatment, at 5 ± 2 
weeks. It is recommended that this sample be obtained at the time of brachytherapy delivery, 
so that biopsy can be performed conveniently.   


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3. Treatment completion: Fresh tissue must be collected from an office biopsy performed at 12 
weeks ± 10 days following completion of CRT.   
Fresh tumor tissue should be divided into portions for several preparations including formalin fixed 
paraffin embedded (FFPE) in blocks, flash freezing and single cell isolations. Detail instructions for 
tissue processing and shipping will be provided in a separate study manual. 
6.3.4.2.2 
Blood Samples 
Blood samples will be collected from subjects at the intervals specified in the Trial Flow Chart.  
At each collection, approximately 70 cc of blood should be collected in heparinized green top tubes. 
Detail instructions for blood processing and shipping will be provided in a separate study manual.  
 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. 
6.3.5.1 
Screening 
Prior to the performance of any study-specific procedures, the patient will have the nature of the study 
explained to them, and will be asked to give written informed consent. Informed consent must be 
obtained prior to any study-specific procedures that do not form a part of the patient’s normal care. 
However, assessments performed according to standard of care prior to receipt of informed consent 
may be utilized to fulfill the screening requirement, if completed within the required window for 
screening.  
6.3.5.2 
Treatment Period 
The treatment period will consist of the duration of chemoradiation and pembrolizumab treatments. 
Subject should receive study assessments as defined in the Trial Flow Chart. 
6.3.5.3 
Post-treatment Visits 
6.3.5.3.1 
Follow-up Visit 1 
A follow-up visit should be scheduled within 30 - 40 days following administration of the last study 
treatment in all subjects to perform the safety assessments defined in the Trial Flow Chart. Any 
assessments that were performed within 3 days prior to this visit do not need to be repeated. 
6.3.5.4 
Survival Follow-up  
Following completion of treatment, subjects should be followed for 5 years to monitor disease and 
survival. No assessments are specified for this interval, but it is recommended that surveillance follow 
NCCN guidelines. Subjects should be contacted by telephone annually to assess for disease and 
survival status until death, withdrawal of consent, or the end of the study, whichever occurs first. 


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6.4 
Assessing and Recording Adverse Events 
Adverse events should be collected from the start of treatment through a minimum of 30 days 
following the last study treatment.  
After informed consent has been obtained, and prior to initiation of investigational treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported (e.g., serious 
adverse events related to invasive procedures such as biopsies). 
After initiation of study treatment, all adverse events will be reported according to the guidelines in 
the following sections. Throughout the study, investigators should report any deaths, serious adverse 
events, or other adverse events of concern that are believed to be related to the investigational 
intervention. 
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 pembrolizumab, is also an adverse event. 
Adverse events may occur during the course of the use of Pembrolizumab 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. 
A summary of the adverse event collection and reporting is provided in Table 6. 
Table 6. Adverse Event Reporting Overview 
Event Type 
Collection Timeframe 
Reporting Timeframe 
Reference 
Routine Adverse 
Events 
the start of treatment through at 
least 30 days following the last 
study treatment 
Within 30 days to UVa 
Section 6.4 
Serious Adverse 
Events† 
Within 24h to UVa  
Section 6.4.4.1 
Events of Clinical 
Interest 
the start of treatment through 90 
days following the last dose of 
pembrolizumab  (or date subject 
starts new cancer treatment) 
Within 24h to UVa  
Section 6.4.4.2 
Overdose 
On pembrolizumab dosing days 
Within 24h to UVa  
Section 6.4.2 
Pregnancy 
the start of treatment through 120 
days following the last dose of 
pembrolizumab (or 30 days 
following the last dose of 
pembrolizumab if subjects start 
new cancer treatment) 
Within 24h to UVa  
Section 6.4.3 
†Serious and unexpected adverse events should also be reported to the site IRB per their institutional 
guidelines 
 


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Assessment of Adverse Events 
All adverse events, whether reported by the subject or noted by study personnel, should be recorded 
in the subject’s medical record. Adverse events should be assessed for seriousness, severity, 
attribute and expectedness, in relation to Pembrolizumab treatment, by the Principal Investigator or 
designee. The following sections provide definitions for adverse event characteristics and reporting 
requirements.   
6.4.1.1 
Expectedness 
The expectedness of the adverse event will be determined by the Investigator based on current 
literature, the Investigator’s Brochure or package insert and the Investigator’s experience. Adverse 
events commonly observed with the standard of care chemoradiation treatment, such as 
hematological, genitourinary and gastrointestinal, should be expected during the CRT interval. 
6.4.1.2 
Severity 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.03. A copy of the CTCAE version 4.03 
can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
6.4.1.3 
Attribution  
The Principal Investigator will evaluate all AEs and assess their toxicity and attribution, if any, to 
pembrolizumab.  See Table 8 for further guidance on evaluation of attribute. The following criteria will 
define the attribution: 
Definite:  The AE is clearly related to the investigational intervention. 
Probable: The AE is likely related to the investigational intervention. 
Possible: The AE may be related to the investigational intervention. 
Unlikely: The AE is doubtfully related to the investigational intervention. 
Unrelated: The AE is NOT related to the investigational intervention. 
6.4.1.4 
Seriousness  
A serious adverse event is any adverse event 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 another important medical event  
*Hospitalization or prolonged hospitalization should be documented and reported as a serious adverse 
event, except if the hospitalization meets at least one of the following criteria: 


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 
The hospitalization is less than 24 hours without an admission 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for anticipated or protocol 
specified procedures such as administration of Intravenous fluids, central line 
insertion, biopsy procedures ) 
 
Hospitalization for a preexisting condition, provided that all of the following criteria are 
met: 
o 
The hospitalization was planned prior to the study or was scheduled during 
the study when elective surgery became necessary because of the expected 
normal progression of the disease.  
o 
The subject has not suffered an adverse event. 
If the hospitalization meets any of these criteria, then it is not considered a serious adverse event.  
Refer to Table 7 for additional details regarding each of the above criteria. 
 Definition of an Overdose  
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed dose for 
pembrolizumab by 20% over the prescribed dose. No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, pembrolizumab should be 
discontinued and 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 Pembrolizumab, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are met. 
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose 
without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to the 
Sponsor-Investigator (Fax notification to UVa) using the Safety Reporting Form. 
 Reporting of Pregnancy and Lactation to the Sponsor-Investigator  
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 or within 120 days of completing the pembrolizumab 
treatment, or 30 days following cessation of pembrolizumab treatment if the subject initiates new 
anticancer therapy, whichever is earlier.  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-Investigator using the Safety Reporting 
Form. 


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 Immediate Reporting of Adverse Events to the Sponsor-Investigator 
6.4.4.1 
Serious Adverse Events 
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 of start of 
treatment through 30 days following the last dose of study treatment, or the initiation of new anti-
cancer therapy, whichever is earlier, whether or not related to pembrolizumab, must be reported 
within 24 hours to the Sponsor-Investigator.  Additionally, after informed consent has been obtained, 
and prior to start of treatment, serious adverse events determined to be caused by a protocol-
mandated intervention should also be reported.  
Non-serious Events of Clinical Interest (See Section 6.4.4.2) will be forwarded to Sponsor-Investigator 
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 Pembrolizumab that is brought to the attention of the investigator at any time outside of the 
time period specified in the previous paragraph also must be reported immediately to the Sponsor-
Investigator. 
All subjects with serious adverse events must be followed up for outcome. 
6.4.4.2 
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-Investigator using the Safety Reporting Form. 
Events of clinical interest for this trial include: 
1.  an overdose of Pembrolizumab, as defined in Section 6.4.2 - Definition of an Overdose for This 
Protocol and Reporting of Overdose to the Sponsor-Investigator, 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 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). 
3. Additional adverse events: 
 
A separate guidance document has been provided titled “Event of Clinical Interest Guidance 
Document” (previously entitled, “Event of Clinical Interest and Immune-Related Adverse Event 
Guidance Document”).  This document provides guidance regarding identification, evaluation and 
management of ECIs and irAEs.   


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ECIs (both non-serious and serious adverse events) identified in this guidance document from the 
date of first dose through 90 days following cessation of treatment, or 30 days after the initiation 
of a new anticancer therapy, whichever is earlier, need to be reported within 24 hours to the 
Sponsor-Investigator using the Safety Reporting Form. 
 
Subjects should be assessed for possible ECIs prior to each dose.  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. 
 


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Table 7.  Evaluating Adverse Events 
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? 
Expectedness 
Events included in Pembrolizumab Investigator’s Brochure should be considered expected with pembrolizumab treatment for the purposes of assessment for 
expedited reporting requirements.  
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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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? 


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6.4.4.3 
UVA Cancer Center DSMC Reporting Requirements 
All adverse events must be reported into the University of Virginia Cancer Center OnCore database 
within the time frame specified below: 
Table B: Medium Risk Studies 
Reporting requirements for AEs that occur within 30 days of the last dose of protocol specified treatment 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 & 5 
 
Expected 
and 
unexpected 
 
Expected 
 
Unexpected 
Expected 
 
Unexpected 
Expected 
 
Unexpected 
Without 
hospitalization 
With 
hospitalization 
Without 
hospitalization 
With 
hospitalization 
Unrelated 
Unlikely 
Not 
required 
Not 
required 
Not 
required 
OnCore 
30 days 
OnCore 
15 days 
OnCore 
30 days 
OnCore 
15 days 
OnCore 
15 days 
OnCore 
15 days 
Possible 
Probable 
Definite 
OnCore 
30 days 
OnCore 
30 days 
OnCore 
15 days 
OnCore 
30 days 
OnCore 
15 days 
OnCore 
15 days 
OnCore 
15 days 
OnCore 
15 days 
OnCore 
(24-hrs)* 
7 days 
 
*Enter into Cancer Center database within 24 hours if unexpected and definitely related to protocol specified treatment 
Hospitalization defined as an inpatient hospital stay or prolongation of a hospital stay equal to or greater than 24 hours 
 
6.4.4.4 
IRB Reporting Requirements 
Serious and unexpected adverse events must be submitted to the site Institutional Review Board 
according to the participating site institutional policies. 
6.4.4.5 
Reporting to the FDA 
The Sponsor-Investigator for the study (the UVA PI or designee) is responsible for providing safety 
updates to the FDA per the following guidelines. The reporting times refer to the time the Sponsor-
Investigator received knowledge of the AE. 
Table 8. FDA Reporting Requirements 
UVa PI HELD IND 
Type of Event 
To whom will it 
be reported: 
Time Frame for 
Reporting 
How reported? 
Life-threatening and/or fatal 
unexpected events related or 
possibly related to the use of 
the investigational agent. 
FDA 
Within 7 calendar days 
of the study team 
learning of the event 
Form FDA 3500A (MedWatch) or 
narrative 
Serious, unexpected and 
related or possibly related 
adverse events 
FDA 
Within 15 calendar days 
after the study team 
receives knowledge of 
the event 
Form FDA 3500A (MedWatch) or 
narrative 
All adverse events 
FDA 
Annually 
IND annual report 
 
 
6.4.4.6 
Reporting to Participating Sites 
The Sponsor-Investigator for the study (the UVA PI or designee) is responsible for providing safety 
updates to all participating sites per the following guidelines: 
Table 9. Required Reporting to Participating Sites 
UVA PI of MULTI-SITE TRIAL 
Type of Event 
To whom will it be 
reported: 
Time Frame for 
Reporting 
How reported? 


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Serious, unexpected and 
related or possibly related 
adverse events 
All Research Sites 
Within 15 calendar days 
after the Overall PI 
receives knowledge of 
the event 
IND/IDE Safety Report 
(Cover letter, copy of 
MedWatch/narrative) 
Unanticipated Problem 
All Research Sites 
Within 15 calendar days 
from the time the Overall 
PI receives knowledge of 
the event. 
Letter to Participating PIs, 
Copy of MedWatch or narrative 
 
 
Data Safety Monitoring Plan 
The Data and Safety Monitoring Board for this study is the UVA Data Safety Monitoring Committee 
(DSMC). 
6.4.5.1 
UVA Cancer Center Data Safety Monitoring Committee 
The University of Virginia Cancer Center Data and Safety Monitoring Committee (DSMC) will provide 
oversight of the conduct of this study. The CC DSMC will report to the UVA Protocol Review 
Committee (PRC). The DSMC will review the following: 
 
All adverse events 
 
Audit results 
 
Application of study designed stopping/decision rules 
 
Whether the study accrual pattern warrants continuation/action 
 
Protocol violations 
The CC DSMC will meet every month for aggregate review of AE data. Tracking reports of the 
meetings are available to the PI for review.  Issues of immediate concern by the DSMC are brought to 
the attention of the PI (and if appropriate to the PRC and IRB) and a formal response from the PI is 
requested. Per the Cancer Center NIH approved institutional plan this study will be audited 
approximately every 6 or 12 months.  


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7.0 STATISTICAL CONSIDERATIONS 
This is a randomized phase II study to assess the safety of CRT in combination with pembrolizumab 
given as consolidation therapy or current with CRT, and to obtain preliminary estimates of the 
immunologic effect of the addition of pembrolizumab to CRT in this patient population. Eligible 
participants will be randomized 1:1 between the two arms. All participants receiving any protocol 
treatment will be evaluated for safety and the primary immunologic endpoint which is the ratio of the 
phenotype of HPV-specific CD8+ T cells to regulatory T cells (CD8+/Treg). Patterns of change in 
other immunologic endpoints assessed in the tissue and blood will be estimated along with 90% 
confidence intervals. The purpose is not to make definitive comparisons between arms but to obtain 
preliminary estimates of change in CD8+ T-cells and regulatory T cells over time for the different 
treatment schedules.   
Arm 1: pembrolizumab after completion of CRT 
Arm 2: pembrolizumab concurrent to CRT 
7.1 
Evaluation Criteria 
 Safety Endpoints 
All patients receiving any protocol treatment will be evaluated for safety. Safety assessments will 
include:  
i. 
Incidence and severity of adverse events. 
ii. 
Incidence of dose limiting toxicities (DLT) defined in section 7.4. 
 Immunologic Endpoints 
All eligible patients for which the required follow-up tissue and blood samples are obtained will be 
evaluated for the difference in pre and post-CRT samples; difference in pre and during CRT samples; 
and difference in during CRT and post-CRT samples: 
i. 
ratio of CD8+ T cells to Tregs 
ii. 
HPV E2 
iii. 
E7 specific CD8+ T cells 
iv. 
regulatory FoxP3+ T cells (Tregs) 
 
 Efficacy Endpoints 
All eligible patients for which a PET/CT imaging is obtained 12 weeks after CRT will be evaluated for 
complete metabolic response. 
All eligible patients with follow-up information on disease status will be evaluated for the occurrence 
of distant metastasis as the first site of recurrence, progression-free survival and overall survival. 
 Exploratory Endpoints 
Levels of specific markers involved in regulation of T cell activation and lymphocyte infiltration as 
assessed in the tumor immune microenvironment and the systemic immune response. 


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7.2 
Sample size and accrual 
Results in Jordanova ES, et al 2008, report estimates of CD8+/Treg for normal cervix and cervical 
cancers tissue for cervical cancer patients who underwent radical hysterectomy with 
lymphadenectomy.[4] These data provide the assumed "natural baseline" of cancer patients’ in this 
study with CD8+/Tregs being lower in cancer tissue, and results in a Cohen’s dav effect size (ES) of 
0.45. Estimated sample size is based upon being able to detect a similar effect size between 
CD8+/Tregs at baseline and end of CRT, and baseline to the 12 weeks post CRT assessment without 
correction for multiple comparisons. Data from Nilges, K et al, 2003, indicates a mean (standard 
deviation) of 23.32 (15.39) in CD8+/Tregs measured in the tumor infiltrating lymphocytes (TIL) from 
patients with cervical cancer. Given these data, 44 eligible patients are required (per arm) to assess 
change in pre/post CD8+/Tregs with an ES of 0.45 with type I and II errors of 10%. Each within arm 
comparison supports the following hypothesis. Cisplatin can kill T cells, therefore the CRT may 
eliminate both CD8+ HPV CTL and Tregs, and the ensuing or concurrent pembrolizumab treatment 
may increase the CD8+/Treg ratio (test that pembrolizumab will increase CD8+/Tregs to an ES of 
0.45). 
Adjusting for an overall 10% ineligibility/drop-out rate, maximum accrual to the study is estimated at 
98 patients. Accrual is estimated at 4 patients a month, thus accrual to the study should be completed 
by 2.0 years with primary analysis at 3 years. 
7.3 
Randomization 
Patients will be randomized in a 1:1 ratio to arms 1 and 2, respectively. Block randomization within 
site with random block sizes of 2, 4 or 6 will be employed. 
7.4 
Safety and Futility Monitoring 
 Safety monitoring 
Dose Limiting Toxicity (DLT) is defined as an adverse event which: i) is determined to be at least 
possibly related to treatment with pembrolizumab; ii) occurs within the first 30 days after the first 
pembrolizumab infusion; and iii) meets one of the below criteria: 
 
Pneumonitis Grade ≥ 3 
 
Any non-hematological toxicity Grade ≥ 3, except for the following: 
o 
Grade 3 toxicity that is expected from standard of care cisplatin and radiation 
o 
Grade 3 Colitis, hypophisitis, or hyperthyroidism  lasting less than 7 days 
o 
Grade 3 electrolyte toxicities that are corrected to grade 1 or less within 24 
hours 
o 
Grade 3 hypertension that can be controlled with oral medications and does 
not require treatment delay for > 7 days 
o 
Grade 3 diarrhea that is not refractory to anti diarrhea medications and is 
corrected to Grade 1 or less within 48 hours 
o 
Grade 3 nausea and vomiting that is not refractory to anti-emetic therapy and 
is corrected to Grade 1 or less within 48 hours 
o 
Grade 3 rise in creatinine, if corrected to Grade 2 or less after up to 2 liters of 
intravenous fluids within 24 hours 
o 
Grade 3 elevation in AST/ALT if < 1.5 times the baseline level  
o 
Grade 3 elevation of ALP (alkaline phosphatase)  
o 
Grade 3 hypoalbuminemia  
o 
Grade 3 lymphopenia  


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o 
Grade 3 rash if it returns to ≤ grade 2 after 1 week of symptomatic treatment 
 
Any Grade ≥ 4 toxicity 
 
Other AEs if they are clearly related to pembrolizumab and are causing substantial 
morbidity for subjects, as determined by the study chair. 
Within each arm, safety will be assessed by monitoring the number of patients who experience a 
DLT. Results reported in ASCO 2015 abstracts [22, 23] for pembrolizumab in combination with other 
treatments resulted in an overall DLT rate of 1/59=2% with a 90%CI(1%, 8%). For this study the 
upper boundary of a sequential probability ratio test (SPRT) based upon a binomial test of proportions 
for DLT will be used for monitoring to protect against excessive failure rates.  The stopping boundary 
is for a SPRT contrasting a 5% versus 25% DLT rate, with nominal type I and II errors of 10% and 
10%, respectively. The slope of the parallel line for monitoring is 1.190 and the intercept is 0.128. 
Safety stopping guidelines for the occurrence of DLTs are detailed in the following table. If a stopping 
bound is crossed in either arm then accrual to the study will be suspended until the study PI, co-
investigators and the DSMC can review the data, and determine if the study should  continue, be 
amended or be closed to further accrual. 
 
Incidence of treatment related DLTs 
Number of patients in an Arm 
Stopping boundary 
2-6 
≥ 2 
7-14 
≥ 3 
15-21 
≥ 4 
22-29 
≥ 5 
30-37 
≥ 6 
38-44 
≥ 7 
 
 
Futility monitoring 
In general, for futility assessment, destroying all the CD8s in the tumor and all the HPV-specific 
response in the blood would argue that we are likely preventing an immune response with the current 
CRT treatment, thus making the addition of pembrolizumab ineffective. Clinical response to 
pembrolizumab is most commonly associated with CD8+ T cell infiltration into tumors, and response 
rates for other solid malignancies are approximately 20% with pembrolizumab as a monotherapy.  
Thus, if CRT causes a reduction in the number of patients with T cell infiltration we could anticipate 
that CRT reduces the likelihood of patients responding to treatment. Assuming the current study 
population has a similar potential to respond to pembrolizumab, we would deem the study futile if 
early evidence indicates a potential to respond in a much lower percentage of subjects. We have set 
this lower target to be 5%. Futility will be monitored separately for each arm.   
For each subject, the potential to respond will be determined at the end of the 12 week treatment 
window. We will assess the subject’s tumor and blood for the presence of immune infiltrate and HPV 
specific T cell responses. Futility will be assessed by monitoring the number of patients with the 
absence of both CD8+ T cells and NK cells in the tumor, and a concomitant loss of HPV T cell 
reactivity in the blood. For the assessment of futility, each subject will be deemed to have the 
potential to respond if there are CD8+ T cells or NK cells in the tumor, or no loss of HPV T cell 


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reactivity in the blood. A 3-stage design structure will be used to monitor for a null potential to 
respond of 5% versus and alternative rate of 20%. 
Within an arm, the futility assessments will occur after accrual of 14, 29 and 44 subjects have been 
accrued and followed for 12 weeks. The study specific arm will be deemed futile if 0/14, <4/29 or 
<6/44 subjects have the potential to respond for assessment at stages 1, 2 or 3, respectively. The 
decision guideline has type I and II error rates of 0.015 and 0.185, respectively. 
 
7.5 
Analyses 
The study is designed with sufficient power to assess pre/post change in immune measures with an 
ES of .45 within each arm and not to detect a predetermined difference in the changes overtime 
between the two arms. However, data from the study will be used to estimate; the magnitude of the 
difference in pre/post change for all parameters of interest between the two arms; as well as 
progression–free and overall survival. With 44 eligible patients per arm we have 67%, 75% and 87% 
power to detect an ES of 0.45, 0.5 and 0.6, respectively, for continuous immune parameters 
(normality assumed) with a 10% level t-test. With 44 patients the width of a 90% CI (exact Clopper-
Pearson) around the complete metabolic response at 3 months of 70% and the distant metastases 
rate at 3 years of 20% are (57%, 81%) and (10%, 33%), respectively. Thus, any estimated rate 
outside of these bounds would be considered promising. For each arm, progression free survival 
(PFS) and overall survival will be estimated by the product-limit method of Kaplan and Meier along 
with 90% confidence bands. In patients with complete metabolic response at 3 months, 3-year PFS is 
78% (Schwartz et al, 2007).  This result will be used to guide interpretation of results on PFS from this 
study. 


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8.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
8.1 
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 10. 
Table 10.  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
8.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
8.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor-Investigator 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. 
8.4 
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. 
8.5 
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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9.0 
ADMINISTRATIVE AND REGULATORY DETAILS 
9.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  The IRB should approve the consent form and protocol. 
In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s), and should adhere to all ICH E6 principles and Good Clinical Practice 
(GCP), to ethical principles that have their origin in the Declaration of Helsinki. 
Before recruitment and enrollment onto this study, the subject will be given a full explanation of the 
study and will be given the opportunity to review the consent form. Each consent form must include 
all the relevant elements currently required by the FDA Regulations and local or state regulations. 
Once this essential information has been provided to the subject and the investigator is assured that 
the subject understands the implications of participating in the study, the subject will be asked to give 
consent to participate in the study by signing an IRB-approved consent form. 
Prior to a subject’s participation in the trial, the written informed consent form should be signed and 
personally dated by the subject and by the person who conducted the informed consent discussion. 
9.2 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being of 
the study subject requires alternative treatment, the study shall be conducted exactly as described in 
the approved protocol.  The Institutional Review Board will approve all aspects of this study, including 
the clinical trial protocol, informed consent documents, and patient materials.  Modifications to the 
protocol or consent form will be reviewed and approved by the IRB prior to implementation, except 
when necessary to eliminate apparent immediate hazards to the study participants. The study will 
undergo continuing IRB review based on the level of risk as assessed by the IRB. This review will 
take place no less than annually. Participating sites will be responsible for ensuring their consent 
forms are written in accord with 21 CFR 50. 
 
Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to trial subjects without prior IRB approval/favorable opinion.   
For any such emergency modification implemented, a UVA IRB modification form must be completed 
by study Personnel within five (5) business days of making the change.   
 
Other Protocol Deviations/Violations 
Protocol Deviations: A protocol deviation is any unplanned variance from an IRB approved protocol 
that:  
 
Is generally noted or recognized after it occurs 
 
Has no substantive effect on the risks to research participants 


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 
Has no substantive effect on the scientific integrity of the research plan or the value of the 
data collected  
 
Did not result from willful or knowing misconduct on the part of the investigator(s).  
Study personnel will record the deviation, and report to any Sponsor-Investigator or data and safety 
monitoring committee in accordance with their policies.  Deviations should be summarized and 
reported to the IRB at the time of continuing review. 
Protocol Violations: An unplanned protocol variance is considered a violation if the variance: 
 
Has harmed or increased the risk of harm to one or more research participants. 
 
Has damaged the scientific integrity of the data collected for the study. 
 
Results from willful or knowing misconduct on the part of the investigator(s). 
 
Demonstrates serious or continuing noncompliance with federal regulations, State laws, or 
University policies. 
Violations should be reported by study personnel to the IRB within one (1) week of the investigator 
becoming aware of the event.  
9.3 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents 
(e.g., protocol and amendments, IRB correspondence and approval, signed subject consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
Government agency regulations and directives require that all study documentation pertaining to the 
conduct of a clinical trial must be retained by the study investigator.  In the case of a study with a drug 
seeking regulatory approval and marketing, these documents shall be retained for at least two years 
after the last approval of marketing application in an International Conference on Harmonization (ICH) 
region.  In all other cases, study documents should be kept on file until three years after the 
completion and final study report of this investigational study. 
9.4 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance 
with Title 21 of the Code of Federal Regulations, all applicable local regulatory laws and regulations 
and/or the Declaration of Helsinki.  The Principal Investigator is responsible for personally overseeing 
the treatment of all study subjects.  The Principal Investigator must assure that all study site 
personnel, including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study 
completion. It is the responsibility of the Principal Investigator to ensure that all study site personnel 
are aware that the study protocol and all data generated is confidential and should not be disclosed to 
third parties (with the exception of local and national regulatory bodies which require access for 
oversight purposes).  


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The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered onto the Case Report Forms. Periodically, monitoring 
visits will be conducted and the Principal Investigator will provide access to his/her original records to 
permit verification of proper entry of data. At the completion of the study, all case report forms will be 
reviewed by the Principal Investigator and will require his/her final signature to verify the accuracy of 
the data. 
9.5 
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. 
 


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10.0 REFERENCES 
1. 
Ferlay, J., et al., Cancer incidence and mortality worldwide: sources, methods and major 
patterns in GLOBOCAN 2012. International journal of cancer Journal international du cancer, 
2015. 136(5): p. E359-86. 
2. 
Chemoradiotherapy for Cervical Cancer Meta-Analysis, C., Reducing uncertainties about the 
effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of 
individual patient data from 18 randomized trials. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology, 2008. 26(35): p. 5802-12. 
3. 
Santin, A.D., et al., Induction of tumor-specific cytotoxicity in tumor infiltrating lymphocytes by 
HPV16 and HPV18 E7-pulsed autologous dendritic cells in patients with cancer of the uterine 
cervix. Gynecologic oncology, 2003. 89(2): p. 271-80. 
4. 
Jordanova, E.S., et al., Human leukocyte antigen class I, MHC class I chain-related molecule 
A, and CD8+/regulatory T-cell ratio: which variable determines survival of cervical cancer 
patients? Clinical cancer research : an official journal of the American Association for Cancer 
Research, 2008. 14(7): p. 2028-35. 
5. 
Mellman, I., G. Coukos, and G. Dranoff, Cancer immunotherapy comes of age. Nature, 2011. 
480(7378): p. 480-9. 
6. 
Karim, R., et al., Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and 
survival of patients with cervical carcinoma. Clinical cancer research : an official journal of the 
American Association for Cancer Research, 2009. 15(20): p. 6341-7. 
7. 
Yang, W., et al., Increased expression of programmed death (PD)-1 and its ligand PD-L1 
correlates with impaired cell-mediated immunity in high-risk human papillomavirus-related 
cervical intraepithelial neoplasia. Immunology, 2013. 139(4): p. 513-22. 
8. 
Kroemer, G., et al., Immunogenic cell death in cancer therapy. Annu Rev Immunol, 2013. 31: 
p. 51-72. 
9. 
Schuler, P.J., et al., Effects of adjuvant chemoradiotherapy on the frequency and function of 
regulatory T cells in patients with head and neck cancer. Clinical cancer research : an official 
journal of the American Association for Cancer Research, 2013. 19(23): p. 6585-96. 
10. 
Dijkgraaf, E.M., et al., Chemotherapy alters monocyte differentiation to favor generation of 
cancer-supporting M2 macrophages in the tumor microenvironment. Cancer research, 2013. 
73(8): p. 2480-92. 
11. 
Postow, M.A., M.K. Callahan, and J.D. Wolchok, Immune Checkpoint Blockade in Cancer 
Therapy. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology, 2015. 33(17): p. 1974-1982. 
12. 
Schwarz, J.K., et al., Association of posttherapy positron emission tomography with tumor 
response and survival in cervical carcinoma. JAMA, 2007. 298(19): p. 2289-95. 
13. 
Narayan, K., et al., Patterns of failure and prognostic factor analyses in locally advanced 
cervical cancer patients staged by positron emission tomography and treated with curative 
intent. Int J Gynecol Cancer, 2009. 19(5): p. 912-8. 
14. 
Mell, L.K., et al., Dosimetric predictors of acute hematologic toxicity in cervical cancer patients 
treated with concurrent cisplatin and intensity-modulated pelvic radiotherapy. Int J Radiat Oncol 
Biol Phys, 2006. 66(5): p. 1356-65. 
15. 
Charra-Brunaud, C., et al., Impact of 3D image-based PDR brachytherapy on outcome of 
patients treated for cervix carcinoma in France: results of the French STIC prospective study. 
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and 
Oncology, 2012. 103(3): p. 305-13. 


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16. 
Sun, B., et al., Three-dimensional dose accumulation in pseudo-split-field IMRT and 
brachytherapy for locally advanced cervical cancer. Brachytherapy, 2015. 14: p. 481-489. 
17. 
Boyle, J., et al., Methods, safety, and early clinical outcomes of dose escalation using 
simultaneous integrated and sequential boosts in patients with locally advanced gynecologic 
malignancies. Gynecol Oncol, 2014. 135: p. 239-243. 
18. 
Lim, K., et al., Consensus guidelines for delineation of clinical target volume for intensity-
modulated pelvic radiotherapy for the definitive treatment of cervix cancer. Int J Radiat Oncol 
Biol Phys, 2011. 79(2): p. 348-55. 
19. 
Poorvu, P.D., et al., Duodenal and other gastrointestinal toxicity in cervical and endometrial 
cancer treated with extended-field intensity modulated radiation therapy to paraaortic lymph 
nodes. Int J Radiat Oncol Biol Phys, 2013. 85(5): p. 1262-1268. 
20. 
Viswanathan, A.N., et al., American Brachytherapy Society consensus guidelines for locally 
advanced carcinoma of the cervix. Part II: high-dose-rate brachytherapy. Brachytherapy, 2012. 
11(1): p. 47-52. 
21. 
Haie-Meder, C., et al., Recommendations from Gynaecological (GYN) GEC-ESTRO Working 
Group (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer 
brachytherapy with emphasis on MRI assessment of GTV and CTV. Radiotherapy and 
oncology : journal of the European Society for Therapeutic Radiology and Oncology, 2005. 
74(3): p. 235-45. 
22. 
Patnaik, A., et al., Phase 1 study of pembrolizumab (pembro; MK-3475) plus ipilimumab (IPI) 
as second-line therapy for advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 
cohort D. Journal of Clinical Oncology, 2015. 33(15). 
23. 
Papadimitrakopoulou, V., et al., Pembrolizumab (pembro; MK-3475) plus platinum doublet 
chemotherapy (PDC) as front-line therapy for advanced non-small cell lung cancer (NSCLC): 
KEYNOTE-021 Cohorts A and C. Journal of Clinical Oncology, 2015. 33(15). 
 
 


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11.0 APPENDICES 
 
 


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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. 
 
 
 


Product:  Pembrolizumab 
66 
Protocol/Amendment No.:  UVA-LACC-PD201, Version 4.0, 06 March 2018 
 
 
  
 
 
 
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 
4.03 
will 
be 
utilized 
for 
adverse 
event 
reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 

ICF_001.pdf: 
Title: Pembrolizumab and Chemoradiation Treatment for Advanced Cervical Cancer
NCT02635360
Document Date: Apr 24, 2020


IRB-HSR# 18472: A randomized Phase II study of chemoradiation and pembrolizumab for locally 
advanced cervical cancer 
Page 1 of 19 
Version Date: 24 APR 2020 
Consent of an Adult to Be in a Research Study 
In this form "you" means a person 18 years of age or older who is being asked to volunteer to participate in 
this study. 
Participant’s Name_____________________________   Medical Record # ___________________ 
Principal Investigator: 
Linda Duska, MD 
University of Virginia School of Medicine 
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology 
PO Box 800712 
Charlottesville, VA 22908         Telephone:  (434) 924-1570 
Sponsor: 
The University of Virginia Cancer Center 
Funding Source: 
Merck Sharp & Dohme Corporation 
What is the purpose of this form? 
This form will provide you with information about this research study. You do not have to be in the study if 
you do not want to. You should have all your questions answered before you agree to be in this study.  
Please read this form carefully.  If you want to be in the study, you will need to sign this form. You will be given 
a signed copy of this form.   
Who is funding this study? 
The University of Virginia Cancer Center. The study drug, Pembrolizumab, and some financial support is 
provided by Merck, the manufacturer of Pembrolizumab. 
Why is this research being done? 
The purpose of this study is to test the safety and effectiveness of an investigational drug called 
pembrolizumab when added to chemoradiation, for treatment of advanced cervical cancer.   
Pembrolizumab has not been approved for the treatment of cervical cancer and the combination of 
pembrolizumab and chemoradiation (CRT) is not approved for treatment of any cancers by the Food and Drug 
Administration (FDA).   
The current standard treatment for advanced cervical cancer includes chemoradiation, which is administration 
of the drug cisplatin during several weeks of radiation treatments.  Cisplatin is approved by the FDA for the 
treatment of advanced cervical cancer.   


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Page 2 of 19 
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This study will help determine if adding pembrolizumab treatment to the standard treatment is safe and if 
providing this study drug at the same time will be more effective in treating advanced cervical cancer than 
providing pembrolizumab after chemoradiation.  
 
You are being asked to participate in this research study because you have advanced cervical cancer. 
 
Up to 25 patients will be in this study at UVA.  Up to 88 patients will be in this study at other institutions in the 
United States. 
 
How long will this study take? 
You will be required to make weekly office visits while you are receiving study treatment. 
 
Your participation in this study will add about 30 minutes to each of your routine clinic visits and may require 
up to 3 study visits in addition to the visits for your routine clinical care assuming your tumor is not growing 
and you are not experiencing any unacceptable side effects. After you complete your study treatment, you will 
be followed for 5 years.   
 
What will happen if you are in the study? 
 
SCREENING (will take about 4-6 hours to complete): 
If you agree to participate, you will sign this consent form before any study related procedures take place.  
Before you can start in the study, there will be a screening period.  You will have tests and procedures during 
this time to make sure you are eligible and it is safe for you to participate.   
 
THE FOLLOWING TESTS WILL BE PERFORMED AS PART OF YOUR ROUTINE CLINICAL CARE AND THE RESULTS 
WILL BE RECORDED FOR RESEARCH PURPOSES:  
• History and physical exam which may include a pelvic exam.  You will also have your heart rate, blood 
pressure and temperature taken. 
• Blood tests to assess blood cell counts, liver and kidney function, blood mineral levels, blood clotting 
function and thyroid function.  The amount of blood that will be drawn is approximately 2 tablespoons. 
• A urine or serum pregnancy test if you are capable of becoming pregnant (this will be done within 72 
hours of first dose of study treatment). 
• PET/CT scan of the whole body to measure detectable tumor. 
• MRI of the pelvis. 
• Review of medications and supplements that you are currently taking. 
THE FOLLOWING TESTS ARE NOT PART OF ROUTINE CANCER CARE AND WILL BE PERFORMED FOR 
RESEARCH PURPOSES: 
• About 5 tablespoons of blood will be drawn for biomarker tests.  Biomarkers such as DNA sequences, 
proteins, or cells are substances in your body that can be used to detect a disease or to find out if the 
cancer treatment is working.   
• Fresh tumor tissue will be collected for screening purposes by biopsy, which is a procedure to remove 
a small sample of your cervix tissue.  This procedure will likely be performed in your doctor’s office, but 


IRB –HSR#18472:  A randomized Phase II study of chemoradiation and pembrolizumab for 
locally advanced cervical cancer 
 
 
Page 3 of 19 
Version Date: 24 APR 2020 
it could take place in a procedure room under anesthesia if another procedure requiring anesthesia is 
happening at the same time.  Your study doctor will explain the details of the procedure to you.  
Archival tumor tissue from a previous biopsy or surgical procedure may also be collected in addition to 
the fresh tumor tissue.   
• You will be asked about any previous unpleasant symptoms or reactions from previous procedures 
and biopsies. 
 
If these tests show you are eligible, you will return to the clinic (within 4 weeks) for randomization and to 
begin study treatment. 
 
RANDOMIZATION  
You will be randomly assigned (like the flip of a coin) to 1 of 2 study treatment groups. You have an equal 
chance of being assigned to any one of the groups.  Neither you nor your doctor can choose which group you 
are assigned.   
 
Both GROUPS A and B will receive: 
• Cisplatin- the standard chemotherapy drug for treatment of advanced cervical cancer.  This drug is 
administered into your vein (intravenously, IV) over 60 minutes for 5-6 weeks.  
• Radiation treatments will occur for 5-6 weeks. 
• Pembrolizumab- the study drug.  You will receive this study drug intravenously over 30 minutes.  This 
treatment will last for 3 cycles of 21 days each with the infusion occurring on the first day of each cycle.   
 
GROUP A: will receive the study drug after chemotherapy and radiation. 
 
GROUP B: will receive the study drug during chemotherapy and radiation. 
 
** For the purpose of this study we will refer to Pembrolizumab as the "study drug"** 
 
STUDY TREATMENT (will take about 4-6 hours to complete) 
The study treatments and schedules below are separated for Groups A and B.   
 
GROUP A:  
THE FOLLOWING TESTS WILL BE PERFORMED AS PART OF YOUR ROUTINE CLINICAL CARE AND THE RESULTS 
WILL BE RECORDED FOR RESEARCH PURPOSES:  
• History and physical exam which may include a pelvic exam will be performed at your physician’s 
recommendation.  You will also have your heart rate, blood pressure and temperature taken every 
week for Weeks 1-6 and then again at Weeks 9, 12, and 15. 
• Blood tests to assess blood cell counts, liver and kidney function, blood mineral levels, blood clotting 
function.  Every week during Weeks 1-6, the amount of blood that will be drawn is approximately 2 
tablespoons. 
• You will be asked questions about your ability to complete daily activities every week during Weeks 1-
6 and then again at Weeks 9, 12, and 15. 


IRB –HSR#18472:  A randomized Phase II study of chemoradiation and pembrolizumab for 
locally advanced cervical cancer 
 
 
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• You will be given the standard chemotherapy and radiation every week during Weeks 1-6. 
 
THE FOLLOWING TESTS ARE NOT PART OF ROUTINE CANCER CARE AND WILL BE PERFORMED FOR 
RESEARCH PURPOSES: 
• You will be given the study drug every 3 weeks during Weeks 9-15. 
• Up to 1 teaspoon of blood will be drawn to check your thyroid function on the day of study drug 
treatment during Weeks 9-15. 
• Up to 2 teaspoons of blood will be drawn to check for certain minerals and proteins in your blood and 
your blood count every 3 weeks during Weeks 9-15.  
• About 5 tablespoons of blood will be drawn for biomarker tests.  Biomarkers such as DNA sequences, 
proteins, or cells are substances in your body that can be used to detect a disease or to find out if the 
cancer treatment is working.  This will occur around the 5th week of your radiation treatment. 
• Fresh tumor tissue will be collected around the 5th week of your radiation treatment by biopsy, which 
is a procedure to remove a small sample of your cervix tissue.  This procedure will likely be performed 
in your doctor’s office, but it could take place in a procedure room under anesthesia if another 
procedure requiring anesthesia is happening at the same time.  Your study doctor will explain the 
details of the procedure to you. 
• You will be asked about if you have had any unpleasant symptoms or reactions to the study drug at 
every visit during Weeks 1-15. 
 
GROUP B:  
THE FOLLOWING TESTS WILL BE PERFORMED AS PART OF YOUR ROUTINE CLINICAL CARE AND THE RESULTS 
WILL BE RECORDED FOR RESEARCH PURPOSES:  
• History and physical exam which may include a pelvic exam will be performed at your physician’s 
recommendation.  You will also have your heart rate, blood pressure and temperature taken every 
week while you are receiving treatment. 
• Blood tests to assess blood cell counts, liver and kidney function, blood mineral levels, and blood 
clotting function will be performed every week while you are receiving treatment.  The amount of 
blood that will be drawn is approximately 2 tablespoons. 
• You will be asked questions about your ability to complete daily activities weekly during treatment. 
• You will be given the standard chemotherapy and radiation every week during Weeks 1-6. 
 
THE FOLLOWING TESTS ARE NOT PART OF ROUTINE CANCER CARE AND WILL BE PERFORMED FOR 
RESEARCH PURPOSES: 
• You will be given the study drug every 3 weeks at Week 1, Week 4, and Week 7. 
• Up to 1 teaspoon of blood will be drawn to check your thyroid function prior to each treatment with 
the study drug. 
• About 5 tablespoons of blood will be drawn for biomarker tests.  Biomarkers such as DNA sequences, 
proteins, or cells are substances in your body that can be used to detect a disease or to find out if the 
cancer treatment is working.  This will occur around the 5th week of your radiation treatment. 
• Fresh tumor tissue will be collected through a biopsy around the 5th week of your radiation treatment 
by biopsy, which is a procedure to remove a small sample of your cervix tissue. This procedure will 
likely be performed in your doctor’s office, but it could take place in a procedure room under 


IRB –HSR#18472:  A randomized Phase II study of chemoradiation and pembrolizumab for 
locally advanced cervical cancer 
 
 
Page 5 of 19 
Version Date: 24 APR 2020 
anesthesia if another procedure requiring anesthesia is happening at the same time.  Your study doctor 
will explain the details of the procedure to you, depending on how the biopsy sample will be obtained. 
• You will be asked about if you have had any unpleasant symptoms or reactions to the study drug every 
week. 
 
END OF STUDY VISIT (GROUPS A and B): 
You will be asked to come to the clinic for an end of treatment visit 35 ± 5 days after you complete your study 
treatment, if your disease becomes worse, or if your study treatment has been stopped due to unpleasant 
symptoms and reactions to the study drug.  
 
If you stop taking the study drug because your disease has progressed, your study physician will ask you to 
return to the clinic within 30 days after you stop the study drug. 
 
THE FOLLOWING TESTS WILL BE PERFORMED AS PART OF YOUR ROUTINE CLINICAL CARE AND THE RESULTS 
WILL BE RECORDED FOR RESEARCH PURPOSES:  
• History and physical exam which may include a pelvic exam.  You will also have your heart rate, blood 
pressure and temperature taken. 
• Blood tests to assess blood cell counts, liver and kidney function, blood mineral levels, blood clotting 
function.  The amount of blood that will be drawn is approximately 2 tablespoons. 
• You will be asked questions about your ability to complete daily activities. 
• PET/CT scan of the whole body to measure detectable tumor 12 weeks after completion of treatment. 
 
THE FOLLOWING TESTS ARE NOT PART OF ROUTINE CANCER CARE AND WILL BE PERFORMED FOR 
RESEARCH PURPOSES: 
• Up to 1 teaspoon of blood will be drawn check your thyroid function 1 Month after your last study 
treatment.  
• About 5 tablespoons of blood will be drawn for biomarker tests.  Biomarkers such as DNA sequences, 
proteins, or cells are substances in your body that can be used to detect a disease or to find out if the 
cancer treatment is working.  This will be collected 3 Months after your last radiation treatment.  
• Fresh tumor tissue will be collected at about 3 Months after your last radiation treatment.  This will 
procedure will be done the same as your previous tumor biopsies. 
• You will be asked about if you have had any unpleasant symptoms or reactions to the study drug 1 
Month after your last study treatment.  
 
FOLLOW UP (GROUPS A and B): 
If you discontinue study treatment prior to your disease becoming worse, you will be followed every 3 months 
from the date of the last dose of study drug until your disease becomes worse or for up to 5 years whichever 
comes first.   
 
 
 
 


IRB –HSR#18472:  A randomized Phase II study of chemoradiation and pembrolizumab for 
locally advanced cervical cancer 
 
 
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Version Date: 24 APR 2020 
Study Schedule: GROUP A 
 
Screening 
Visit 
Treatment Visits 
End of Treatment Visits 
Follow-up  
Visit 
Weeks 1-6, 
Day 1 every 
week  
Weeks 9-15, 
Day 1 every 3 
weeks 
Visit 1 
(1 month 
post-
treatment) 
Visit 2 (3 
months 
post-
treatment) 
Informed 
Consent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Physical Exam  
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
 
 
Medication 
Assessment 
X 
 
 
 
 
 
Disease 
Assessment 
X 
X 
X 
X 
X 
X 
Standard 
Cisplatin 
Chemotherapy 
 
X 
 
 
 
 
Radiation  
 
X 
 
 
 
 
Pembrolizumab 
Administration 
 
 
X 
 
 
 
Tissue Collection  
X 
X1 
 
 
X 
 
Blood Draws for 
Research 
X 
X 
X 
X 
X 
 
Blood Draws for 
Clinical Care 
X 
X 
X 
X 
 
 
Pregnancy Test 
(Urine or Serum) 
X 
 
 
 
 
 
MRI Scan 
X 
 
 
 
 
 
CT Scan 
X 
 
 
 
X 
 
*Gray highlighted boxes include tests/assessments done for research. 
1 Tissue collection will occur at Week 5 +/- 2 weeks 
 
 
 
 
 
 
 


IRB –HSR#18472:  A randomized Phase II study of chemoradiation and pembrolizumab for 
locally advanced cervical cancer 
 
 
Page 7 of 19 
Version Date: 24 APR 2020 
Study Schedule: GROUP B 
 
Screening 
Visit 
Treatment 
Visits 
End of Treatment Visits 
Follow-up 
Visits 
Weeks 1-7, 
Day 1 every 
week 
Visit 1 
(1 month post-
treatment) 
Visit 2 (3 months 
post-treatment) 
Informed 
Consent 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Physical Exam  
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
 
 
Medication 
Assessment 
X 
 
 
 
 
Disease 
Assessment 
X 
X 
X 
X 
X 
Standard 
Cisplatin 
Chemotherapy 
 
X 
 
 
 
Radiation  
 
X 
 
 
 
Pembrolizumab 
Administration 
 
X1 
 
 
 
Tissue 
Collection  
X 
X2 
 
X 
 
Blood Draws 
for Research 
X 
X 
X 
X 
 
Blood Draws 
for Clinical Care 
X 
X 
X 
 
 
Pregnancy Test 
(Urine or 
Serum) 
X 
 
 
 
 
MRI Scan 
X 
 
 
 
 
CT Scan 
X 
 
 
X 
 
*Gray highlighted boxes include tests/assessments done for research. 
1 Pembrolizumab infusions will occur on the first day of Weeks 1, 4, and 7 
2 Tissue collection will occur at Week 5 +/- 2 weeks 
 
 
 
What are your responsibilities in the study? 
 You have certain responsibilities to help ensure your safety. These responsibilities are listed below: 
• You must come to each study visit. 
• You must be completely truthful about your health history. 


IRB –HSR#18472:  A randomized Phase II study of chemoradiation and pembrolizumab for 
locally advanced cervical cancer 
 
 
Page 8 of 19 
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• Follow all instructions given. 
• You should tell the study doctor or study staff about any changes in your health or the way you feel. 
• Ensure that the study drug is taken as instructed, keep the study drug in a safe place away from other 
children, return any unused study drug at each visit, and report any lost or missed tablets. 
• Ensure that the study drug is taken only by you, the person for whom it has been prescribed. 
• Answer all of the study-related questions completely. 
• You must not eat grapefruit or drink grapefruit juice during the course of your participation in this 
study. 
• Inform the study doctor or study staff as soon as possible if you have to take any new medications, 
including anything prescribed by a doctor or those that you can buy without a prescription (over-the-
counter), including herbal supplements and vitamins.  The study doctor will let you know if you can 
take these medications. 
 
Blood Testing 
We will take (or “draw”) up to 2-3 tablespoons of blood per week, and up to 5 tablespoons of blood for 
research testing while you are receiving treatment.   
 
The 2 tablespoons of blood per week will be used to measure how well your kidney and liver are doing, sugar 
and salts in your blood, and to measure the white and red blood cells. This is considered routine blood work 
for someone receiving chemotherapy.  If you are in Group A, these blood draws will be collected for research 
purposes during Months 3-4.   
 
1 tablespoon of blood will be drawn prior to your pembrolizumab treatment to check how well your thyroid 
functions.  This will be done for research purposes.  
 
5 tablespoons will be collected for research purposes during screening, around the 5th week of your radiation 
treatment, and about 3 months after your last radiation treatment.  This blood is used for looking at things 
called biomarkers, a characteristic in your blood that would indicate if the study drug was having the desired 
effect on your body. 
 
When these tests are done any left-over sample will be thrown away or they will be de-identified.  This means 
there is no information that could be used by anyone to determine who the sample came from.   
 
If you want to know about the results before the study is done: 
During the study your study leader will let you know of any test results that may be important to your 
health.  In addition, as the research moves forward, your study leader will keep you informed of any new 
findings that may be important for your health or may help you decide if you want to continue in the 
study.  The final results of the research will not be known until all the information from everyone is combined 
and reviewed.  At that time you can ask for more information about the study results.  
 


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locally advanced cervical cancer 
 
 
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What are the risks of being in this study?  
Risks from Cisplatin include: 
Likely (equal to or more than 10 out of 100): 
• Fatigue 
• Lowered white blood count may increase risk of infection 
• Lowered red blood cells may lead to anemia, tiredness, or shortness of breath 
• Decrease in kidney function 
• Loss of appetite and weight loss 
• Diarrhea, constipation, nausea, and vomiting, and abdominal pain 
• Complete hair loss 
• Numbness or tingling in fingers or toes 
• Skin rash 
• Changes in taste 
• Ringing in the ears and hearing loss 
• Changes in electrolytes in the blood such as magnesium and potassium or an increase in 
calcium 
 
Less Likely (equal to or greater than 1 but less than 10 out of 100): 
• Allergic reactions 
• Chills and fever with aches and pains 
• Lowered platelets may lead to an increase in bruising or bleeding 
• Sores in mouth and throat (that can lead to difficulty swallowing and dehydration) 
• Altered vision 
• Skin irritation and swelling if the drug leaks from the vein into which it is being injected into the 
surrounding skin 
• Changes in heart rhythm 
 
Rare but serious (less than 1 out of 100): 
• Seizures 
• Secondary cancers such as acute leukemia 
• Kidney failure requiring dialysis 
• Deafness 
• Hemolytic uremic syndrome (low red blood cell count, low platelet count and kidney damage) 
 
Risks from Pembrolizumab include: 
What is known about this study drug? 
 
Pembrolizumab works by helping your immune system to fight your cancer.  However, pembrolizumab 
can also cause your immune system to attack normal organs and tissues in your body and can affect the 
way they work, which can result in side effects.  These side effects may be serious (i.e. causing 
hospitalization or be life-threatening), may result in death, and/or may occur after you stop taking 


IRB –HSR#18472:  A randomized Phase II study of chemoradiation and pembrolizumab for 
locally advanced cervical cancer 
 
 
Page 10 of 19 
Version Date: 24 APR 2020 
pembrolizumab. These side effects can affect more than one of your normal organs and tissues at the 
same time. 
 
Very Common, Some May be Serious (i.e. causing hospitalization, life-threatening or where noted, may 
cause death) Side Effects (greater than 20 in every 100) seen in people taking Pembrolizumab include 
the following: 
• Itching of the skin 
• Loose or watery stools 
• Cough 
 
Common, Some May be Serious (i.e. causing hospitalization, life-threatening or where noted, may 
cause death) Side Effects (between 5 and 20 in every 100) seen in people taking Pembrolizumab include 
the following: 
• Joint pain 
• Fever 
• Back pain 
• Rash 
• Pain in your belly 
• Loss of skin color 
• Not enough thyroid hormone so you may 
feel tired, gain weight, feel cold, or have 
infrequent or hard stools (hypothyroidism) 
• Low level of salt in the blood that may cause 
you to feel tired, feel confused, have a 
headache, have muscle cramps and/or feel 
sick to your stomach (hyponatremia) 
 
Uncommon, Some May be Serious (i.e. causing hospitalization, life-threatening or where noted, may 
cause death) Side Effects (between 1 and 5 in every 100) seen in people taking Pembrolizumab include 
the following: 
• Inflammation of the lungs so you may feel short of breath and cough (pneumonitis). Sometimes this 
might lead to death.  
• Too much thyroid hormone so you may feel anxious, feel angry, have trouble sleeping, feel weak, 
tremble, sweat, feel tired, have loose and watery stools (hyperthyroidism) 
• Infusion reaction, where you may feel dizzy or faint, feel flushed, get a rash, have a fever, feel short 
of breath, experience a decrease in your blood pressure at the time of receiving your infusion (IV) or 
just after, or have pain at the site of infusion  
• Inflammation of the bowels/gut, which may cause severe pain in your belly with loose or watery 
stools, and black, tarry, sticky stools or stools with blood or mucus (colitis) 
• Inflammation of the skin so you may have peeling of the skin, itchiness, and/or skin redness.  The 
skin inflammation (i.e. peeling, itching, and redness) could also be widespread throughout your 
body.  More severe skin reactions may involve the inside of your mouth, the surface of your eye, 
and genital areas, and/or may cause the top layer of your skin to peel from all over your body 
which can cause severe infection.  These severe conditions can sometimes lead to death. (Severe 
skin reactions, including Stevens-Johnson syndrome/or toxic epidermal necrolysis) 
 
Rare, Some May be Serious (i.e. causing hospitalization, life-threatening or where noted, may cause death) 
Side Effects (less than 1 in every 100) seen in people taking Pembrolizumab include the following: 


IRB –HSR#18472:  A randomized Phase II study of chemoradiation and pembrolizumab for 
locally advanced cervical cancer 
 
 
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• Inflammation of the nerves that may cause pain, weakness or tingling in your hands and feet, and may 
spread to your legs, arms and upper body leading to severe muscle weakness and possible temporary 
paralysis (Guillain-Barre syndrome).  
• Inflammation of the muscles so you may feel weakness or pain in the muscles (myositis) 
• Inflammation of pancreas (a gland in your abdomen that controls sugar levels) so you may have severe 
pain in the top part of your belly that may move to your back, feel sick to your stomach, and have 
vomiting that gets worse when you eat (pancreatitis).  
• Inflammation of the eye so you may have eye redness, blurred vision, sensitivity to light, eye pain, see 
floaters or have headaches (uveitis). 
• Inflammation of the liver that may make you feel sick to your stomach and vomit, feel like not eating, 
feel tired, have a mild fever,  a pain in the right side of your belly, yellow eyes and skin, and dark urine 
(hepatitis) 
• Inflammation of the pituitary gland (a gland in the head), which may cause you to feel sick to your 
stomach or have headaches, changes in your behavior, double vision, few to no menstrual cycles, 
weakness, vomiting and dizziness or fainting (hypophysitis).   
• Adrenal glands (glands on top of the kidneys) that may not make enough hormone, which could cause 
tiredness, weight loss, muscle weakness, feeling faint, having joint, muscle and belly aches, nausea, 
vomiting, loose or watery stools, fever, salt craving, and sometimes darkening of the skin like a suntan 
(adrenal insufficiency) 
• Type 1 Diabetes, a condition that can cause too much sugar in your blood, feeling thirstier than usual, 
frequent urination and weight loss.  You are likely to need regular insulin shots. 
• Inflammation of the kidney so you may pass less urine or have cloudy urine, or bloody urine, swelling 
and low back pain (nephritis) 
• Inflammation of the middle layer of your heart wall that may cause your heart to have difficulty 
pumping blood throughout your body, which can cause chest pain, shortness of breath and swelling of 
the legs.  You may experience a fast or irregular heartbeat that may cause dizziness or fainting.  
Sometimes this condition can lead to death (myocarditis) 
• Inflammation of the thyroid gland, an organ that makes and stores thyroid hormones.  This condition 
may lead to change in your heart rate, blood pressure, body temperature, and the rate at which food is 
converted into energy (thyroiditis) 
• A condition that may make you feel week and tired and may cause drooping of the eyelids, blurred or 
double vision, difficulty swallowing, slurred speech, weakness in your arms and legs, or difficulty 
breathing (myasthenic syndrome/myasthenia gravis including exacerbation) 
• The formation of small clusters of immune cells (called granulomas) in parts of your body such as your 
lymph nodes, eyes, skin, or lungs (sarcoidosis) 
• Inflammation of the brain with confusion and fever.  This may also include: disorientation, memory 
problems, seizures (fits), changes in personality and behavior, difficulty speaking, weakness or loss of 
movement in some parts of your body, and loss of consciousness (encephalitis) 
• Inflammation of the spinal cord with pain, numbness, tingling or weakness in the arms or legs, bladder 
or bowel problems including needing to urinate more frequently, urinary incontinence, difficulty 
urinating, and constipation (myelitis) 
 


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Additionally, since pembrolizumab was approved in September 2014, the following side effects have been 
reported by people receiving pembrolizumab.  These side effects were voluntarily reported from a group 
of people of unknown size.  It is not possible to estimate the frequency of this side effect: 
• Inflammation of the joints which may include joint pain, stiffness and/or swelling (arthritis) 
• Severe responses of the immune system that cause the body to attack its own blood cells, spleen, 
liver, lymph nodes, skin and brain. This may include fever, rash, inflammation of the liver, yellowing 
of the skin, an enlarged liver and spleen, low blood counts, and enlarged lymph nodes. The nervous 
system may also be affected and cause confusion, seizures, and even coma (hemophagocytic 
lymphohistiocytosis). 
• Changes in eyesight, eye pain, whitish patches of the skin and hearing loss (Vogt-Koyanagi-Harada 
syndrome) 
In addition to the above, if you have had an allogeneic stem cell transplant (a procedure in which a person 
receives blood-forming stem cells from a donor), you may experience graft versus host disease (GvHD), 
which may include diarrhea, skin rashes, and liver damage, after receiving pembrolizumab.  Sometimes 
this condition can lead to death. 
 
If you have had a solid organ transplant (for example, if you have received a kidney or heart transplant), 
you may experience rejection of the transplanted organ.  Your doctor will monitor you and should tell you 
what signs and symptoms you should report depending on the type of organ transplant that you have had. 
 
Risks from study procedures include: 
Tumor Biopsy: We will ask you to allow us to obtain tissue from a biopsy procedure. Having biopsies 
performed may cause pain, bruising, bleeding, redness, low blood pressure, swelling and/or infection at the 
site of the biopsy.   Other potential risks will be described to you and discussed with you by physicians who 
conduct these biopsies. 
Risks of having your blood drawn: 
Having blood drawn may cause: 
✓ pain (common), 
✓ a bruise (sometimes), 
✓ fainting or passing out (not very often), and  
✓ infection (rare). 
 
If the people doing the study are exposed to your blood or body fluids in a way that could give them a disease, 
your blood may be tested. The tests might check for: 
✓ hepatitis,  
✓ HIV (Human Immunodeficiency Virus), or  
✓ other infections.   
 
You and the person exposed would be told the test results. However, your name would be kept private. If your 
test is positive for hepatitis or HIV or any other infection that may affect your clinical care, we will tell you the 
results and help you understand what the results mean for you.  


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Risks of taking blood from an IV catheter: 
Risk of Repeated Sticks 
Sometimes the catheter stops working.  In order to get the blood we need, we may have to stick you again 
with another needle. 
 
Risks for women: 
Pregnancy and Contraception 
The drug(s) used in this study can harm an unborn or nursing baby.  Therefore, you cannot be in this study if 
you are pregnant or nursing a baby.  A pregnancy blood test will be done about 3 days before starting this 
study if you are a woman able to become pregnant.  You MUST NOT become pregnant while on this study or 
for up to 120 days after your last dose of study drug. 
You and your partner must use an approved form of birth control during this study.  Examples of birth control 
you may use are  
• Norplant 
• Birth Control Pills 
• IUD (intrauterine device) 
• Birth Control Patch 
• Depo-Provera 
• Sterilization 
The birth control methods listed below are less effective.  They may be used if combined with other birth 
control methods 
• Condoms 
• Diaphragm 
• Jellies or foam 
• Rhythm 
• Withdrawal 
• Cervical cap 
• Sponge 
 
 
Ask your doctor for more details about the proper birth control method for you.  If you become pregnant during 
this study, you must tell your doctor right away.  Your doctor will discuss your treatment and the effect on the 
pregnancy. 
 
Other unexpected risks: 
You may have side effects that we do not expect or know to watch for now.  Call the study leader if you have 
any symptoms or problems. 
 
Could you be helped by being in this study? 
You may or may not benefit from being in this study. Possible benefits include: lessen symptoms from your 
disease, shrink your tumor, and/or may lengthen your survival; however, no guarantees can be made.  In 
addition, information researchers get from this study may help others in the future.  
 
What are your other choices if you do not join this study? 
You do not have to be in this study to be treated for your illness or condition. You can get the usual treatment 
even if you choose not to be in this study.  The usual treatment would include: 


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• Getting treatment or care for your cancer without being in a study which could include chemoradiation 
with cisplatin 
• Taking part in another study 
• Supportive comfort care (also called palliative care).  This type of care helps reduce pain, tiredness, 
appetite problems, and other problems caused by the cancer.  It does not treat the cancer directly, but 
instead tries to improve how you feel.  Comfort care tries to keep you as active and comfortable as 
possible. 
• Getting no treatment 
 
If you are an employee of UVa your job will not be affected if you decide not to participate in this study.  
If you are a student at UVa, your grades will not be affected if you decide not to participate in this study.   
 
Will you be paid for being in this study? 
You will not get any money for being in this study. 
 
By agreeing to be in this study, you are donating your blood, tissue samples for research, and giving up any 
property rights you may have in them.  The results of this research using your donated materials may have 
commercial value.  However, you will not receive any payments.   
 
Will being in this study cost you any money? 
The following procedures/tests, which are being done for research purposes, will be provided at no cost to you or 
your health insurance: 
• Blood testing for the following: 
o The amount of biomarkers (body substances that detect disease or finds out if the cancer 
treatment is working) 
o To check your thyroid function 
o Certain blood tests (assessing blood cell counts, liver and kidney function, blood mineral levels, 
blood clotting function) if not already done as part of your standard of care 
• Disease assessments to check for unpleasant symptoms or reactions from the study drug 
• Any additional costs related to tissue biopsy collection  
• The study drug pembrolizumab will be provided by the study at no cost to you.  However, the cost of 
administering the drug will be billed to you and/or your insurance. 
 
You and/or your insurance company must pay for any tests or care given beyond what is required in this study.  
In addition, you and/or your health insurance may also have to pay for other drugs or treatments that are given 
to help you control any side effects.  You will have to pay for any costs not covered by your health plan.  You 
may be responsible for any co-payments or deductibles.  You may wish to ask for an estimate of your financial costs.  
You may also wish to check with your insurance company before the study starts. Ask what they will cover and 
if they require you to get their permission before you decide to be in the study. 
 
You will be responsible for the cost of travel to come to any study visit and for any parking costs.    
 


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What if you are hurt in this study? 
If you are hurt as a result of being in this study, there are no plans to pay you for medical expenses, lost wages, 
disability, or discomfort. The charges for any medical treatment you receive will be billed to your insurance. You 
will be responsible for any amount your insurance does not cover.   You do not give up any legal rights, such as 
seeking compensation for injury, by signing this form.    
 
What happens if you leave the study early? 
You can change your mind about being in the study any time. You can agree to be in the study now and 
change your mind later. If you decide to stop, please tell us right away. You do not have to be in this study to 
get services you can normally get at the University of Virginia.  
 
Even if you do not change your mind, the study leader can take you out of the study.  Some of the reasons for 
doing so may include  
a) Your study physician is concerned about your health 
b) Your disease gets worse  
c) The side effects of the treatment are too dangerous for you 
d) New information shows the treatment will not work or is not safe for you 
e) You do not follow your doctor’s instructions 
f) The study sponsor closes the study for safety, administrative or other reasons 
If you decide to stop being in the study, we will ask you to complete the End of Study procedures and follow the 
instructions of the study staff.  
 
How will your personal information be shared? 
The UVa researchers are asking for your permission to gather, use and share information about you for this 
study.  If you decide not to give your permission, you cannot be in this study, but you can continue to receive 
regular medical care at UVA.  
 
If you sign this form, we may collect any or all of the following information about you: 
o Personal information such as name, address and  date of birth  
o Social Security number ONLY IF you are being paid to be in this study 
o Your health information if required for this study.  This may include a review of your medical records and 
test results from before, during and after the study from any of your doctors or health care providers.  This 
may include mental health care records, substance abuse records, and/or HIV/AIDS records. 
o Tissue or blood samples if you agree to provide them for genetic testing for this study 
 
Who will see your private information?   
o The researchers to make sure they can conduct the study the right way,  observe the effects of the study 
and understand its results   
o People or groups that oversee the study to make sure it is done correctly   
o The sponsor(s) of this study, and the people or groups it hires to help perform  or review this research 
o Insurance companies or other organizations that may need the information in order to pay your medical 
bills or other costs of your participation in the study   


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o Tax reporting offices (if you are paid for being in the study) 
o People who evaluate study results, which can include sponsors and other companies that make the drug or 
device being studied, researchers at other sites conducting the same study, and government agencies that 
provide oversight such as the Food and Drug Administration (FDA) if the study is regulated by the FDA.  
 
Some of the people outside of UVa who will see your information may not have to follow the same privacy 
laws that we follow. They may release your information to others, and it may no longer be protected by those 
laws. 
 
The information collected from you might be published in a medical journal.  This would be done in a way that 
protects your privacy.  No one will be able to find out from the article that you were in the study. 
 
A description of this clinical trial will be available on http:// www.ClinicalTrials.gov, as required by U.S. Law. 
This Web site will not include information that can identify you. At most, the Web site will include a summary 
of the results. You can search this Web site at any time. 
 
What if you sign the form but then decide you don't want your private information shared?  
You can change your mind at any time.  Your permission does not end unless you cancel it.  To cancel it, please 
send a letter to the researchers listed on this form.  Then you will no longer be in the study.  The researchers 
will still use information about you that was collected before you ended your participation.   
 
A copy of this consent form will be put in your medical record. (This is not the same as the record of this 
research study.) This means that everyone who is allowed to see your medical records will be able to find out 
that you are in this study. This is done so your regular doctors will know what you receive as part of this study.   
If you have other health problems during the study, they will be able to treat you properly.
 
Please contact the researchers listed below to: 
• Obtain more information about the study 
• Ask a question about the study procedures or treatments 
• Report an illness, injury, or other problem (you may also need to tell your regular doctors) 
• Leave the study before it is finished 
• Express a concern about the study 
 
Linda Duska, MD 
University of Virginia School of Medicine 
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology 
PO Box 800712 
Charlottesville, VA 22908         Telephone:  (434) 924-1570 
  
What if you have a concern about this study?  
You may also report a concern about this study or ask questions about your rights as a research subject by 
contacting the Institutional Review Board listed below. 


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University of Virginia Institutional Review Board for Health Sciences Research 
PO Box 800483 
Charlottesville, Virginia 22908 
Telephone: 434-924-9634 
When you call or write about a concern, please give as much information as you can. Include the name of the 
study leader, the IRB-HSR Number (at the top of this form), and details about the problem.  This will help 
officials look into your concern. When reporting a concern, you do not have to give your name.
 
 
 


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Signatures 
 
What does your signature mean? 
Before you sign this form, please ask questions about any part of this study that is not clear to you.  Your 
signature below means that you have received this information and all your questions have been answered.  If 
you sign the form it means that you agree to join the study.  You will receive a copy of this signed document.  
 
 
Consent From Adult 
 
______________________ 
PARTICIPANT 
(SIGNATURE) 
 ________________________ 
PARTICIPANT 
(PRINT) 
 _______ 
DATE 
 
 
To be completed by participant if 18 years of age or older.  
 
If an interpreter is involved in the consent process because the potential subject does not speak English well or at all, the 
participant should NOT sign on the line above – leave this line blank.  Instead, the participant should sign the Short Form or full 
consent written in the language they can understand.  
 
 
 
Person Obtaining Consent 
By signing below you confirm that you have fully explained this study to the potential subject, allowed them 
time to read the consent or have the consent read to them, and have answered all their questions.  
 
_______________________________ 
PERSON OBTAINING CONSENT 
(SIGNATURE) 
 
_____________________________ 
PERSON OBTAINING 
CONSENT 
(PRINT) 
 
________ 
DATE 
 
 
 
 
Interpreter 
By signing below you confirm that the study has been fully explained to the potential subject in a language 
they understand and have answered all their questions. 
 
____________________________ 
INTERPRETER 
(SIGNATURE) 
 _____________________________ 
INTERPRETER 
(PRINT) 
 ________ 
DATE 
If an interpreter was used to explain this study to a potential subject, the interpreter must sign and date the 
line above.  
 
 
 


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Consent from Impartial Witness 
If this consent form is read to the subject because the subject is blind or illiterate, an impartial witness not 
affiliated with the research or study doctor must be present for the consenting process and sign the 
following statement.  The subject may place an X on the Participant Signature line above.  
 
I agree the information in this informed consent form was presented orally in my presence to the identified 
individual(s) who has had the opportunity to ask any questions he/she had about the study.   I also agree that 
the identified individual(s) freely gave their informed consent to participate in this trial.  
 
Please indicate with check box the identified individual(s): 
 Subject  
 
_______________________________ 
IMPARTIAL WITNESS 
(SIGNATURE) 
 _____________________________ 
IMPARTIAL WITNESS 
(PRINT) 
 ________ 
DATE