Conditions: Endometrial Cancer Endometrial Adenocarcinoma
Keywords: Pembrolizumab Keytruda Anti-Programmed [Cell] Death Protein 1 (PD-1) Antibody Carboplatin Paclitaxel
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 46
Healthy volunteers: no

Brief summary:
This is a single-arm, open-label, multi-center phase II study for subjects with measurable advanced or recurrent endometrial cancer using pembrolizumab in combination with carboplatin and paclitaxel chemotherapy. As this combination of agents has not been tested in this subject population, the first six subjects enrolled will constitute a safety run-in cohort.

Detailed description:
OUTLINE: This is a multi-center study.

INVESTIGATIONAL TREATMENT:

To ensure the safety of this combination treatment, an initial safety run-in will be conducted for the first 6 subjects. This initial cohort of 6 subjects will be enrolled and treated with standard doses as described below. Based on toxicity analysis of the initial 6 subjects following completion of 18 weeks of treatment, it will be determined if an extended safety run-in period would be beneficial.

In the absence of receiving any prior therapy, eligible subjects will be treated as follows on D1 of cycles lasting 21 days (3 weeks) for a maximum of 6 cycles:

* Pembrolizumab 200mg will be administered as a 30-minute intravenous (IV) infusion every 3 weeks.
* Paclitaxel will be dosed at 175mg/m2 and be administered as a 3-hour continuous IV infusion.
* Carboplatin will be dosed at area under the curve (AUC) of 6 and given as an IV infusion in 250ml of D5W over 30 minutes.

Subjects who have had prior radiotherapy/platinum-based chemotherapy must initiate paclitaxel and carboplatin at the following reduced dose levels if they have had prior external radiotherapy involving the whole pelvis or abdomen or over 50% of their spine, and/or prior platinum-based chemotherapy for this, or any other cancer. Eligible subjects will be treated as follows on Day 1 (D1) of cycles lasting 21 days (3 weeks) for a maximum of 6 cycles:

* Pembrolizumab 200mg administered as a 30-minute intravenous (IV) infusion every 3 weeks.
* Paclitaxel will be dosed at 135mg/m2 and be administered as a 3-hour continuous IV infusion.
* Carboplatin will be dosed at an AUC of 5 and given as an IV infusion in 250ml of D5W over 30 minutes.

Subsequent doses of paclitaxel and carboplatin may be escalated to the higher doses as indicated above, provided these subjects do not exhibit hematologic or nonhematologic toxicity \> Grade 1, except alopecia.

The following laboratory values must be obtained within 14 days prior to registration for protocol therapy:

Hematopoietic:

* Hemoglobin (Hgb) \> 9 g/dL (without transfusion or erythropoietin (EPO) dependency within 7 days of assessment)
* Platelets \> 100 K/mm3
* Absolute neutrophil count (ANC) ≥ 1.5 K/mm3

Renal:

* Creatinine or measured/calculated creatinine clearance (as calculated by institutional standard) ≤ 1.5 X institutional upper limits of normal (ULN) OR ≥60mL/min for subjects with creatinine levels \> 1.5 x institutional ULN

Hepatic:

* Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN
* Aspartate aminotransferase (AST), alanine transaminase (ALT) or alkaline phosphatase (ALP) \< 2.5 x ULN OR ≤ 5 x ULN for subjects with liver metastases
* Albumin ≥ 2.5 mg/dL

Coagulation (Blood Clotting) Tests:

* International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless subject is receiving anti-coagulant therapy as long as partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
* Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless subject is receiving anti-coagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

Arms:
arm 1: Subjects with no prior therapy:

* Pembrolizumab administered at 200 mg
* Paclitaxel administered at 175mg/m2
* Carboplatin administered at an AUC of 6

Subjects with prior external beam radiation therapy (XRT) and/or platinum-based chemotherapy must initiate paclitaxel and carboplatin at a reduced dose:

* Pembrolizumab administered at 200 mg
* Paclitaxel administered at 135mg/m2
* Carboplatin administered at an AUC of 5

Interventions: intervention 1: Pembrolizumab intervention 2: Paclitaxel intervention 3: Carboplatin
Intervention descriptions: intervention 1: Pembrolizumab 200 mg will be administered every 3 weeks for all subjects intervention 2: For subjects with no prior therapy, paclitaxel will be dosed at 175mg/m2 and be administered as a 3-hour continuous IV infusion.

Subjects with prior XRT/platinum-based chemotherapy must initiate paclitaxel at 135mg/m2 and be administered as a 3-hour continuous IV infusion. intervention 3: For subjects with no prior therapy, carboplatin will be dosed at an AUC of 6 and given as an IV infusion in 250ml of D5W over 30 minutes.

Subjects with prior XRT/platinum-based chemotherapy must initiate carboplatin at an AUC of 5 given as an IV infusion in 250ml of D5W over 30 minutes.

Protocol document:
Prot_000.pdf: 
 
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Protocol Title 
Phase II Study of Pembrolizumab in Combination with Carboplatin and Paclitaxel  
for Advanced or Recurrent Endometrial Adenocarcinoma  
Big Ten Cancer Research Consortium BTCRC-GYN15-013 
 
Sponsor-Investigator 
Daniela E. Matei, MD 
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University 
Feinberg School of Medicine 
daniela.matei@northwestern.edu 
 
Co-Investigators  
Mario Javier Pineda, MD, PhD 
Lorna Rodriguez, MD, PhD 
 
Statistician 
Alfred Rademaker, PhD 
 
Trial Supported by  
Merck Sharp & Dohme Corp. 
(MISP 52552) 
 
Trial Management by 
BTCRC Administrative Headquarters at Hoosier Cancer Research Network 
500 N. Meridian, Suite 100 
Indianapolis, IN 46204 
 
Investigational New Drug (IND) Application Number 
131231 
 
Initial Protocol Version Date:  
13OCT2016 
 
Protocol Amendment Date: 
27FEB2017 
17APR2017 
31MAY2017 
08JUN2018 (current) 
 


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PROTOCOL SIGNATURE PAGE  
 
Phase II Study of Pembrolizumab in Combination with Carboplatin and Paclitaxel for Advanced 
or Recurrent Endometrial Adenocarcinoma 
 
 
VERSION DATE:  08JUN2018 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and to 
the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, or the applicable laws and regulations of the country of the 
study site for which I am responsible, whichever provides the greater protection of the individual. I 
will accept the monitor’s overseeing of the study. I will promptly submit the protocol to applicable 
ethical review board(s). 
 
 
 
 
 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Site Investigator 
 
 
 
 
       Date 
 
 
____________________________________ 
Site Investigator Name (printed) 
 
 
____________________________________ 
Site Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 Location of Facility (City and State) 
 
____________________________________ 
❑ Not Submitting to IRB 
 Expected IRB Approval Date 
 
PLEASE COMPLETE AND EMAIL TO BTCRC ADMINISTRATIVE HEADQUARTERS  
Instructions to the site investigator:  Please SIGN and DATE this signature 
page.  PRINT your name and title, the name and location of the facility in 
which the study will be conducted, and the expected IRB approval date.  Scan 
and email the completed form to BTCRC Administrative Headquarters and 
keep a record for your files. 


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STUDY SYNOPSIS 
 
TITLE 
Phase II study of pembrolizumab in combination with carboplatin and paclitaxel 
for advanced or recurrent endometrial adenocarcinoma 
SHORT TITLE 
Phase II pembro/carbo/Taxol in endometrial cancer 
PHASE  
II 
OBJECTIVES 
Primary Objective: 
To estimate the objective response rate of pembrolizumab in combination with 
standard carboplatin/paclitaxel in subjects with measurable advanced or 
recurrent endometrial cancer. 
Secondary Objectives: 
To determine the toxicities of pembrolizumab in combination with standard 
carboplatin/paclitaxel in subjects with advanced or recurrent endometrial 
cancer. 
Correlative Objectives: 
To evaluate potential biomarkers or prognostic factors for those who may 
respond to pembrolizumab. 
 
OUTCOME 
MEASURES 
Primary Endpoint 
Objective response rate is defined as the proportion of subjects with a partial 
response or complete response according to immune-related RECIST criteria. 
 
Secondary Endpoints 
Toxicity is defined as the proportion of subjects who experience ≥ Grade 3 
toxicity according to CTCAE v4. 
 
Correlative/ Exploratory Endpoints 
Immunohistochemical evaluation of expression of PD-L1; Treg, Tumor 
Infiltrating Lymphocytes, and Myeloid Derived Suppressor Cell abundance in 
formalin-fixed, paraffin-embedded endometrial tumor and fresh frozen biopsy 
specimen, if available.   
Characterization of circulating immune cell populations (TIM3+/PD-1+/CD8+, 
PD-1+/Treg) will be evaluated on samples collected prior to the start of and 
upon completion of combination pembrolizumab/cytotoxic chemotherapy. 
Determination of the mutational landscape of endometrial cancer and its 
influence in the response to pembrolizumab. Exome sequencing and targeted 
next generation sequencing, targeting all exons of approximately 300 cancer 
related genes will be performed from FFPE tissue from participants’ tumors.   
STUDY DESIGN 
This is a single-arm, open-label, multi-center phase II study for subjects with 
measurable advanced or recurrent endometrial cancer using pembrolizumab in 
combination with carboplatin and paclitaxel chemotherapy. As this combination 
of agents has not been tested in this subject population, the first six subjects 
enrolled will constitute a safety run-in cohort (see Section 5.2). 


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ELIGIBILITY 
CRITERIA  
Inclusion Criteria 
Subjects must meet all of the following applicable inclusion criteria to participate 
in this study: 
 
1. Written informed consent and HIPAA authorization for release of personal 
health information prior to registration for protocol therapy. 
NOTE:  HIPAA authorization may be included in the informed consent or 
obtained separately. 
2. Age ≥ 18 years at the time of consent. 
3. ECOG Performance Status of 0 or 1 within 28 days prior to registration for 
protocol therapy. 
4. Histological evidence of newly diagnosed Stage III or IV or recurrent 
endometrial carcinoma who have had definitive surgery for endometrial 
cancer (at least hysterectomy and bilateral salpingo-oophorectomy). 
Pathologic documentation of the recurrence (i.e., biopsy) will be performed 
per standard of care, at the treating physician’s discretion.  If a subject with 
recurrence is undergoing a biopsy for clinical indications and is willing and 
able, an optional collection of 3 frozen tissue cores of the recurrence site is 
requested for correlative analysis. 
5. Measurable disease according to RECIST v1.1 and obtained by imaging 
within 28 days prior to registration for protocol therapy.  Disease in an 
irradiated field as the only site of measurable disease is acceptable only if 
there has been clear progression since completion of radiation treatment. 
6. The subject must have recovered (≤ grade 1) from the acute toxic effects of 
prior therapy.  
7. Prior treatment: Subjects may have received none or one platinum-based 
chemotherapy regimen and none or one non-platinum regimen. Subjects 
having received prior platinum-based chemotherapy must have a disease-free 
interval > 6 months (be platinum sensitive).  
8. Prior therapy with hormones or biologic agents is allowed. These treatments 
must be discontinued at least 28 days prior to registration for protocol therapy.  
9. The subject must have completed prior radiation therapy at least 28 days prior 
to registration for protocol therapy, provided that toxicity has resolved to ≤ 
grade 1.  
NOTES: Subjects may have received prior radiation therapy for treatment of 
endometrial carcinoma. Prior radiation therapy may have included pelvic 
radiation therapy, extended field pelvic/para-aortic radiation therapy, and/or 
intravaginal brachytherapy.  Chemotherapy used for radiation sensitization is 
allowed.  Chemotherapy used for radiation sensitization will not count as 
second chemotherapy regimen. 
Palliative radiation given primarily for symptom relief, without the intent to 
treat or cure the patient’s endometrial cancer is excluded from the above 
criteria. Treatment-directed radiation will be defined as more than 30 Gy of 
radiation. 


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10. No prior malignancy is allowed except for adequately treated basal cell or 
squamous cell skin cancer, in situ cervical cancer, or other cancer for which 
the subject has been disease-free for at least 5 years. 
11. Female subjects must be of non-childbearing potential.  Women of 
childbearing potential are those who have not been surgically sterilized or 
have not been free from menses for ≥1 year. 
12. Laboratory values must be obtained within 14 days prior to registration for 
protocol therapy.  Note: Institutional/laboratory upper limit of normal (ULN) 
• Hemoglobin (Hgb) > 9 g/dL (without transfusion or EPO dependency 
within 7 days of assessment) 
• Platelets > 100 K/mm3 
• Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 
• Creatinine or measured/calculated creatinine clearance (as calculated by 
institutional standard) ≤ 1.5 X institutional ULN OR ≥ 60mL/min for 
subjects with creatinine levels > 1.5 x institutional ULN 
• Serum total bilirubin ≤ 1.5  ULN OR Direct bilirubin ≤ ULN for subjects 
with total bilirubin levels > 1.5 ULN  
• AST, ALT or alkaline phosphatase < 2.5  ULN OR ≤ 5 x ULN for 
subjects with liver metastases 
• Albumin ≥ 2.5 mg/dL  
• International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x 
ULN unless subject is receiving anti-coagulant therapy as long as PTT is 
within therapeutic range of intended use of anticoagulants 
• Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless 
subject is receiving anti-coagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants 
Exclusion Criteria 
1. Subjects with carcinosarcoma. 
2. Subjects who have a solitary central pelvic recurrence which can be curatively 
resected. 
3. Hypersensitivity to pembrolizumab or any of its excipients. 
4. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior 
to registration for protocol therapy or who has not recovered (i.e. ≤ Grade 1 or 
at baseline) from adverse events due to agents administered more than 4 
weeks earlier. 
5. 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 registration for protocol therapy and 


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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 registration for protocol therapy. This exception does not include 
carcinomatous meningitis, which is excluded regardless of clinical stability.   
Note: Subjects with neurological symptoms must undergo a head CT scan or 
brain MRI to exclude brain metastasis. 
6. Treatment with any investigational agent within 28 days prior to registration 
for protocol therapy.  
7. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
8. Active autoimmune disease that has required systemic treatment in past 2 
years (i.e. with use of disease modifying agents, corticosteroids, or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 
9. Has received systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to registration for protocol 
therapy. (Prednisone (or equivalent) < 10mg/ day is allowed). 
10. Has a known history of active TB (Bacillus Tuberculosis) 
11. Pulmonary conditions such as sarcoidosis, silicosis, idiopathic pulmonary 
fibrosis, or hypersensitivity pneumonitis. 
12. Has a history of (non-infectious) pneumonitis that required steroids or has 
current pneumonitis. 
13. Evidence of interstitial lung disease 
14. Has an active infection requiring systemic therapy with the exception of an 
uncomplicated urinary tract infection. 
15. Pre-existing peripheral neuropathy that is ≥ Grade 2 by CTCAE v 4 criteria. 
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 
agent. 
17. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen 
[HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA 
[qualitative] is detected) infection. Note: no testing for Hepatitis B and 
Hepatitis C is required unless mandated by local health authority. 
18. Has received a live vaccine within 30 days of registration for protocol 
therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-
Mist®) are live attenuated vaccines, and are not allowed. 
19. History of solid organ or stem cell transplant requiring immunosuppressive 
medications 


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STATISTICAL 
CONSIDERATIONS 
Analysis Plan for Primary Objective 
The principal parameter employed to evaluate efficacy of the addition of 
pembrolizumab to the combination of carboplatin and paclitaxel is the frequency 
of objective response. The response rates will be compared with actual data from 
the historical control using Fisher’s exact test. 
Analysis Plan for Secondary Objective 
All adverse events and safety monitoring measures will be described 
longitudinally using descriptive statistics such as frequencies, proportions, and 
ranges. Individual data will be reported for values out of normal range. 
For the primary outcome, response rate (RR), a single stage, single arm design 
will assume a historical control response rate of 50%.  A meaningful clinical 
response would be an improvement in RR of 15% given the potential risks and 
increased cost for the additional immunotherapy; for our purposes, we will target 
a 65% response rate.  The proposed sample size will be 46 subjects total.  A 
single group of 46 subjects will give us a 77% power to detect a higher overall 
response rate (65%) than the historical control (50%), assuming a one-tailed test 
and a Type I error rate of 10%.  All subjects who receive pembrolizumab will be 
evaluated for treatment efficacy and toxicity. 
Statistical analysis will be done by the Biostatistics Core Facility of the Robert H. 
Lurie Comprehensive Cancer Center. 
TOTAL  
NUMBER OF 
SUBJECTS  
46 subjects 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 18 months 
ESTIMATED 
STUDY 
DURATION  
Estimated 36 months 
 
 
 


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TABLE OF CONTENTS 
 
SECTION                                                                                                                 
PAGE 
SCHEMA ........................................................................................................................................... 9 
1. 
BACKGROUND & RATIONALE ...................................................................................... 10 
2. 
OBJECTIVES AND ENDPOINTS ...................................................................................... 12 
3. 
ELIGIBILITY CRITERIA.................................................................................................... 13 
4. 
SUBJECT REGISTRATION................................................................................................ 16 
5. 
TREATMENT PLAN ........................................................................................................... 17 
6. 
DOSE MODIFICATIONS ................................................................................................... 22 
7. 
STUDY CALENDAR & EVALUATIONS ......................................................................... 30 
8. 
CRITERIA FOR DISEASE EVALUATION ....................................................................... 35 
9. 
BIOLOGICAL CORRELATIVES ....................................................................................... 42 
10. 
DRUG INFORMATION ...................................................................................................... 44 
11. 
ADVERSE EVENTS ............................................................................................................ 49 
12. 
STATISTICAL CONSIDERATIONS.................................................................................. 56 
13. 
TRIAL MANAGEMENT ..................................................................................................... 59 
14. 
DATA HANDLING AND RECORD KEEPING ................................................................ 60 
15. 
ETHICS................................................................................................................................. 62 
16. 
REFERENCES ..................................................................................................................... 64 
 


 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 1, Every 3 Weeks** 

Carboplatin AUC 6 

Paclitaxel 175mg/m2 

Pembrolizumab 200mg 
 
Up to 6 cycles of treatment 
 
** If prior XRT and/or prior platinum-based 
chemotherapy:  

Carboplatin AUC 5 

Paclitaxel 135mg/m2 

Pembrolizumab 200mg 

Advanced or Recurrent Endometrial Cancer 

At least 4 weeks since completion of Radiation 

No chemotherapy in last 6 months 
Tissue biopsy prior to treatment, if indicated 
Safety Run-in: 6 subjects 
Single Arm 
Correlative 
blood sample 
prior to initiation 
of treatment 
Phase II: 40 subjects 
Single Arm 
CT Scan every 3 cycles  
(9 weeks) 
Correlative 
blood sample 
upon completion 
of treatment 
Surveillance Q3 months until progression or up to 18 months. 
 
Imaging Q3 months × 12 months, then as clinically indicated. 


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1. BACKGROUND & RATIONALE 
The hypothesis of this study is that the addition of pembrolizumab, an anti-PD-1 antibody, to 
carboplatin/paclitaxel for the treatment of patients with advanced and recurrent endometrial 
adenocarcinoma will improve the objective response rate by 15% (from 50% to 65%) when 
compared to historical controls of patients treated with carboplatin/paclitaxel alone. 
1.1 Endometrial Adenocarcinoma 
Endometrial cancer is the most common cancer of the female reproductive tract and the fourth 
most common cancer in the United States.  It is estimated that more than 60,000 new endometrial 
cancer diagnoses will have been made in 2016.  For many women initial therapy is curative.  
However, 20-25% of patients with endometrial cancers are initially detected at an advanced stage; 
these women have a guarded prognosis, poor overall response to chemotherapy and an increased 
risk of recurrence compared to patients with early-stage disease.   In women with advanced 
endometrial cancer response rates to the most active single agent chemotherapies range from 20-
35%.  The most recently reported large randomized clinical trial in this patient population 
compared two active combination regimens (doxorubicin/cisplatin with and without paclitaxel).  
The objective response rates were 57% v 34%, respectively, and overall survival intervals were 
15.3 v 12.3 months, respectively 1.   
In the advanced and recurrent setting chemotherapeutic interventions are limited (NCCN 
Guidelines Uterine Neoplasms V 1.2015).  There is a desperate need to identify additional active 
therapies for this patient population.  In a retrospective analysis of patients with histologically 
confirmed endometrial carcinoma or uterine carcinosarcoma who received second-line platinum-
based chemotherapy, the response rate for the entire cohort was 50% (129 CR+PR out of 262 total 
evaluable patients).  All patients had received primary platinum-based chemotherapy with or 
without concurrent chemoradiation therapy2.  A similarly designed, but significantly smaller, trial 
examined 22 patients with uterine papillary serous carcinoma who were treated with a platinum-
based chemotherapy for recurrent disease3.  Most of these patients (18) had received platinum-
based chemotherapy as part of their definitive upfront treatment.  The overall response rate was 
50%. 
1.2 Carboplatin/Paclitaxel 
The combination of carboplatin/paclitaxel every three weeks has become the clinical standard of 
care chemotherapy for advanced and recurrent endometrial cancer.  This is based upon the 
recently reported widespread clinical experience with this regimen and an interim analysis of a 
randomized phase III, non-inferiority trial demonstrating that the commonly used doublet 
carboplatin/paclitaxel is not inferior to the most active regimen previously identified: doxorubicin, 
cisplatin, and paclitaxel4,5. 
1.3 Immune Checkpoints 
T cell-mediated immunity is a sequential multistep process that is regulated by complex 
counterbalancing co-stimulatory and inhibitory signals termed immune checkpoints.  These 
checkpoints are important for maintenance of self-tolerance and to protect healthy tissues from the 
immune system from damage from the immune response to pathogenic infection6.  T cells are 
activated when their cognate antigens are presented by antigen presenting cells (APC) to the T cell 
receptor.  This activation is amplified by a co-stimulatory signal triggered by CD80 (also known 
as B7) on the APC binding to the T cell-expressed CD28.  After activation of the T-cell, cytotoxic 


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T-lymphocyte antigen 4 (CTLA-4), a receptor expressed on T cells, is upregulated and also binds 
to CD80.  CTLA-4 counteracts the stimulatory activity of CD28.  The programmed cell death 
protein 1 (PD-1) is another inhibitory signaling pathway functioning to limit the activity of 
activated effector T cells in the peripheral tissues at the time of an inflammatory response to 
infection/tissue injury and to limit autoimmunity7,8.  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 proteins9,10.  Binding of either PD-L1 or PD-L2 to PD-1 
inhibits T-cell activation triggered through the T-cell receptor. P D-L1 is expressed at low levels 
on various non-hematopoietic tissues, most notably on vascular endothelium; whereas PD-L2 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 tissues11.   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 and in various tumors12,13. 
1.4 PD-1 Pathway and Cancer 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformations has been well recognized.  The presence of tumor-infiltrating lymphocytes in cancer 
tissue correlates with favorable prognosis in various malignancies.  In particular, the presence of 
CD8+ T cells and the ratio of CD8+ effector T cells/FoxP3+ regulatory T cells (Tregs) correlate with 
improved prognosis and long-term survival in multiple solid malignancies including ovarian 
carcinoma.  PD-1 is expressed on activated lymphocytes including peripheral CD4+ and CD8+ T 
cells, B cells, Tregs and Natural Killer cells6.  High expression of PD-L1 on tumor cells has been 
found to correlate with poor prognosis and survival in various solid tumors14-16. On the other hand, 
a higher mutation burden in tumors may be associated with improved and durable objective 
responses and progression-free survival in patients receiving anti- PD-1 therapy.17 Deleterious 
mutations in genes such as POLE, and POLD1, specifically if the mutations are in the proofreading, 
exonuclease domain of the polymerase, are likely to exhibit a hypermutated tumor phenotype. 
Although most of these mutations are likely ‘passenger mutations’ that do not drive tumor growth, 
they may lead to protein alterations that can serve as neo-antigens that in turn will stimulate T-cell 
immunity. Additionally, POLE mutations are seen in ~ 10% of endometrial cancers and are 
associated with high mutation burden, increased expression of immune checkpoint ligands PD-L1 
and T-cell markers.18-23 This leads to the hypothesis that tumors with high mutational burdens, due 
to underlying DNA repair defects, may be more “immunogenic” and thus vulnerable to immune 
checkpoint disruption. Additionally, high expression of the programmed death receptor 1 ligand 
(PD-L1) is under investigation as a potential predictor of response to therapy. However, while 
patients with higher PD-L1 expression may indeed sustain greater benefit, there are a subset of 
patients with PD-L1 negative cancers who sustain important responses.18 Thus use of PD-L1 
expression alone to select patients for anti-PD-1 therapy may not be optimal for every patient and 
the discovery of additional predictive markers may complement its utility. 
 
Therefore, we hypothesize that endometrial cancers with high mutation burden will respond better 
to anti-PD-1 therapy and that specific mutations in DNA polymerases and DNA repair genes, as 
well as high mutational burden, will predict response to anti-PD-1 treatment. 
 


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1.5 Pembrolizumab 
The PD-1 pathway represents a major pathway hijacked by tumors to suppress immune control.  
Pembrolizumab (also known as Keytruda® and MK-3475) is a potent and highly selective 
humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2.   
Pembrolizumab potently blocks binding to both ligands with half maximal inhibitory 
concentration (IC50) values below 1 nM. Pembrolizumab enhances T cell responses in human 
donor blood cell cultures with an EC50 of ~0.1 to 0.3 nM. Pembrolizumab binds to cynomolgus 
PD-1 with similar affinity, blocking activity, and demonstrates equivalent enhancement of 
cynomolgus T cell responses. It does not cross-react with rodent PD-1 (Merck, pembrolizumab 
Investigator’s Brochure).  
Pembrolizumab strongly enhances T lymphocyte immune responses in cultured blood cells from 
healthy human donors, cancer patients, and primates. The antibody potentiates existing immune 
responses only in the presence of antigen-receptor stimulation and does not nonspecifically 
activate all T cells. Using an anti-mouse PD-1 analog antibody, PD-1 blockade is demonstrated to 
significantly inhibit tumor growth in a variety of syngeneic murine tumor models. In experiments 
in mice, anti-PD-1 therapy is synergistic with chemotherapeutic agents such as gemcitabine and 5-
FU and combination therapy results in increased efficacy and increased complete regression rates 
in vivo. In addition, there has been significant clinical experience with pembrolizumab (Merck 
pembrolizumab Investigator’s Brochure).  
 
1.6 Study Rationale 
The observed correlation of clinical prognosis with PD-L1 expression in multiple cancers 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.  Data remains limited for the role of 
anti-PD-1 treatment in gynecologic malignancies and additional investigation is warranted to 
determine if pembrolizumab is an effective addition to a cytotoxic backbone in the treatment of 
endometrial cancer.  A recent publication reported greater than 90% of endometrial cancers 
evaluated expressed the PD-1 ligand, PD-L124; this suggests that PD-1 blockade may be a 
common and targetable mechanism for endometrial cancer immune evasion.    
 
This phase II trial will study the effects of pembrolizumab in combination with carboplatin/ 
paclitaxel for the treatment of subjects with advanced or recurrent endometrial cancer. 
 
2. OBJECTIVES AND ENDPOINTS 
2.1. Objectives 
2.1.1. Primary Objective 
To estimate the objective response rate of pembrolizumab in combination with standard 
carboplatin/paclitaxel in subjects with measurable advanced or recurrent endometrial 
cancer. 
2.1.2. Secondary Objectives 
To determine the toxicities of pembrolizumab in combination with standard 
carboplatin/paclitaxel in subjects with advanced or recurrent endometrial cancer. 


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2.1.3. Correlative/ Exploratory Objectives 
To evaluate potential biomarkers or prognostic factors for those who may respond to 
pembrolizumab. 
2.2. Endpoints 
2.2.1. Primary Endpoint 
Objective response rate is defined as the proportion of subjects with a partial response or 
complete response according to immune-related RECIST criteria. 
2.2.2. Secondary Endpoints 
Toxicity is defined as the proportion of subjects who experience ≥ Grade 3 toxicity 
according to CTCAE v4. 
2.2.3. Correlative/ Exploratory Endpoints 
2.2.3.1 Immunohistochemical evaluation of expression of PD-L1; Treg, Tumor 
Infiltrating Lymphocytes, and Myeloid Derived Suppressor Cell abundance in formalin-
fixed, paraffin-embedded endometrial tumor and fresh frozen biopsy specimen, if 
available.   
2.2.3.2 Characterization of circulating immune cell populations (TIM3+/PD-1+/CD8+, 
PD-1+/Treg) will be evaluated on samples collected prior the start of and upon 
completion of combination pembrolizumab/cytotoxic chemotherapy. 
2.2.3.3 Determination of the mutational landscape of endometrial cancer and its 
influence in the response to pembrolizumab. Exome sequencing and targeted next 
generation sequencing, targeting all exons of approximately 300 cancer related genes 
will be performed from FFPE tissue from participants’ tumors.   
 
3. ELIGIBILITY CRITERIA 
3.1. Inclusion Criteria 
Subjects must meet all of the following applicable inclusion criteria to participate in this study: 
 
1. Written informed consent and HIPAA authorization for release of personal health 
information prior to registration for protocol therapy. 
NOTE:  HIPAA authorization may be included in the informed consent or obtained 
separately. 
2. Age ≥ 18 years at the time of consent. 
3. ECOG Performance Status of 0 or 1 within 28 days prior to registration for protocol 
therapy. 
4. Histological evidence of newly diagnosed Stage III or IV or recurrent endometrial 
carcinoma who have had definitive surgery for endometrial cancer (at least hysterectomy 
and bilateral salpingo-oophorectomy). Pathologic documentation of the recurrence (i.e., 
biopsy) will be performed per standard of care, at the treating physician’s discretion.  If a 
subject with recurrence is undergoing a biopsy for clinical indications and is willing and 


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able, an optional collection of 3 frozen tissue cores of the recurrence site is requested for 
correlative analysis. 
5. Measurable disease according to RECIST v1.1 and obtained by imaging within 28 days 
prior to registration for protocol therapy.  Disease in an irradiated field as the only site of 
measurable disease is acceptable only if there has been clear progression since completion 
of radiation treatment. 
6. The subject must have recovered (≤ grade 1) from the acute toxic effects of prior therapy. 
7. Prior treatment: Subjects may have received none or one platinum-based chemotherapy 
regimen and none or one non-platinum regimen. Subjects having received prior platinum-
based chemotherapy must have a disease-free interval > 6 months (be platinum sensitive).  
8. Prior therapy with hormones or biologic agents is allowed.  These treatments must be 
discontinued at least 28 days prior to registration for protocol therapy.   
9. The subject must have completed radiation therapy at least 28 days prior to registration for 
protocol therapy, provided that toxicity has resolved to ≤ grade 1.  
NOTES: Subjects may have received prior radiation therapy for treatment of endometrial 
carcinoma. Prior radiation therapy may have included pelvic radiation therapy, extended 
field pelvic/para-aortic radiation therapy, and/or intravaginal brachytherapy.  
Chemotherapy used for radiation sensitization is allowed.  Chemotherapy used for 
radiation sensitization will not count as second chemotherapy regimen.  
Palliative radiation given primarily for symptom relief, without the intent to treat or cure 
the patient’s endometrial cancer is excluded from the above criteria. Treatment-directed 
radiation will be defined as more than 30 Gy of radiation. 
10. No prior malignancy is allowed except for adequately treated basal cell or squamous cell 
skin cancer, in situ cervical cancer, or other cancer for which the subject has been disease-
free for at least 5 years. 
11. Female subjects must be of non-childbearing potential.  Women of childbearing potential 
are those who have not been surgically sterilized or have not been free from menses for ≥1 
year. 
12. Laboratory values must be obtained within 14 days prior to registration for protocol 
therapy.  Note: Institutional/laboratory upper limit of normal (ULN) 
• Hemoglobin (Hgb) > 9 g/dL (without transfusion or EPO dependency within 7 days of 
assessment) 
• Platelets > 100 K/mm3 
• Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 
• Creatinine or measured/calculated creatinine clearance (as calculated by institutional 
standard) ≤ 1.5 X institutional ULN OR ≥60mL/min for subjects with creatinine levels 
> 1.5 x institutional ULN 
• Serum total bilirubin ≤ 1.5  ULN OR Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN  


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• AST, ALT or alkaline phosphatase < 2.5  ULN OR ≤ 5 x ULN for subjects with liver 
metastases 
• Albumin ≥ 2.5 mg/dL  
• International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless 
subject is receiving anti-coagulant therapy as long as PTT is within therapeutic range 
of intended use of anticoagulants 
• Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless subject is receiving 
anti-coagulant therapy as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
3.2. Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. Subjects with carcinosarcoma. 
2. Subjects who have a solitary central pelvic recurrence, which can be curatively resected. 
3. Hypersensitivity to pembrolizumab or any of its excipients. 
4. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to 
registration for protocol therapy or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to agents administered more than 4 weeks earlier. 
5. 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 
registration for protocol therapy 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 registration for protocol therapy. This exception does not include 
carcinomatous meningitis, which is excluded regardless of clinical stability.   
NOTE: Subjects with neurological symptoms must undergo a head CT scan or brain MRI 
to exclude brain metastasis. 
6. Treatment with any investigational agent within 28 days prior to registration for protocol 
therapy.  
7. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
8. Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with 
use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
9. Has received systemic steroid therapy or any other form of immunosuppressive therapy 
within 7 days prior to registration for protocol therapy. (Prednisone (or equivalent) < 
10mg/ day is allowed). 
10. Has a known history of active TB (Bacillus Tuberculosis). 


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11. Pulmonary conditions such as sarcoidosis, silicosis, idiopathic pulmonary fibrosis, or 
hypersensitivity pneumonitis. 
12. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis. 
13. Evidence of interstitial lung disease. 
14. Has an active infection requiring systemic therapy with the exception of an uncomplicated 
urinary tract infection. 
15. Pre-existing peripheral neuropathy that is ≥ Grade 2 by CTCAE v4 criteria. 
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
17. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) 
infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by 
local health authority. 
18. Has received a live vaccine within 30 days prior to registration for protocol therapy. 
NOTE:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
19. History of solid organ or stem cell transplant requiring immunosuppressive medications. 
 
4. SUBJECT REGISTRATION  
All subjects must be registered through BTCRC Administrative Headquarters’ electronic data 
capture (eDC) system. A subject is considered registered when an ‘On Study’ date is entered into 
the eDC system. 
 
Detailed guidelines for subject registration can be found in the electronic case report form (eCRF) 
guidelines associated with this protocol.  
 
Subjects must be registered prior to starting protocol therapy. Subjects must begin therapy within 5 
business days of registration.  
 
 


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5. TREATMENT PLAN 
5.1. 
 Rationale for Pembrolizumab 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 pembrolizumab.  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 pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg, 
and 10 mg/kg Q2W).  No MTD has been identified to date.  Recent data from other clinical 
studies within the pembrolizumab program has shown that a lower dose of pembrolizumab and a 
less frequent schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (Merck pembrolizumab 
Investigator’s Brochure).  Pharmacodynamic data (IL-2 release assay) suggested that peripheral 
target engagement is durable (>21 days).  This early PK and pharmacodynamic data provides 
scientific rationale for testing a Q2W and Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 subjects. Within the resulting population PK model, clearance and volume parameters of 
pembrolizumab were found to be dependent on body weight. The relationship between clearance 
and body weight, with an allometric exponent of 0.59, is within the range observed for other 
antibodies and would support both body weight normalized dosing or a fixed dose across all body 
weights.  Pembrolizumab has been found to have a wide therapeutic range based on the melanoma 
indication.  The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg 
Q3W body weight based regimen are anticipated to remain well within the established exposure 
margins of 0.5 – 5.0 for pembrolizumab in the melanoma indication. The exposure margins are 
based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the alternate 
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 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 subject exposures in the 
exposure range established in melanoma as associated with maximal efficacy response and 3) will 
maintain individual subject 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. 


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5.2. 
 Safety run-in  
To ensure the safety of this combination treatment, an initial safety run-in will be conducted for 
the first 6 subjects. This initial cohort of 6 subjects will be enrolled and treated with standard 
doses as described below. Upon the sixth subject’s completion of the first two cycles of treatment, 
the toxicity data will be reviewed by the investigators in partnership with the Data Monitoring 
Committee at Northwestern University to determine if further subjects could be treated at the 
current dose level. Based on the experience with the initial 6 subjects, it will be determined if an 
extended safety run-in period would be beneficial. The decision will be based on the following 
criteria:  
• If 0 or 1 of the 6 subjects experience DLT (see definition below), the study will proceed to 
enroll and treat the rest of the subjects on the current dose level to reach the enrollment 
goal. 
• If 2 or more subjects experience DLT, the safety run-in will be repeated with an additional 
6-subject cohort.  The dose of carboplatin will be reduced to AUC of 5, the dose of 
paclitaxel will be reduced to 135mg/m2 and pembrolizumab will be held for the first cycle.  
Toxicity data will again be reviewed following completion of first two cycles of treatment 
for the additional cohort. 
o If >33% of subjects in the additional cohort experience DLT at the reduced levels of 
carboplatin (AUC of 5)/paclitaxel (135mg/m2) per dose (dose level -1), then the study 
will be suspended for further review.  Next steps will be determined following DMC 
review of toxicity data, which will be formally communicated to site investigators and 
the industry supporter Merck. 
The dose determination rules listed above only apply to subjects who have received at least 1 dose 
of pembrolizumab.  If one or more of the first 6 subjects terminate treatment without receiving at 
least 1 dose of pembrolizumab, additional subjects will be accrued during the safety run-in period 
to achieve an initial cohort of 6 subjects, each with at least 1 dose of pembrolizumab. 
5.2.1. Definition of Dose-limiting Toxicity (DLT) 
A DLT is defined as any adverse event observed during the first two cycles which is judged to be 
possibly, probably, or definitely related to any study drug (pembrolizumab, carboplatin or 
paclitaxel) and fulfilling one of the criteria below. Fatigue and alopecia will be excluded from the 
DLT definitions. 
• Dose modifications of more than one missed dose of pembrolizumab 
• Grade 4 non-hematologic toxicity (not laboratory) 
• Sepsis requiring intravenous antibiotics 
• Grade 3 non-hematologic toxicity related to treatment lasting ≥ 3 days despite optimal 
supportive care 
• Any Grade 3 or Grade 4 laboratory value if: 
o Medical intervention, including granulocyte colony-stimulating factors, is required 
to treat the subject, or 
o The abnormality leads to hospitalization, or 
o The abnormality persists for ≥ 7 days (other than as noted for thrombocytopenia) 
• Febrile neutropenia Grade 3 or Grade 4: 
o Grade 3 is defined as ANC < 1000/mm3 with a single temperature of > 38.3°C 


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(101°F) or a sustained temperature of ≥ 38°C (100.4°F) for > 1 hour. 
o Grade 4 is defined as ANC < 1000/mm3 with a single temperature of > 38.3°C 
(101°F) or a sustained temperature of ≥ 38 degrees C (100.4° F) for more > 1 hour, 
with life-threatening consequences and urgent intervention indicated 
• Thrombocytopenia < 25,000/mm3 if associated with: 
o A bleeding event which does not result in hemodynamic instability but requires an 
elective platelet transfusion, or 
o A life-threatening bleeding event which results in urgent intervention and admission 
to an Intensive Care Unit 
o Prolonged delay (> 14 days) in initiating Cycle 2 due to treatment-related toxicity 
• Missing > 10 % of carboplatin or paclitaxel doses as a result of AE(s) during a cycle 
• Grade 5 toxicity 
 
5.3. 
Pre-medication   
Pembrolizumab does not require any pre-medications unless indicated for an infusion reaction 
(section 6.1.3 and Table 4). 
Paclitaxel will be administered as a 3-hour infusion on this study. For all courses where paclitaxel 
is to be administered, it is recommended that a preparative regimen be employed to reduce the risk 
associated with hypersensitivity reactions. This regimen should include dexamethasone (either IV 
or PO), antihistamine H1 (such as diphenhydramine), and antihistamine H2 (such as cimetidine, 
ranitidine, or famotidine).  Institutional standards should be followed for hydration and pre-
medications.   
Carboplatin does not require any pre-medications. 
5.4. 
 Drug Administration 
All subjects will be treated in cycles lasting 21 days (3 weeks).  The drugs being used in this study 
include pembrolizumab, paclitaxel, and carboplatin.  Pembrolizumab will be administered first, 
followed sequentially by paclitaxel and carboplatin. 
 
Table 1: Drug dosing in the absence of prior therapy 
Drug 
Administration 
sequence 
Dose 
Frequency of 
administration 
Route of 
administration 
Number 
of cycles 
Pembrolizumab 
1st 
200mg 
Day 1 
Every 21 days 
IV 
6 
Paclitaxel 
2nd 
175mg/m2 
Day 1 
Every 21 days 
IV 
Carboplatin 
3rd 
AUC 6 
Day 1 
Every 21 days 
IV 
 
NOTE:  Infusions may be given ±3 days for reasons such as observed holidays, inclement 
weather, scheduling conflicts, etc. This should be clearly documented in the subject’s chart and 
case report forms.  
 


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5.4.1.  Dosing and Route of Administration 
 
5.4.1.1. 
Pembrolizumab 
Pembrolizumab 200 mg will be administered as a 30-minute intravenous (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 will be administered prior to other chemotherapy agents. 
 
Please refer to the separate Pharmacy Manual for specific instructions regarding the preparation of 
the pembrolizumab infusion fluid and administration of infusion solution. 
 
5.4.1.2. 
Paclitaxel 
Paclitaxel will be dosed at 175mg/m2 and be administered as a 3-hour continuous IV infusion. 
Paclitaxel dose should be completely administered before initiating carboplatin dose.  A window 
of -5 minutes and +10 minutes is permitted (i.e., infusion time is 3 hours: -5 min/+10 min).   
 
5.4.1.3. 
Carboplatin 
Carboplatin will be dosed at an AUC of 6 and given as an IV infusion according to institutional 
standards. A window of -5 minutes and +10 minutes is permitted. 
 
5.4.1.4. 
Dosing in Subjects with Prior Radiotherapy/Platinum-based Chemotherapy 
Subjects must initiate paclitaxel and carboplatin at a reduced dose if they have had: 
• prior external radiotherapy involving the whole pelvis or abdomen or over 50% of their 
spine,  
• prior platinum-based chemotherapy for this, or any other cancer (see below and Section 
6.1.1.).  
The subsequent doses of paclitaxel and carboplatin may be escalated (to dosing given in Table 1 
above), provided these subjects do not exhibit hematologic or non-hematologic toxicity > Grade 1, 
except alopecia. 
 
Table 2: Drug Dosing in subjects with prior radiotherapy involving the whole pelvis or 
abdomen or over 50% of their spine or prior platinum-based chemotherapy 
Drug 
Administration 
sequence 
Dose 
Frequency of 
administration 
Route of 
administration 
Number 
of cycles 
Pembrolizumab 
1st 
200mg 
Day 1 
Every 21 days 
IV 
6 
Paclitaxel 
2nd 
135mg/m2 
Day 1 
Every 21 days 
IV 
Carboplatin 
3rd 
AUC 5 
Day 1 
Every 21 days 
IV 
NOTE:  Infusions may be given ±3 days for reasons such as observed holidays, inclement 
weather, scheduling conflicts, etc. It should be clearly documented in subject’s chart and case 
report forms.  
 


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5.4.1.5. 
Dose Calculations 
The body surface area and drug dose should be recalculated only if the subject’s weight changes 
by ≥ 10% during the course of the study.  
 
Body Surface Area (BSA)  
BSA calculations will be used for dosing of paclitaxel. BSA should be calculated on Day 1 of each 
cycle based on the subject’s current height and weight using the DuBois formula. 
 
Area Under the Curve (AUC)  
Dosing of carboplatin will be calculated using the Calvert formula, using the target AUC and 
glomerular filtration rate (GFR) on Day 1 of each cycle. This formula is as follows: mg = AUC x 
(GFR +25). GFR should be calculated using the Cockcroft & Gault method using the subject’s 
actual body weight. For the dosing calculation, the maximum GFR should be capped at 125 
mL/min.   
 
5.4.2.  Missed doses 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, subject vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the sponsor-investigator in collaboration with the 
BTCRC AHQ project manager. The reason for interruption should be documented in the subject’s 
study record. 
 
5.5. 
Supportive Care 
 
5.5.1. Antiemetics 
Carboplatin, paclitaxel, and pembrolizumab: 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.   
 
Anti-emetic prophylaxis should follow pembrolizumab infusion, but otherwise timing and rate of 
administration are per institutional standard. Suggested supportive care measures for the 
management of adverse events with potential immunologic etiology are outlined below (see 
Section 6).   
5.6. 
Concurrent Therapy 
5.6.1. Concomitant Medications/Vaccinations (allowed and prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this with 
the BTCRC AHQ project manager.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject’s primary physician.  


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5.6.2. Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 11.3. 
5.6.3. Prohibited Concomitant Medications and Therapies 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Radiation therapy 
• Systemic glucocorticoids for any purpose other than to treat symptoms from an event of 
clinical interest of suspected immunologic etiology or as premedication for paclitaxel or 
imaging studies.  The use of physiologic doses of corticosteroids for other indications may 
be approved after consultation with the Sponsor-investigator 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive 
other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications that are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
6. DOSE MODIFICATIONS  
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4 will be used to 
grade adverse events.  These can be located on the CTEP website at http://ctep.cancer.gov. 
 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in the Study 
Calendar and Evaluations section. 


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Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse 
events requiring protocol therapy interruption or discontinuation at each study visit for the 
duration of their participation in the study.   
 
6.1. 
Dose Modifications 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These immune-related AEs (irAEs) may occur shortly after 
the first dose or several months after the last dose of pembrolizumab treatment and may affect 
more than on body system simultaneously. Therefore, early recognition and initiation of treatment 
is critical to reduce complications.  Based on existing clinical study data, most irAEs were 
reversible and could be managed with interruptions of pembrolizumab, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation to 
confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity of irAEs, 
withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab are 
provided in the Table 5 below. 
6.1.1. Dose Levels and Toxicity Management 
Table 3 should be used for all dosing adjustments based on the toxicities described in this section.  
There will be no dose escalations except those specified for subjects with prior radiotherapy/ 
platinum-based chemotherapy (in Section 5.4.1.4). 
 
Table 3: Dose levels for carboplatin, paclitaxel, pembrolizumab 
Dose level 
Carboplatin 
Paclitaxel 
Pembrolizumab 
Starting dose     
(no prior therapy) 
AUC 6 
175 mg/m2 
200 mg 
Starting dose    
(for prior therapy) 
AUC 5 
135 mg/m2 
200 mg 
First dose 
reduction 
AUC 5 
(AUC 4, prior therapy) 
135 mg/m2 
(110 mg/m2, prior therapy) 
See Table 5 
Second dose 
reduction 
 AUC 4 
(Discontinue, prior 
therapy) 
110 mg/m2  
(Discontinue, prior 
therapy) 
See Table 5 
Discontinuation 
Toxicity resulting in dose 
delay >21 days 
Toxicity resulting in dose 
delay >21 days 
See Table 5 
 
 
 


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6.1.3. Dose Modifications for Treatment Related Hematological Toxicity: 
Treatment modifications will be based on the absolute neutrophil count (ANC) rather than the 
total white cell count (WBC). Subsequent cycles of therapy will not begin until the ANC is > 
1,500/mm3 and the platelet count is > 100,000/mm3.  Therapy will be delayed on a week-by-week 
basis until these values are achieved.  
• Treatment modifications will be employed in a sequential manner using cycle delay and dose 
reduction. 
• There will be no dose modifications based on uncomplicated nadirs.  
• Prophylactic use of colony-stimulating factors including Granulocyte Colony-Stimulating 
Factor (G-CSF), pegylated G-CSF or Granulocyte Macrophage Colony-Stimulating Factor 
(GM CSF) should follow national standards (see ASCO guidelines). Prophylactic use of 
colony-stimulating factors in patients who have received prior pelvic radiotherapy is allowed, 
according to ASCO guidelines. 
• Subjects who experience dose-limiting neutropenia, defined as febrile neutropenia or Grade 4 
neutropenia lasting ≥7 days, or sepsis requiring intravenous antibiotics will receive a dose 
reduction of one level using the table above, without addition of G-CSF.  
• Carboplatin and/or paclitaxel will be discontinued in subjects who require a delay of > 21 days 
for toxicities associated with carboplatin and/or paclitaxel (See Table 3). Single-agent 
pembrolizumab may continue per protocol. 
• Subjects who experience grade 4 thrombocytopenia (<25,000/mm3) will have a dose reduction 
of carboplatin one level, without a change in paclitaxel dosage. Transfusion of platelets may be 
used if clinically indicated.  
• Transfusions may be utilized as clinically indicated for the treatment of anemia.  
6.1.4. Guidelines for 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 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
Table 4 Pembrolizumab 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 
Subject may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of 
pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 
mg po (or equivalent 


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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
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 pembrolizumab 
administration. 
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. 
**In cases of anaphylaxis, epinephrine should be used 
immediately. 
Subject is permanently discontinued from further 
pembrolizumab administration. 
No subsequent dosing 
An appropriate resuscitation plan must be in place and a physician readily available during drug administration. 
6.1.5. Dose Modifications for Other Treatment-Related Non-Hematological Toxicity 
6.1.5.1. 
Paclitaxel Hypersensitivity Reaction 
If hypersensitivity reactions to paclitaxel or its vehicle (Cremophor) occur, it will usually be 
during the first few minutes of infusion. Appropriate symptomatic therapy should be given. 
Continued treatment may be considered if the reaction is not life threatening; however, subjects 
must be cautioned about potential recurrences of the reaction. Should the subject decide to 
continue with treatment, it is preferable that this be done on the same day of the occurrence. A 
suggested procedure would be to administer the drug first with 1 cc of the original IV solution 
diluted in 100 ml over one hour, then 5 cc in 100 ml over one hour, then 10 cc in 100 ml over one 
hour, and finally, the original solution at the original speed.  Subjects who elect not to have 
continued treatment with paclitaxel after experiencing a hypersensitivity reaction may continue on 
protocol therapy with pembrolizumab and carboplatin only. 
 


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6.1.5.2. 
Renal Toxicity 
If creatinine rises to > 2.0 mg/dL, a calculated creatinine clearance (CalCcr) should be obtained 
(calculated per institutional standard). If CalCcr is less than 50 cc/min, hold treatment and check 
weekly CalCcr.  Resume therapy when CalCcr is ≥50 cc/min. Carboplatin may be resumed at one 
dose level lower (See Table 3) once the CalCcr returns to ≥ 50 cc/min or returns to Grade 1 toxicity 
level.  If CalCcr is < 50 cc/min or serum creatinine is >2 mg/dL after treatment has been held for 2 
weeks, carboplatin will be discontinued and the BTCRC AHQ project manager notified. Paclitaxel 
and pembrolizumab can be continued, based on discussion with the Sponsor Investigator. 
 
6.1.5.3. 
Myalgias 
Myalgias in the several days following paclitaxel treatment may be severe, and should receive 
aggressive symptomatic treatment, including narcotics or steroids as required. They are not, 
however, an indication for dose reduction.  
 
6.1.5.4. 
Neurologic Toxicity 
Grade 2 or greater peripheral neuropathy requires discontinuation of protocol therapy until 
symptoms resolve to ≤ Grade 1. When treatment resumes, the carboplatin dose should be reduced 
one level and the paclitaxel should be reduced a level (See Table 3). Discontinue protocol regimen 
in subjects with recurrent Grade 3 or any Grade 4 neurologic toxicity.   
 
6.1.5.5. 
Hepatic Toxicity 
Hepatic function labs should be assessed on Day 1 of each cycle.  
See specific recommendations for immune-related hepatic toxicity in section 6.1.4.8 Immune- 
Related Adverse Events (irAE).  
Bilirubin must return to within normal limits prior to further therapy.  
 
6.1.5.6. 
Other Toxicity 
For any Grade 3 or 4 toxicity not mentioned above, protocol treatment should usually be withheld 
until subjects recover completely or to Grade 1 status. The next dose of the agent believed 
responsible will be given at a one dose level reduction. In general, any Grade 3 or 4 toxicity not 
mentioned above should be discussed with the BTCRC AHQ project manager in collaboration 
with sponsor-investigator. Subjects whose treatment is delayed > 21 days because of toxicity 
attributable to carboplatin and/or paclitaxel, should discontinue carboplatin and/or paclitaxel (See 
Table 3). Single-agent pembrolizumab may continue per protocol. 
 
6.1.5.7. 
Dose Modification Specifically For Pembrolizumab 
If a dose of pembrolizumab is withheld for toxicity, subjects may resume dosing with 
pembrolizumab if that is appropriate at their next scheduled appointment or when toxicity has 
improved as described below in Table 5: Dose Modification and Toxicity Management Guidelines 
for Immune-Related Adverse Events Associated with Pembrolizumab   


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Table 5: Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events Associated with 
Pembrolizumab 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot 
be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should 
be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
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). 
• 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. 
Grade 4 
Permanently discontinue 
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 


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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 
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).   
 


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If toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, pembrolizumab 
should be discontinued after consultation with the BTCRC project manager and the sponsor-
investigator. With site investigator and sponsor-investigator agreement, subjects with a laboratory 
AE still at Grade 2 after 12 weeks may continue treatment in the trial only if asymptomatic and 
controlled. If a subject has more than 3 delays in pembrolizumab dosing due to other toxicities 
specific to this medication, they will be discontinued from pembrolizumab. 
 
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of pembrolizumab should be discontinued from pembrolizumab.  
 
Subjects who permanently discontinue pembrolizumab due to toxicity but who have not 
progressed may remain on chemotherapy per physician discretion until progression, intolerable 
toxicity or completion of six cycles of carboplatin and paclitaxel per protocol treatment. 
 
6.1.5.8. 
Immune-Related Adverse Events (irAE) 
Where appropriate, guidelines include the use of oral or intravenous treatment with corticosteroids 
as well as additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids. Note that several courses of steroid tapering may be necessary as symptoms may 
worsen when the steroid dose is decreased.  For each disorder, attempts should be made to rule out 
other causes such as metastatic disease or bacterial or viral infection, which might require 
additional supportive care. The treatment guidelines are intended to be applied when the 
investigator determines the event to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance.  
 
It may be necessary to perform diagnostic procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
 
6.1.5.9. 
Anti-infective  
Subjects with a documented infectious complication should receive oral or IV antibiotics or other 
anti-infective agents as considered appropriate by the treating investigator for a given infectious 
condition, according to standard institutional practice.  


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7. STUDY CALENDAR & EVALUATIONS 
Study Day 
Cycle= 21 days 
Screen 
Cycle 114 
Cycles 2-6 
30 Days Post 
Treatment 
Follow up 
-28 days 
Day 1 
Day 1 (±3) 
30 days (±7) 
after last dose 
Every 3 months 
for 18 mos (±14) 
REQUIRED ASSESSMENTS 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
Medical History1; Diagnosis and Staging2 
X 
 
 
 
 
Physical Exam  
X 
X 
X 
X 
X 
Vital Signs (as listed in 7.1.1) & ECOG PS 
X 
X 
X 
X 
X 
AEs, ECIs & Concomitant Medications 
X 
X 
X 
X 
X 
Neuropathy Assessment 
X 
X 
X 
X 
 
LABORATORY TESTS 
 
 
 
 
 
Complete Blood Cell Count (CBC) with diff and platelets 
-14 
X 
X 
X 
 
Comprehensive Metabolic Profile (CMP)3 
-14 
X 
X 
Basic profile3 
 
Mg, Phos, LDH 
-14 
X 
X 
 
 
PT/INR and aPTT 
-14 
X 
X 
 
 
Thyroid Function Panel (TSH, T3 and free T4)4 
-14 
 
Even cycles 
TSH only4 
 
Urinalysis5 
-14 
X 
X 
X 
 
DISEASE ASSESSMENT 
 
 
 
 
 
CT Chest  
X 
 
Pre Cycle 4 
X 
 
CT (MR) abdomen/pelvis6 
X 
 
Pre Cycle 4 
X 
X15 
CT or MRI brain, if indicated7 
[X] 
 
 
 
 
Biopsy of Recurrence8 
X 
 
 
 
 
TREATMENT EXPOSURE 
 
 
 
 
 
Pembrolizumab, Paclitaxel, Carboplatin 
 
X 
X 
 
 
CORRELATIVE STUDIES (SPECIMEN COLLECTION) 
 
 
 
 
 
Whole Blood for Circulating Immune Cell Analysis9- Mandatory 
 
X 
 
X 
 
Unstained Slides10-Mandatory (If Available) 
 
X 
 
 
 
Tissue Collection from Biopsy of Recurrence8 
X 
 
 
 
 
BANKING SAMPLES (SPECIMEN COLLECTION) 
 
 
 
 
 
Whole Blood11 
 
X 
 
 
 
Unstained Slides12 (If Available) 
 
X 
 
 
 
Serum and Plasma13 
 
X 
 
X 
 
FOLLOW UP 
 
 
 
 
 
Survival 
 
 
 
 
X 
 


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Footnotes: 
1: Medical History to include Lynch Syndrome status, if tested, demographics, tobacco and alcohol use, trial awareness question, prior treatments, radiation 
and surgical history.  
2: Diagnosis and Staging to include pathology report (with mismatch repair protein status, if available) and FIGO staging. 
3: Comprehensive Metabolic Profile will include: sodium, potassium, serum creatinine, calcium, albumin, ALT, AST, total bilirubin, alkaline phosphatase, 
total protein. Basic Metabolic Profile (calcium, sodium, potassium, creatinine) will be performed at 30-Day post-treatment visit. 
4: Thyroid Function panel should be obtained at screening, cycle 2, and every other cycle thereafter. Only TSH will be collected at 30-Day post-treatment visit. 
5: Urinalysis including blood, glucose, protein, specific gravity, reflex microscopy 
6: CT is preferred, MR is acceptable; see Section 8.2.1.  Regardless, the same type of scanner and image acquisition should be as consistent as possible 
throughout the study. 
7: Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis. 
8: Pathologic documentation of the recurrence (i.e., biopsy) will be performed per standard of care, at the treating physician’s discretion.  It is preferred that all 
subjects with recurrence undergo a biopsy for confirmation prior to initiating treatment; in this setting, a collection of 3 frozen tissue cores of the recurrence 
site is requested for correlative analysis. See Correlative Laboratory Manual (CLM) for collection, labeling, and shipping instructions. 
9: Whole blood for circulating immune cell analysis is to be collected at Pre-Treatment Cycle 1 Day 1 and at the 30-Day Post Treatment visit. See CLM for 
collection, labeling, and shipping instructions. 
10: Submission of unstained slides from the subject’s archived primary tumor block is mandatory (if available) for PD-L1 expressions and other biomarker 
analyses. See CLM for collection, labeling, and shipping instructions. 
11: Submission of whole blood for banking is to be collected at Pre-Treatment Cycle 1 Day 1. See CLM for collection, processing, labeling, and shipping 
instructions. 
12: Submission of unstained slides for banking from an archived FFPE tumor block is requested (if available). See CLM for collection, labeling, and shipping 
instructions. 
13: Submission of serum and plasma for banking are to be collected at Pre-Treatment Cycle 1 Day 1 and at the 30-Day Post Treatment visit. See CLM for 
collection, labeling, processing, and shipping instructions. 
14: Cycle 1 Day 1 lab testing need not be repeated if completed within 3 days of starting protocol therapy. 
15: Imaging of abdomen and pelvis to be repeated every 3 months for the first 12 months of follow-up. 
 


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7.1 
Screening 
 
7.1.1 Within 28 days prior to registration  
The screening procedures include the following assessments:  
• All eligibility requirements according to Section 3 must be satisfied.  
• Pathologic confirmation of advanced or recurrent endometrial adenocarcinoma diagnosis 
(see Section 3 Pathology Requirements for Enrollment and Calendar footnote #8)   
• Document relevant medical history including history of subject’s endometrial cancer and 
prior treatments, other past medical and surgical histories (including Lynch Syndrome 
status, if available), current medications, allergies, social history (including tobacco and 
alcohol use), and family history. Trial awareness question will also be collected.  
• Physical exam (includes height and weight), vital signs (temperature, blood pressure, heart 
rate, respiratory rate and pulse oximetry) and ECOG PS (Study Procedures Manual [SPM])  
• Sensory neuropathy assessment by history and graded by CTCAE v4. Subjects with pre-
existing peripheral neuropathy ≥ Grade 2 are excluded. 
• Screening scans including: CT Chest, CT Abdomen/Pelvis per institutional standards.  CT 
Abd/Pelvis is preferred, MR is acceptable. Regardless, the same type of scanner and image 
acquisition protocol should be as consistent as possible throughout the study (see Section 
8.2.1).  Note: Additional other imaging may be used at the discretion of the treating 
physician to assess other areas based on previously known disease or suspicion of new 
areas of involvement due to subject complaints. These baseline tests will be used to 
determine the location(s) of baseline disease that may be used for responses assessment 
(see Section 8 Criteria for Disease Evaluation) (within 28 days of registration).   
• Biopsy of recurrence: Pathologic documentation of the recurrence (i.e., biopsy) will be 
performed per standard of care, at the treating physician’s discretion.   
o Tissue Collection from Biopsy of Recurrence: If a subject with recurrence is 
undergoing a biopsy for clinical indications and is willing and able, a collection of 3 
frozen tissue cores of the recurrence site is requested for correlative analysis (see also 
Section 3.1.4). 
 
7.1.2 Within 14 days prior to registration 
• CBC with differential and platelets 
• Comprehensive Metabolic Panel (sodium, potassium, serum creatinine, calcium, albumin, 
ALT, AST, total bilirubin, alkaline phosphatase, total protein) 
• Magnesium, Phosphorus, LDH  
• Thyroid function test including; TSH, T3, and free T4  
• PT/INR, aPTT  
• Urinalysis (including blood, glucose, protein, specific gravity, reflex microscopy) 
 
7.2 
On Treatment 
The following assessments will be completed prior to chemotherapy treatment. Lab values will be 
recorded and checked for toxicity that would necessitate a dose reduction (most notably white 
blood count and differential to calculate absolute neutrophil count (ANC), platelet count, 
creatinine, AST, ALT, Alk Phos, and bilirubin). Grading of all toxicities will be according to 


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CTCAE v4.  Only if subject’s weight changes by ≥ 10% during the course of the study, the body 
surface area and drug dose should be recalculated (see Section 5.4.1.5 Dose Calculations).  
 
7.2.1 Cycle 1 Day 1: 
Note: Cycle 1 Day 1 lab testing need not be repeated if completed within 3 days of starting 
protocol therapy. 
• Physical exam (includes weight), vital signs (temperature, blood pressure, heart rate, 
respiratory rate, and pulse oximetry) and ECOG Performance Status   
• Sensory neuropathy assessment. 
• AE assessment including ECIs and concomitant medications   
• CBC with differential and platelet count   
• Comprehensive Metabolic Panel (including sodium, potassium, serum creatinine, calcium, 
albumin, ALT, AST, total bilirubin, alkaline phosphatase, total protein) 
• Magnesium, Phosphorus, Lactate dehydrogenase (LDH) 
• PT/INR and aPTT 
• Urinalysis (including blood, glucose, protein, specific gravity, reflex microscopy) 
• Pembrolizumab, Paclitaxel, and Carboplatin administration (IV) 
• Collect unstained slides from an archived primary tumor block. Refer to the Correlative 
Laboratory Manual (CLM) for the amount of tissue required to be deemed adequate.  Note: 
if an adequate amount of tissue is unavailable, a pre-treatment biopsy of recurrent disease 
is preferred but not mandatory.    
• Correlative and Banking samples. See CLM for specific instructions. 
• Pembrolizumab, Paclitaxel, and Carboplatin administration (IV) 
 
7.2.2 Cycles 2-6 Day 1 (±3 days): 
• Physical exam (includes weight), vital signs (temperature, blood pressure, heart rate, 
respiratory rate and pulse oximetry) and ECOG Performance Status   
• Sensory neuropathy assessment. 
• AE assessment including ECIs and concomitant medications   
• CBC with differential and platelet count   
• Comprehensive chemistry panel (including sodium, potassium, serum creatinine, calcium, 
albumin, ALT, AST, total bilirubin, alkaline phosphatase, total protein 
• Magnesium, Phosphorus, Lactate dehydrogenase (LDH) 
• PT/INR and aPTT 
• Thyroid function test including; TSH, T3 and free T4 (Cycle 2 and every other cycle 
thereafter)  
• Urinalysis (including blood, glucose, protein, specific gravity, reflex microscopy) 
• Pembrolizumab, Paclitaxel, and Carboplatin administration (IV) 
 
7.2.3 Prior to Cycle 4 
• A CT of the chest with IV contrast and CT Abd/Pelvis with PO and IV contrast. CT 
Abd/Pelvis is preferred, MR is acceptable. Regardless, the same type of scanner and image 
acquisition should be as consistent as possible throughout the study (see Section 8.2.1).  
Note: Repeat all other imaging studies at these same intervals if disease was identified at 
baseline.  Additional imaging studies may be obtained at these intervals or at any time as 


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directed in Section 8.3, if clinically indicated and at investigator discretion. Results from 
all imaging, whether at the scheduled interval or otherwise, should be recorded and used 
for response assessments (see Section 8.3 Response Assessment)   
 
7.3 
Off Treatment 
 
7.3.1 Protocol therapy discontinuation: 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any adverse 
events that are present at the time of discontinuation/withdrawal should be followed in accordance 
with the safety requirements outlined in Section 11 - Adverse Events.   
 
A subject will be discontinued from the protocol therapy under the following circumstances: 
• 
If there is evidence of disease progression (per immune related RECIST [irRECIST]) 
• 
If the treating physician thinks a change of therapy would be in the best interest of the 
subject 
• 
If the subject requests to discontinue protocol therapy 
• 
If the protocol therapy exhibits unacceptable toxicity 
• 
If carboplatin and/or paclitaxel is interrupted for > 21 days due to a treatment-related 
adverse event attributable to carboplatin and/or paclitaxel, discontinue carboplatin and/or 
paclitaxel. Single-agent pembrolizumab may continue per protocol.  
• 
If pembrolizumab therapy is interrupted for >12 weeks due to a treatment-related adverse 
event attributable to pembrolizumab, discontinue pembrolizumab but continue 
carboplatin/paclitaxel per protocol. 
 
7.4 
End of Treatment Assessment/Safety Follow-up: 30 days (±7 days) after final dose of 
protocol therapy  
The Safety Follow-Up Visit should be conducted within 30 days of the last dose of trial treatment 
or before the initiation of a new anti-cancer treatment, whichever comes first.  Once new anti-
cancer therapy has been initiated the subject will move into survival follow-up.  All AEs that 
occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with an AE of Grade > 1 
will be followed until the resolution of the AE to Grade 0-1 or until the beginning of a new anti-
neoplastic therapy, whichever occurs first.  SAEs that occur within 90 days of the end of treatment 
or before initiation of a new anti-cancer treatment should also be followed and recorded.  
• Physical exam (includes weight), vital signs (temperature, blood pressure, heart rate, 
respiratory rate and pulse oximetry) and ECOG Performance Status  
• Sensory neuropathy assessment. 
• AE assessment including ECIs and concomitant medications  
• CBC with differential and platelet count   
• Basic Metabolic Profile (calcium, sodium, potassium, creatinine) 
• TSH 
• Urinalysis (including blood, glucose, protein, specific gravity, reflex microscopy) 
• A CT of the chest with IV contrast and CT Abd/Pelvis with PO and IV contrast.  CT 
Abd/Pelvis is preferred, MR is acceptable; regardless, the same type of scanner and image 
acquisition protocol should be followed as closely as possible throughout the study (see 
Section 8.2.1).  Note: Additional imaging studies may be obtained if clinically indicated 


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and at investigator discretion. Results from all imaging should be recorded and used for 
response assessments (see Section 8 Response Assessment).  
• Correlative and Banking samples. See CLM for specific instructions. 
 
7.5 
Follow-up 
• Physical exam (includes weight), vital signs (temperature, blood pressure, heart rate, 
respiratory rate and pulse oximetry) and ECOG Performance Status  
• AE assessment including ECIs and concomitant medications  
• Repeat imaging if clinically indicated and at the discretion of the investigator  
Subjects who discontinue treatment without evidence of progression will have repeat imaging 
every 3 months for the first year off treatment.  Follow-up for survival every 3 months thereafter 
until completion of the study period.  
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted by telephone every 12 
weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.  
Every effort should be made to collect information regarding disease status until the start of new 
anti-neoplastic therapy, disease progression, or death.  Information regarding post-study anti-
neoplastic treatment will be collected if new treatment is initiated. 
 
Subjects can stop study participation at any time.  However, if they decide to stop, subjects will 
continue to be followed every 3 months for 18 months from the time of treatment discontinuation 
(if they have not withdrawn consent).   
 
8. 
CRITERIA FOR DISEASE EVALUATION 
In this study, disease parameters (section 8.1) and methods for tumor evaluation (Section 8.2)—
but not evaluation of tumor response—will be in accordance with the Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline Version 1.1. 
RECIST 1.1 response criteria are primarily designed to evaluate the early effects of cytotoxic 
agents, and depend on tumor shrinkage to demonstrate biologic activity.  However, clinical 
evidence of tumor responses seen with immunotherapeutic agents such as pembrolizumab can take 
longer to achieve, and may occur after a period of disease stabilization or following an initial 
increase in tumor burden.  In light of the limitations of utilizing RECIST 1.1 to evaluate 
immunomodulatory agents, immune-related response criteria (irRC) have been proposed to 
systematically detect the novel response patterns observed with immunologic agents26. Therefore, 
in this study, tumor response will be evaluated with an irRC modification of RECIST v1.1. (See 
section 8.3).  
 
8.1 Definitions Associated with Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.127 
8.1.1 Measurable disease: The presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion less than 2 cm, its neoplastic nature should be 
confirmed by cytology/histology.  


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8.1.1.1 Measurable lesions: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
8.1.1.2 Non-measurable lesions: All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI) are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
 
8.1.1.3 Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
8.1.1.4 Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters.  If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
 
8.1.1.5 Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
 


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8.2 Methods of Measurement 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 28 days before the beginning of the treatment. 
 
Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical exam. The same imaging 
modality must be used throughout the study to measure disease. 
 
8.2.1 
CT and MRI: 
CT and MRI are the best currently available and most reproducible methods for measuring target 
lesions. This guideline has defined measurability of lesions on CT scan based on the assumption 
that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  MRI is also acceptable 
in certain situations (e.g., for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI 
is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT.  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data that may bias an investigator if it is not routinely or serially performed.   
 
8.2.2 
Chest X-Ray: 
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by an aerated lung (CT is preferable).   
 
8.2.3 
Clinical Examination: 
Clinically detected lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes).  For skin lesions, documentation by color photography, 
including a ruler to estimate size of the lesion, is recommended.  Photographs should be retained 
at the institution. 
 


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8.2.4 
Cytology and Histology: 
Cytologic and histologic techniques can be used to differentiate between complete and partial 
responses in rare cases (e.g., after treatment to differentiate residual benign lesions and residual 
malignant lesions in germ cell tumors).  Cytologic confirmation of the neoplastic nature of any 
effusion that appears or worsens during treatment is required when the measurable tumor has met 
response or stable disease criteria. 
 
8.3 Response Assessment: Immune-Related RECIST 
As previously noted, this study will assess tumor response with an immune-related modification of 
RECIST 1.1 (see Table 6 below).  Determination of response via irRECIST should take into 
consideration all target and non-target lesions.  
A key distinction between standard RECIST 1.1 criteria and immune-related response criteria is 
that irRECIST requires early evidence of progressive disease (i.e., a determination of irPD ≤ 12 
weeks after starting study treatment) be confirmed by repeat, consecutive imaging ≥ 4 weeks after 
the initial documentation in the absence of rapid clinical deterioration.  During this interim ≥ 4-
week period, subjects should continue to be followed per protocol, including continued dosing of 
the study drug(s).  
Additionally, the immune-mediated responses expected from pembrolizumab require activation of 
the immune system prior to the observation of clinical responses, and such immune activation may 
take weeks to months to be clinically evident. Some subjects with advanced cancer may have 
objective volume increase of tumor lesions within 12 weeks following the start of dosing on study. 
Such subjects may not have had sufficient time to develop the required immune activation or, in 
some subjects, tumor volume increases may represent infiltration of lymphocytes into the original 
tumor. In traditional oncology studies, such increases in tumor volume during the first 12 weeks of 
the study would constitute progressive disease and lead to discontinuation of study treatment and 
of imaging to detect response, thus disregarding the potential for subsequent immune- mediated 
clinical response. Therefore, in this study, the first imaging assessment will be performed at Week 
9 (prior to Cycle 4).  Subsequent imaging will be performed upon completion of the study and 
every 12 weeks thereafter for the first year. 
 
 


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Table 6: Tumor Response Evaluation: Comparison between RECIST 1.1 and irRECIST 
Criteria 
RECIST 1.1 
irRECIST 
New measurable 
lesions (≥10 mm)  
Always represents PD  
Incorporated into tumor burden  
New non-measurable 
lesions (< 10 mm)  
Always represents PD  
Does not define progression but 
precludes irCR   
Non-Target lesions  
Changes contribute to defining BOR 
of CR, PR, SD, and PD  
Contribute to defining irCR 
(complete disappearance required)  
CR  
Disappearance of all lesions  
Disappearance of all lesions  
PR  
≥ 30% decrease in the sum of the 
longest diameter of all target lesions 
compared with baseline, in absence of 
new lesions or unequivocal 
progression of non-target lesions  
≥ 30% decrease in tumor burden 
compared with baseline  
SD  
Neither sufficient shrinkage to qualify 
for PR nor sufficient increase to 
qualify for PD, taking as reference the 
smallest sum diameters while on study 
Neither a 30% decrease in tumor 
burden compared with baseline nor a 
20% increase compared with nadir 
can be established   
PD  
At least 20% increase in sum of 
diameters of target lesions, taking as 
reference the smallest sum on study. 
In addition to the relative increase of 
20%, the sum must also demonstrate 
an absolute increase of at least 5mm. 
The appearance of one or more new 
lesions is also considered progression.  
At least 20% increase in tumor 
burden compared with nadir (at any 
single time point)*  
  
*Subjects with an initial finding of progressive disease (irPD) before or at the 12 week imaging 
assessment, but without rapid clinical deterioration, require confirmation of irPD with a second, 
consecutive scan obtained ≥ 4 weeks from the initiation documentation. Subjects will continue to 
receive study treatment until irPD is confirmed at this later time point. Best overall response 
(BOR) will therefore include responses occurring at any time before disease progression and 
after early progression (i.e., within the first 12 weeks of the study. 
 
8.3.1 Response in Measurable Lesions  
At baseline, the sum of the longest diameters (SumD) of all target lesions (up to 2 lesions per 
organ, up to total 5 lesions) is measured. At each subsequent tumor assessment (TA), the SumD of 
the target lesions and of new, measurable lesions (≥ 10 mm [lymph nodes ≥ 15 mm in shortest 
diameter]; up to 2 new lesions per organ, total 5 new lesions) are added together to provide the 
total measurable tumor burden (TMTB):  
TMTB = SumD target lesions + SumD new, measurable lesions  
Percentage changes in TMTB per assessment time-point describe the size and growth kinetics of 
both old and new, measurable lesions as they appear. At each TA, the response in target and new, 
measurable lesions is defined based on the change in TMTB (after ruling out irPD) as follows:  


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Response in Measurable Lesions 
Complete Response (irCR): 
Complete disappearance of all target and new, measurable 
lesions, with the exceptions of lymph nodes, which must 
decrease to < 10 mm in short axis. 
Partial Response (irPR): 
Decrease in TMTB ≥ 30% relative to baseline (see below). 
Stable Disease (irSD): 
Not meeting criteria for irCR or irPR, in absence of irPD. 
Progressive Disease (irPD): 
Increase in TMTB ≥ 20% relative to nadir. 
 
8.3.2 Response in Non-measurable Lesions  
At each TA, the presence of any new, non-measurable lesions is assessed. The presence of such 
lesions will rule out an overall response of irCR. An increase in the size or number of new, non-
measurable lesions does not necessarily imply an overall response of irPD; if these lesions become 
measurable (≥ 10 mm) at a subsequent TA, their measurement will at that point start to contribute 
to the TMTB.  
In addition, the response in non-target lesions is defined as follows:  
Response in Non-measurable Lesions 
Complete Response (irCR): 
Complete disappearance of all non-target lesions 
Stable Disease (irSD): 
Non-target lesions are stable 
Progressive Disease (irPD): 
Unequivocal increases in number or size of non-target lesions. 
To achieve unequivocal progression of non-target lesions, 
there must be an overall level of substantial worsening of non- 
target disease that is of a magnitude that the treating physician 
would feel it is important to change therapy. 
NOTE: Equivocal findings of progression of non-target lesions (e.g., small and uncertain new 
lesions; cystic changes or necrosis in existing lesions) should be considered irSD, and treatment 
may continue until the next scheduled assessment. 
 
8.3.3 Evaluation of Biomarkers:  Serum CA-125, if collected, must be within normal limits 
for a subject to be considered in complete clinical response.   
8.3.4 Overall Response (OR):   
The OR according to the irRC is derived from the responses in measurable lesions (based on 
TMTB) as well as the presence of any non-measurable lesions as follows:  
Overall Response 
Complete Response (irCR): 
Complete disappearance of all lesions (whether measurable 
or not); lymph nodes must decrease to < 10 mm in shortest 
dimension. Serum CA-125 within normal limits. 
Partial Response (irPR): 
Decrease in TMTB ≥ to 30% relative to baseline. 
Stable Disease (irSD): 
Not meeting criteria for irCR or irPR, in absence of irPD. 
Progressive Disease (irPD): 
Increase in TMTB ≥ 20% relative to nadir. 
 


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The immune-related best overall response (irBOR) is the best irRC OR over the study as a whole, 
recorded between the date of first dose until the last TA prior to subsequent therapy (including 
tumor resection surgery) for the individual subject in the study. As with the primary definitions of 
tumor response, early progression (i.e., irPD occurring prior to Week 12) will not preclude an 
irBOR of irCR, irPR or irSD resulting from the Week 12 assessment. An assessment of irPD at or 
after Week 12 will preclude a subsequent irBOR of irCR, irPR or irSD. However, any post-
progression clinical activity in subjects with irBOR of irPD may be summarized for exploratory 
purposes.    
Table 7: Best Overall Response (irBOR) 
Target Lesions 
Baseline (Index) and New 
Measurable Lesions 
Non-Target Lesions* 
irRC Overall 
Response 
Total Measurable Tumor Burden 
(TMTB) 
Baseline 
Lesions 
Unequivocal 
New Lesions 
irCR 
irCR 
No 
irCR 
irCR 
irSD 
No 
irPR 
irPR 
irCR or irSD 
No 
irPR 
irSD 
irCR or irSD 
No 
irSD 
irPD 
Any 
Yes or No 
irPD 
Any 
Unequivocal 
Progression 
Yes or No 
irPD 
Any 
Any 
Yes  
irPD 
*NOTE: Any increase in the size or number of non-measurable lesions does not necessarily 
imply an overall response of irPD. If these lesions become measurable (≥ 10 mm) at a 
subsequent TA, their measurement will at that point start to contribute to the TMTB. To 
achieve unequivocal progression of non-target lesions, there must be an overall level of 
substantial worsening in non-target disease that is of a magnitude that the treating physician 
would feel it is important to change therapy. Equivocal findings of progression of non-target 
lesions (e.g., small and uncertain new lesions; cystic changes or necrosis in existing lesions) 
should be considered irSD, and treatment may continue until the next schedule assessment. 
 
8.3.5 Objective Response Rate 
Objective response rate is defined as the proportion of subjects with a partial response or complete 
response according to immune-related RECIST criteria. 
8.3.6 Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for irCR or irPR (whichever is first recorded) until the first date that 
progressive disease (irPD) is objectively documented (taking as reference for progressive disease 
the smallest measurements recorded [nadir] since the treatment started).  
The duration of overall irCR is measured from the time measurement criteria are first met for irCR 


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until the first date that irPD is objectively documented.  
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for irPD are met.  
8.3.7 Progression-Free Survival 
Progression-Free Survival: defined as the duration of time from registration to time of progression 
(irPD) or death, whichever occurs first. 
8.3.8 Survival 
Survival: defined as the duration of time from registration to time of death due to any cause, or the 
date the subject was last confirmed to be alive. 
 
9. BIOLOGICAL CORRELATIVES  
9.1 
Objective: To evaluate potential biomarkers or prognostic factors for those who may 
respond to pembrolizumab 
 
Please refer to the Correlative Laboratory Manual for all sample collection, processing, labeling, 
and shipping instructions. 
 
9.1.1 Immunohistochemical evaluation of PD-L1 expression on formalin-fixed, paraffin-
embedded tissue section from primary tumor and/or fresh frozen biopsy of recurrent 
disease, if available 
• PD-L1 staining intensity (-, +/-, +) and percent of tumor positive (<50%, ≥50%) will be 
correlated with response rate. 
9.1.2 Immunohistochemical evaluation of tumor-infiltrating lymphocytes (CD8+), T regulatory 
lymphocytes (Treg, CD4+/Foxp3+) and myeloid derived suppressor cells ([MDSC] 
HLADRlow/-, CD11b+, CD14+) on formalin-fixed, paraffin-embedded tissue section from 
primary tumor and/or biopsy of recurrent disease, if available 
• Cell subset total/field will be correlated with response rate. 
9.1.3 Flow cytometric quantification of tumor-infiltrating lymphocytes (CD8+), T regulatory 
lymphocytes (Treg, CD4+/Foxp3+) and myeloid derived suppressor cells (HLADRlow/-, 
CD11b+, CD14+) on fresh frozen core biopsy of recurrent disease, if available 
• Cell subset total/field will be correlated with response rate. 
9.1.4 Characterization of circulating immune cell populations (TIM3+/PD-1+/CD8+, PD-1+/Treg) 
will be evaluated on samples collected prior the start of and upon completion of 
combination pembrolizumab/cytotoxic chemotherapy. 
• PD-1 Mean Fluorescence Intensity (MFI) on cell subset analyzed, percent of total 
lymphocytes (for each cell subset), and absolute number of cell subset will be 
correlated with response rate.  This analysis will be performed on pre-treatment and 
post-treatment blood sample. 
9.1.5 IFN- and CD107a expression in/on circulating CD8+ T cells will be measured to 
characterize effector function 
• Mean Fluorescence Intensity (MFI) of IFN- and CD107a expression on cell subset 
analyzed, percent of total lymphocytes (for each cell subset), and absolute number of 
cell subset will be correlated with response rate. This analysis will be performed on 


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pre-treatment and post-treatment blood sample. 
9.1.6 Determination of the mutational landscape of endometrial cancer and its influence in the 
response to pembrolizumab.   
• Exome sequencing and targeted next generation sequencing, targeting all exons of 
approximately 300 cancer related genes will be performed from FFPE tissue from 
participants’ tumors.  
 
9.2 
Source of Study Specimens  
9.2.1 Unstained slides from an archived formalin-fixed, paraffin-embedded primary 
tumor block are required (if available) for each subject enrolled.  If unavailable, 
biopsy of recurrence is required for correlative analysis. 
9.2.2 If a biopsy is performed for histologic documentation of recurrence, 3 frozen cores 
will be requested and shipped to laboratory for analysis. 
9.2.3 Whole blood will be collected at pre-treatment Cycle 1 Day 1 and at the 30-Day 
Post Treatment visit as noted in section 7.   
 
9.3 
Banking Samples for Future Studies 
Subject consent will be obtained for additional samples collected for future Big Ten Cancer 
Research Consortium studies. Hoosier Cancer Research Network, as Administrative Headquarters 
for the BTCRC, will manage the banked samples. Samples will be banked indefinitely in the 
Hoosier Cancer Research Network Biorepository.  
 
This includes: 
• 
Whole blood 
o 
Whole blood will be collected prior to treatment on Cycle 1 Day 1.  
• 
Pre- and Post-treatment plasma 
o 
Whole blood for plasma will be collected prior to treatment on Cycle 1 Day 1 and at 
the 30 Day Post Treatment Visit.  
• 
Pre- and Post-treatment serum 
o 
Whole blood for serum will be collected prior to treatment on Cycle 1 Day 1 and at 
the 30 Day Post Treatment Visit. 
• 
Unstained slides (If Available) 
o 
Unstained slides will be obtained from the subject’s archived formalin fixed paraffin 
embedded tumor block.  
 
Please refer to the CLM for all sample collection, processing, labeling, and shipping instructions. 
 
9.4 
Pathology Requirements for Study Specimens 
A pathology report confirming the diagnosis of advanced stage endometrial cancer must be 
available at the time of enrollment on study.  For subjects with advanced or metastatic disease at 
the time of diagnosis, the original pathology from this diagnosis is sufficient.  For subjects with 
early stage disease who later developed metastatic disease, biopsy confirmation of the metastatic 
disease is required.  Additionally, pathologic documentation of the recurrence is required if there 
is only a single site of disease on imaging and that site is less than 2 cm.  It is preferred that all 
subjects with recurrence undergo a biopsy for confirmation; in this setting, an optional collection 
of 3 frozen tissue cores of the recurrence site is requested for correlative analysis.  All 


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surgeries/biopsies done at referring institutions should be reviewed and confirmed by a pathologist 
at the local study site. 
 
10. DRUG INFORMATION  
 
10.1. Pembrolizumab 
 
10.1.1. Other Names 
Keytruda® (Pembrolizumab; MK-3475 [Anti-PD-1 Antibody MK-3475]) 
 
10.1.2. Chemical Name and Properties 
Humanized X PD-1_mAb (H409A11) IgG4 
 
10.1.3. Availability and Distribution 
Merck will supply pembrolizumab directly to sites at no charge to subjects participating in this 
clinical trial.  
The site 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. 
 
10.1.4. Storage 
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. 
 
10.1.5. Preparation and Administration 
Please refer to the Pharmacy Manual for a comprehensive description of pembrolizumab 
preparation. 
 
Pembrolizumab is provided as a white to off-white lyophilized powder (50 mg/vial) or as a liquid 
solution (100 mg/vial) in Type I glass vials intended for single use only. Pembrolizumab Powder 
for Solution for Infusion, 50 mg/vial, is reconstituted with sterile water for injection prior to use. 
The drug product is stored as a stable lyophilized powder or liquid solution under refrigerated 
conditions (2°C - 8°C). 
 
The product after reconstitution with sterile water for injection and the liquid drug product is a 
clear to opalescent solution, essentially free of visible particles. The reconstituted product and 
liquid product are intended for IV administration. The reconstituted drug product solution or the 
liquid drug product can be further diluted with normal saline or 5% dextrose in the concentration 
range of 1 to 10 mg/mL in intravenous (IV) containers made of polyvinyl chloride (PVC) or non-
PVC material. Reconstituted vials should be immediately used to prepare the infusion solution in 
the IV bag and the infusion solution should be immediately administered. Diluted pembrolizumab 
solutions may be stored at room temperature for a cumulative time of up to 4 hours. This includes 


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room temperature storage of admixture solutions in the IV bags and the duration of infusion. In 
addition, IV bags may be stored at 2 to 8 °C for up to a cumulative time of 20 hours.  This 
recommendation is based on up to 24 hours of room temperature and up to 24 hours of refrigerated 
stability data of diluted pembrolizumab solutions in the IV bags. 
 
10.1.6. Side Effects 
Please refer to the current version of the Investigator’s Brochure for a complete list of adverse 
events. 
 
Pembrolizumab is generally well tolerated and demonstrates a favorable safety profile in 
comparison to chemotherapy. Pembrolizumab is an immunomodulatory agent, and based on this 
mechanism of action, immune mediated adverse events are of primary concern. Important 
identified risks for pembrolizumab are of an immune mediate nature, including: pneumonitis, 
colitis, hepatitis, nephritis, endocrinopathies that include hypophysitis (including hypopituitarism 
and secondary adrenal insufficiency), thyroid disorder (hypothyroidism, hyperthyroidism), Type I 
diabetes mellitus, uveitis, myositis, Guillain-Barre syndrome, pancreatitis, myocarditis, severe skin 
reactions including cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis 
(TEN), some with fatal outcome; and “solid organ transplant rejection following pembrolizumab 
treatment in donor organ recipients” (risk applicable to post-marketing setting only, as such 
patients are currently excluded from Merck clinical trials with pembrolizumab). 
 
The majority of immune-mediated adverse events were mild to moderate in severity, manageable 
with appropriate care, and rarely required discontinuation of therapy.  
 
Since the last IB (v13) update, the risk profile for pembrolizumab also includes 2 important 
potential risks – i.e. myasthenic syndrome and increased risk of severe complications (such as 
early severe graft versus host disease and veno-occlusive disease) of allogeneic transplant in 
patients with hematologic malignancies who have previously been treated with PD-1 inhibitors. 
 
Since the last IB (v13) update, Merck received additional information from the clinical trial and 
post-marketing environments, which resulted in the following changes to the risk profile for 
pembrolizumab: 
1. Two new important identified risks of “encephalitis” and “sarcoidosis”. 
2. Further characterization of the existing important identified risk of “Thyroid disorders 
(Hypothyroidism and Hyperthyroidism) to include “thyroiditis”. 
3. Elevation of “myasthenic syndrome” from an important potential risk to an important 
identified risk. 
4. Addition of 1 new potential risk of GVHD after pembrolizumab administration in patients 
with a history of allogeneic HSCT. 
 
Further details around frequency, reporting, and management of immune-related adverse events 
(irAEs) can be found in the current version of the Investigator’s Brochure. In addition to the 
previously noted identified risks, infusion-related reactions are a risk but are not considered 
immune mediated; these are also further described in the current IB. 
 
 
 


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10.2. Carboplatin 
 
10.2.1. Other Names 
CBDCA, Paraplatin®, JM-8, NSC-241240 
 
10.2.2. Classification 
Second-generation tetravalent organic platinum compound 
 
10.2.3. Formulation 
Carboplatin is available as a sterile lyophilized powder in single-dose vials containing 50 mg, 150 
mg, or 450 mg of carboplatin. Each vial contains equal parts by weight of carboplatin and 
mannitol. Commercial supplies of carboplatin will be used in this study. 
 
10.2.4. Preparation  
Carboplatin will be prepared according to the product label and institutional standards. See also 
‘Incompatibilities’ section below.  
 
10.2.5. Availability and Distribution 
Commercial supplies of carboplatin will be used in this study and billed to third party payers or 
the subject. 
 
10.2.6. Storage and Stability 
Intact vials are stored at room temperature protected from light. The reconstituted solution is 
stable for at least 24 hours. When further diluted in glass or polyvinyl plastic to a concentration of 
10mg/mL with normal saline or 5% dextrose carboplatin is stable for 8 hours at 25 degrees C. 
Stability with further dilution to 0.5mg/mL has been reported for up to 8 hours. Other stability 
data indicate that carboplatin is stable for up to 24 hours and may be refrigerated; however, the 
manufacturer recommends that reconstituted solutions be discarded after 8 hours due to the lack of 
preservative in drug formulation. 
 
10.2.7. Handling and Disposal 
Caution should be exercised in handling and preparing carboplatin injection. To minimize the risk 
of dermal exposure, always wear impervious gloves when handling vials containing carboplatin 
injection. If carboplatin injection contacts the skin, immediately wash the skin thoroughly with 
soap and water. If carboplatin injection contacts mucous membranes, the membranes should be 
flushed immediately and thoroughly with water.  
 
10.2.8. Incompatibilities 
Aluminum displaces platinum from the carboplatin molecule, resulting in the formation of a black 
precipitate and loss of potency. Carboplatin solutions should not be prepared or administered with 
needles, syringes, catheters, or IV administration sets containing aluminum parts that might be in 
contact with the drug. 
 
10.2.9. Side Effects 
Incidence rates of adverse events associated with carboplatin are provided in the product package 
insert. Some of the expected adverse events with carboplatin treatment are listed below. 


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Hematologic: Thrombocytopenia (dose limiting), neutropenia, leukopenia, anemia.  
GI: Nausea and vomiting (frequent but less severe than with cisplatin), treatable with appropriate 
antiemetic prophylaxis. Anorexia, diarrhea, and constipation have also been reported.  
Dermatologic: Rash, urticaria. Rarer reactions include alopecia, mucositis, and hypersensitivity 
reactions.  
Hepatic: Abnormal liver function tests, usually reversible with standard doses.  
Neurologic: Rarely peripheral neuropathy is seen. May be more common in subjects greater than 
65 years of age. May also be cumulative, especially in subjects with prior cisplatin treatment. 
Ototoxicity (rare).  
Renal: Elevations in serum creatinine, BUN; electrolyte loss (Mg, K, Na, Ca).  
Miscellaneous: Pain, asthenia, flu-like syndrome. 
 
10.2.10. 
Drug Interactions 
Concomitant myelosuppressive drugs or radiation therapy may potentiate the hematologic toxicity 
of carboplatin.  
 
Concomitant nephrotoxic drugs may potentiate the nephrotoxicity of carboplatin, particularly 
when carboplatin is given in high-dose chemotherapy regimens. 
 
10.3. Paclitaxel 
 
10.3.1. Other Names 
Taxol® 
 
10.3.2. Classification 
Antimicrotubule agent 
 
10.3.3. Mode of Action 
Promotes microtubule assembly and stabilizes tubulin polymers by preventing their 
depolarization, resulting in the formation of extremely stable and nonfunctional microtubules, and 
consequently inhibition of many cell functions. 
 
10.3.4. Availability and Distribution 
Commercial supplies of paclitaxel will be used in this study and billed to third party payers or the 
subject. 
 
10.3.5. Storage and Stability 
Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to 
protect from bright light. Freezing does not adversely affect the product. Solutions diluted to a 
concentration of 0.3 to 1.2 mg/ml are stable for up to 27 hours when stored at room temperature 
and normal room light. 
 
10.3.6. Preparation 
The concentrated solution must be diluted to a concentration of 0.3 - 1.2 mg/ml according to the 


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product label and institutional standards. Solutions exhibit a slight haze, common to all products 
containing non-ionic surfactants. Glass, polypropylene, or polyolefin containers and non-PVC-
containing (nitroglycerin) infusion sets should be used. A small number of fibers (within 
acceptable limits established by the USP) have been observed after dilution. Therefore, a 
hydrophilic 0.22 micron in-line filter should be used. Analyses of solutions filtered through IVEX-
2 and IVEX-HP (Abbott) 0.2 micron filters showed no appreciable loss of potency. 
 
Solutions exhibiting excessive particulate formation should not be used.  
 
10.3.7. Incompatibilities 
Avoid the use of PVC bags and infusion sets due to leaching of DEHP (plasticizer). Prior 
administration of cisplatin may increase myelosuppression because of reduced clearance of 
paclitaxel. Ketoconazole may inhibit paclitaxel metabolism, based on in vitro data. 
 
10.3.8. Side Effects 
1. Hematologic: Myelosuppression (neutropenia, leukopenia, thrombocytopenia, anemia).  
2. Hypersensitivity: Thought to be caused by the Cremophor vehicle. Minor symptoms include 
hypotension, flushing, chest pain, abdominal or extremity pain, skin reactions, pruritus, 
dyspnea, and tachycardia. More severe reactions include hypotension requiring treatment, 
dyspnea with bronchospasm, generalized urticaria, and angioedema. The majority (53%) of the 
reported reactions occurred within 2-3 minutes of initiation of treatment and 78% occurred 
within the first 10 minutes. Reactions usually occurred with the first and second doses.  
3. Cardiovascular: Atrial arrhythmia (sinus bradycardia [usually transient and asymptomatic], 
sinus tachycardia, and premature beats); significant events include syncope, hypotension, other 
rhythm abnormalities (including ventricular tachycardia, bigeminy, and complete heart block 
requiring pacemaker placement), and myocardial infarction. Hypertension (possibly related to 
concomitant medication -- Dexamethasone) may also occur. 
4. Neurologic: Sensory (taste changes); peripheral neuropathy; arthralgia and myalgia (dose-
related, more common when colony-stimulating factors are also administered); seizures; mood 
alterations; neuroencephalopathy; hepatic encephalopathy; motor neuropathy; and autonomic 
neuropathy (paralytic ileus and symptomatic hypotension).  
5. Dermatologic: Alopecia (universal, complete, and often sudden, between days 14-21); 
injection site reactions (erythema, induration, tenderness, skin discoloration); infiltration 
(phlebitis, cellulitis, ulceration, and necrosis, rare); radiation recall; and rash.  
6. Gastrointestinal: Nausea, vomiting, diarrhea, stomatitis, mucositis, pharyngitis, typhlitis 
(neutropenic enterocolitis), ischemic colitis, and pancreatitis.  
7. Hepatic: Increased AST, ALT, bilirubin, alkaline phosphatase; hepatic failure, and hepatic 
necrosis.  
8. Other: Fatigue, headache, light-headedness, myopathy, elevated serum creatinine, elevated 
serum triglycerides, and visual abnormalities (sensation of flashing lights, blurred vision). 
 
 
 


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11. ADVERSE EVENTS  
 
11.1. Definitions 
 
11.1.1. Adverse Event (AE): 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject that does not necessarily have a causal relationship with this treatment. An 
adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product or protocol-specified procedure, whether or not considered related to the 
medicinal product or protocol-specified procedure.  Any worsening (i.e., any clinically significant 
adverse change in frequency and/or intensity) of a preexisting condition that is temporally 
associated with the use of the Merck’s product, is also an adverse event. 
 
Adverse events may occur in screened subjects during any pre-allocation baseline period as a 
result of a protocol-specified intervention, including washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure. Progression of the cancer under study is not considered an 
adverse event unless it is considered to be drug related by the site investigator. 
 
11.1.2. Serious Adverse Event (SAE): 
A serious adverse event is any adverse event that: 
• 
Results in death 
• 
Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may require 
intervention (e.g., medical, surgical) to prevent one of the other serious outcomes listed 
in the definition above).  Examples of such events include, but are not limited to,  
o intensive treatment in an emergency room or at home for allergic bronchospasm;  
o blood dyscrasias or convulsions not resulting in hospitalization;  
o the development of drug dependency or drug abuse. 
• A new cancer (that is not a condition of the study); 
• A pembrolizumab 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. Both 
cases must be immediately reported. See section 11.2.2. 
 
11.1.3. Unexpected Adverse Event: 
An adverse event not mentioned in the Investigator's Brochure or package insert or the specificity 
or severity of which is not consistent with the Investigator's Brochure or package insert. 
 
 
 


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11.2. 
Reporting 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4 will be utilized for AE reporting.  A copy of the CTCAE 
version 4 can be downloaded from the CTEP website at http://ctep.cancer.gov. All AEs considered 
related to trial medication will be followed until resolution, return to baseline, or deemed clinically 
insignificant, even if this occurs post-trial. 
 
11.2.1. 
Adverse Events (AEs) 
Adverse events (AEs) will be recorded from the time of consent, at each time point marked on the 
Study Calendar, and through 30 days following cessation of treatment. All adverse events 
regardless of CTCAE grade must also be evaluated for seriousness. The reporting timeframe for 
adverse events meeting any serious criteria is described in Section 11.2.5.  
 
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).   
 
11.2.2. 
Definition and Reporting of a Pembrolizumab Overdose 
For purposes of this trial, an overdose of pembrolizumab 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.  Appropriate supportive treatment 
should be provided if clinically indicated.  In the event of overdose, the subject should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose 
without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 1 working day 
to BTCRC Administrative Headquarters (AHQ). BTCRC AHQ will report the event within 1 
working day to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229) 
 
11.2.3. 
Definition and Reporting of Events of Clinical Interest (ECI) 
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 1 working day to BTCRC AHQ.  
 
Events of clinical interest for this trial include: 
1. an overdose of Merck product, as defined in Section 11.2.2, that is not associated with 
clinical symptoms or abnormal laboratory results.  


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2. an elevated AST or ALT lab value that is greater than or equal to 3× the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2× the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2× 
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.  
 
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. 
 
ECIs that occur in any subject from the date of first dose through 90 days following cessation of 
treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or not related 
to the Merck’s product, must be reported within 1 working day to BTCRC AHQ. BTCRC AHQ 
will report the event within 1 working day to Merck Global Safety (Attn: Worldwide Product 
Safety; FAX 215-661-6229). 
 
11.2.4. 
Serious Adverse Events (SAE)  
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time the 
consent is signed through 90 days following cessation of treatment, or the initiation of new anti-
cancer therapy, whichever is earlier, whether or not related to Merck product should be followed 
and recorded.   
 
Additionally, any serious adverse event considered to be related to pembrolizumab that is brought 
to the attention of the site investigator outside the 90-day time period specified above must also be 
reported immediately to BTCRC AHQ in collaboration with sponsor-investigator. 


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All adverse events will be evaluated for: 
 
 
CTCAE v4.0 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis); or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event 
when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 


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


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11.2.4.1. Site Requirements for Reporting SAEs to BTCRC Administrative Headquarters: 
Investigators and other site personnel must report all SAEs within one business day of discovery 
of the event using the SAE/ECI submission form.  This includes events both related and unrelated 
to the investigational product.   
 
The definition of "related" being that there is a reasonable possibility the drug caused the adverse 
experience. 
 
Unrelated 
The Adverse Event is clearly not related to the investigational agent(s) 
Unlikely 
The Adverse Event is doubtfully related to the investigational agent(s) 
Possible 
The Adverse Event may be related to the investigational agent(s) 
Probable 
The Adverse Event is likely related to the investigational agent(s) 
Definite 
The Adverse Event is clearly related to the investigational agent(s) 
 
The completed SAE/ECI submission form (see SPM) must be sent electronically to 
SAFETY@hoosiercancer.org or faxed (317-921-2053) to Big Ten Cancer Research 
Consortium (BTCRC) Administrative Headquarters (AHQ) within one business day of 
discovery of the event.   The investigator is responsible for informing the IRB and/or the 
Regulatory Authority of the SAE as per local requirements. 
 
The original copy of the SAE/ECI submission form and the e-mail correspondence or fax 
confirmation sheet must be kept within the Trial Master File at the study site.  
 
Follow-up information will be sent electronically using the SAE/ECI submission form to 
SAFETY@hoosiercancer.org or faxed to BTCRC AHQ.  Each re-occurrence, complication, or 
progression of the original event should be reported as a new follow-up to that event regardless of 
when it occurs.  
 
The follow-up information should describe:  
• whether the event has resolved or continues,  
• if and how it was treated, 
• whether study medication is ongoing, interrupted or stopped,  
• whether the blind was broken or not (if applicable), and  
• whether the subject continued or withdrew from study participation. 
 
In addition to faxing the SAE/ ECI submission form to BTCRC AHQ, sites will also enter the 
event in the SAE tab in the BTCRC electronic data capture system.  
 
11.2.4.2. BTCRC AHQ Requirements for Reporting SAEs: 
 
11.2.4.2.1. BTCRC AHQ Reporting to Merck 
BTCRC AHQ will report any SAE that occurs to any subject from the time the consent is signed 
through 90 days following cessation of treatment, or the initiation of new anti-cancer therapy, 
whichever is earlier, whether or not related to Merck product, to Merck within one business 


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day of receipt of the SAE Reporting Form and to regulatory authorities (FDA) per federal 
guidelines.   
 
BTCRC AHQ will submit all SAE reports to Merck and will provide follow-up information as 
reasonably requested. 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-661-6229 
 
11.2.4.2.2. BTCRC AHQ Reporting to the Northwestern QAM/DMC 
BTCRC AHQ will submit all SAEs) to the assigned Northwestern Quality Assurance Monitor 
(QAM).  The completed SAE Report Form must be emailed to 
croqualityassurance@northwestern.edu within 1 business day of discovery of the event. 
 
11.2.4.2.3. BTCRC AHQ Reporting to the Food and Drug Administration (FDA) 
BTCRC AHQ has been designated to manage the Investigational New Drug Application (IND) 
associated with this protocol on behalf of Mario Javier Pineda, M.D., sponsor-investigator. 
BTCRC AHQ is responsible for all communication with the FDA including but not limited to 15 
Day Reports and Annual Progress Reports. BTCRC AHQ will cross-reference this submission 
according to local regulations to the Merck Investigational Compound Number (IND, CSA, etc.) 
at the time of submission.  Additionally, BTCRC AHQ will submit a copy of these reports to 
Merck Sharp & Dohme Corp. (Attn: Worldwide Product Safety; FAX 215-661-6229) at the time 
of submission to FDA. 
 
BTCRC AHQ will report to the FDA using MedWatch Report form, regardless of the site of 
occurrence, any AE that is serious, unexpected and reasonably related (i.e., possible, probably, 
definite) to the study treatment. The sponsor-investigator will review these reports and 
determine if any revisions are needed to the protocol or consent. 
 
According to CFR 312.32, unexpected fatal or life-threatening events associated with the use of 
the study treatment will be reported to the FDA by fax or by phone as soon as possible but in no 
event later than 7 calendar days after the initial receipt of the information regarding the event. 
The fax should be sent to the FDA project manager assigned to the IND. A comprehensive 
written report will be submitted as an amendment to the IND within an additional 8 days (15 
calendar days total). 
 
All other serious unexpected events associated with the use of the study treatment will be 
reported to FDA as an amendment to the IND as soon as possible but in no event later than 15 
calendar days after initial receipt of the information regarding the event.  
 
11.3. 
Sponsor-Investigator Responsibilities 
BTCRC AHQ will send a SAE summary to the sponsor-investigator (or designated back-up) 
within 1 business day of receipt of SAE Submission Form from a site.  The sponsor-investigator 
will promptly review the SAE summary and assess for expectedness and relatedness. 
 
 
 


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11.4. 
IND Safety Reports Unrelated to This Trial 
Merck will send IND safety reports from external studies that involve the study drug to BTCRC 
AHQ (SAFETY@hoosiercancer.org). BTCRC AHQ will forward the safety reports to the 
sponsor-investigator (or designated back-up) who will review these reports and determine if 
revisions are needed to the protocol or consent. BTCRC AHQ will forward these reports to 
participating sites every 2 weeks.  
 
Upon receipt from BTCRC AHQ, site investigators (or designees) are responsible for submitting 
these safety reports to their respective IRBs, as per their IRB policies. 
 
BTCRC AHQ will also submit IND safety reports to the Northwestern DMC for review 
(croqualityassurance@northwestern.edu).  
 
12. STATISTICAL CONSIDERATIONS 
12.1. Study Design 
This is a single-arm, open-label, multi-center phase II study for subjects with measurable 
advanced or recurrent endometrial cancer using pembrolizumab in combination with carboplatin 
and paclitaxel chemotherapy.  As this combination of agents has not been tested in this subject 
population, the first six subjects enrolled will constitute a safety run-in cohort (see Section 5.2).  
The most recently published Gynecologic Oncology Group trial (GOG-177) evaluating 
chemotherapeutic response rate in advanced and recurrent endometrial cancer was published in 
2004.  In this trial, the triplet combination therapy, paclitaxel, doxorubicin, cisplatin had a 50-59% 
response rate (RR) depending upon histologic subtype; the complete response rate was 22% 1.  In 
a retrospective analysis of patients with histologically confirmed endometrial carcinoma or uterine 
carcinosarcoma who received second-line platinum-based chemotherapy, the response rate for the 
entire cohort was 50% (129 CR+PR out of 262 total evaluable patients).  All patients had received 
primary platinum-based chemotherapy with or without concurrent chemoradiation therapy2.  
Taking both studies into account, we estimate a 50% response rate for combination platinum-
based chemotherapy in the up-front setting or as salvage therapy following initial response.  A 
meaningful clinical response would be an improvement in RR of 15% given the potential risks and 
increased cost for the additional immunotherapy; for our purposes we will target a 65% RR.  The 
proposed sample size will be 46 subjects total.  A single group of 46 subjects will give us a 77% 
power to detect a higher overall response rate (65%) than the historical control (50%), assuming a 
one-tailed test and a Type I error rate of 10%.  All subjects who receive pembrolizumab will be 
evaluated for treatment efficacy and toxicity. The 46 patients will include the six patients in the 
successful safety run-in period.  If one dose reduction is needed during the run-in period, then the 
final sample size of 46 used for the primary objective will include only the six patients at the 
successful run-in dose. The total sample size would then be 52. 
Statistical analysis will be done by the Biostatistics Core Facility of the Robert H. Lurie 
Comprehensive Cancer Center. 
12.2. Definition of Primary Endpoint 
Objective response rate is defined as the proportion of evaluable subjects with a partial response or 
complete response according to irRECIST criteria. 


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12.3. Definitions of Secondary Endpoints 
Toxicity is defined as the proportion of evaluable subjects who experience ≥ Grade 3 toxicity 
according to CTCAE v4. 
12.4. Definitions of Correlative Endpoints 
12.4.1. Immunohistochemical evaluation of PD-L1 expression on formalin-fixed, paraffin-
embedded tissue section from primary tumor and/or biopsy of recurrent disease, if available. 
12.4.2. Immunohistochemical evaluation of tumor-infiltrating lymphocytes (TIL, CD8+), T 
regulatory lymphocytes (Treg, CD4+/Foxp3+) and myeloid derived suppressor cells (MDSC: 
HLADRlow/-, CD11b+, CD14+) on formalin-fixed, paraffin-embedded tissue section from 
primary tumor and/or biopsy of recurrent disease, if available. 
12.4.3. Flow cytometric quantification of tumor-infiltrating lymphocytes (CD8+), T regulatory 
lymphocytes (Treg, CD4+/Foxp3+) and myeloid derived suppressor cells ([MDSC] 
HLADRlow/-, CD11b+, CD14+) on fresh frozen core biopsy of recurrent disease, if available. 
12.4.4. Characterization of circulating immune cell populations (TIM3+/PD-1+/CD8+, PD-
1+/Treg) will be evaluated on samples collected prior the start of and upon completion of 
combination pembrolizumab/cytotoxic chemotherapy 
12.4.5. IFN- and CD107a expression in/on circulating CD8+ T cells will be measured by flow 
cytometry to characterize effector function. 
12.5. Analysis Plan for Primary Objective 
The response rates will be compared with actual data from the historical control using a one 
sample test for proportions where the null hypothesis is that the rate is 50%. 
12.6. Analysis Plan for Secondary Objective 
All adverse events and safety monitoring measures will be described longitudinally using 
descriptive statistics such as frequencies, proportions, and ranges. Individual data will be reported 
for values out of normal range. 
12.7. Analysis Plan for Exploratory Objectives 
12.7.1. PD-L1 staining intensity (-, +/-, +), percent of tumor positive (<50%, ≥50%) 
primary/recurrent tumor and other immunohistochemical markers (TIL, Treg and  
MDSC will be quantified and reported as total number per field) will be related to 
response rate either individually or in a multivariate analysis using logistic regression. 
12.7.2. Characterization of circulating immune cell populations (TIM3+/PD-1+/CD8+, PD-
1+/Treg) will be evaluated on samples collected prior the start of and upon completion 
of combination pembrolizumab/cytotoxic chemotherapy and will be compared 
between time points using either McNemar’s test (for categorical metrics) or the 
Wilcoxon signed rank test (for continuous metrics).  These markers at each time point 
will be related to response using logistic regression. 
12.7.3. Individual genes will be identified as those up- or down-regulated in tumor relative 
to adjacent normal tissue.  False discovery rate adjustment will be used to identify 
candidate genes.  These analyses will define the mutational landscape.  A genetic 
signature for response will be identified using multivariate and data reduction 
methods such as principal components analysis, logistic regression and random forest 
analysis. 


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12.8. Criteria for Stopping Study 
Study will be suspended pending evaluation of toxicity during the safety lead-in as described in 
section 5.2.  There are no interim analyses planned for primary objective.    
 
12.9. Analysis Datasets 
Methods of Statistical Analysis 
 
Population 
Definition 
Enrolled 
This will comprise all subjects who meet the eligibility 
criteria and are registered onto the study.  
Evaluable 
This will comprise all subjects who receive at least one dose 
of trial drug and either undergo at least one post-baseline 
assessment or die before any evaluation.   
Intention-to-treat (ITT) 
This will comprise all subjects who meet the eligibility 
criteria and are registered onto the study irrespective of their 
compliance to the planned course of treatment. (See Intent-
To-Treat principle below). 
Per Protocol Set  (Valid 
Cases, Efficacy 
Sample, Evaluable 
Subjects Sample) 
This will comprise all subjects who complied with the 
protocol sufficiently to ensure that these data would be 
likely to exhibit the effects of treatment, according to the 
underlying scientific model. Compliance covers such 
considerations as exposure to treatment, availability of 
measurements and absence of major protocol violations. 
This population should be specifically defined in the 
protocol. 
Safety 
This will comprise all subjects who receive at least one dose 
of pembrolizumab.  
Treated 
This will comprise all subjects who have been exposed to the 
planned course of treatment to any extent. 
 
Intention-To-Treat Principle - The principle that asserts that the effect of a treatment policy 
can be best assessed by evaluating on the basis of the intention to treat a subject (i.e. the 
planned treatment regimen) rather than the actual treatment given. It has the consequence 
that subjects allocated to a treatment group should be followed up, assessed, and analyzed 
as members of that group irrespective of their compliance to the planned course of treatment. 
 
12.10. Accrual/Study Duration  
Recruitment of 46 subjects will last approximately 18 months and subjects will be followed for 18 
months from enrollment of the last subject.  The estimated study duration is 3 years.   
 
12.11. Subject Characteristics /Other Baseline Characteristics 
Demographic and other baseline data will be summarized descriptively for all subjects in the 
enrolled set.  All protocol deviations will be documented.  The Big Ten Cancer Research 
Consortium participating institutions will not exclude potential subjects from participating in this 


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or any study solely on the basis of ethnic origin or socioeconomic status.  Every attempt will be 
made to enter all eligible subjects into this protocol, thereby addressing the study objectives in a 
subject population that is representative of the entire endometrial cancer population treated by 
participating institutions. 
12.12. Concomitant Medication 
Concomitant medications and significant non-drug therapies at the time of registration and after 
the start of the study drug will be summarized for the treated set. 
12.13. Disposition 
The number of enrolled subjects will be summarized in a flow chart with frequency of completion 
and discontinuation.  The subjects discontinued from study drug and their corresponding 
information will be listed.  Significant protocol violations will be tabulated and/or listed. 
 
13. TRIAL MANAGEMENT 
 
13.1. Data and Safety Monitoring Plan (DSMP) 
 
The Robert H. Lurie Comprehensive Cancer Center’s Data Monitoring Committee (DMC) will 
provide study oversight activities as outlined in Section 13.2. 
 
BTCRC AHQ oversight activities include: 
• Review and processing of all adverse events requiring expedited reporting as defined in the 
protocol 
• Provide trial accrual progress, safety information, and data summary reports to the sponsor-
investigator  
• Submit data summary reports to the lead institution DMC and attend DMC reviews: 
o during the safety run-in portion of the study, semi-monthly to present safety summary 
reports 
o during the Phase II portion of the study, as applicable: following any reports of protocol 
deviations or SAEs; and overall study data delinquency that exceeds 10% incomplete 
forms or sites with data delinquency that are not responding sufficiently to the BTCRC 
AHQ data delinquency escalation process   
o throughout the study, semi-annual comprehensive DMC review  
• During the safety run-in portion of the study there will be weekly safety calls with all 
participating institutions 
 
13.2 
Robert H. Lurie Comprehensive Cancer Center’s DMC  
 
BTCRC AHQ will provide the following for the Robert H. Lurie Comprehensive Cancer Center’s 
DMC to review: 
• Adverse event summary report 
• Monitoring reports 
• Audit results if applicable 
• Study accrual patterns 
• Data delinquency  
• Protocol deviations 
 


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The Robert H. Lurie Comprehensive Cancer Center’s DMC will conduct a comprehensive study 
review semi-annually, based on the date the study was originally opened with NU.  Documentation 
of DMC reviews will be provided to sponsor-investigator and BTCRC AHQ.  Issues of immediate 
concern by the DMC will be brought to the attention of the sponsor-investigator and other regulatory 
bodies as appropriate.  The sponsor-investigator will work with BTCRC AHQ to address the DMC’s 
concerns.   
   
13.3 
Data Quality Oversight Activities 
Remote validation of data will be completed on a continual basis throughout the life cycle of the 
study.  A summary report (QC Report) of these checks together with any queries resulting from 
manual review of the eCRFs will be generated for each site and transmitted to the site and the site 
monitor. Corrections will be made by the study site personnel.  
 
There will be at least one routine visit per site per year for sites that have accrued.  Additional for 
cause visits may occur as necessary. Source documents will be reviewed for verification of 
agreement with data entered into the eDC.  It is important for the site investigator and their 
relevant personnel to be available for a sufficient amount of time during the monitoring visits or 
audit, if applicable. The site investigator and institution guarantee access to source documents by 
BTCRC AHQ or its designee. 
 
The trial site may also be subject to quality assurance audit by Merck or their designee as well as 
inspection by appropriate regulatory agencies. 
 
14. DATA HANDLING AND RECORD KEEPING 
 
14.1. Case Report Forms and Submission 
This study will utilize electronic case report forms (eCRFs) in an electronic data capture (eDC) 
system.  The eDC system will be compliant with Good Clinical Practices and Federal Rules and 
Regulations.   
 
Generally, clinical data will be electronically captured in the eDC and correlative results will be 
captured in the eDC or other secure database(s). If procedures on the study calendar are performed 
for standard of care, at minimum, that data will be captured in the source document. Select 
standard of care data will also be captured in the eDC, according to study-specific objectives. 
Please see the Data and Safety Oversight Process (DSOP) guidelines for further details.  
 
The completed dataset is housed at BTCRC AHQ and is the sole property of the sponsor-
investigator’s institution. It should not be made available in any form to third parties, except for 
authorized representatives of appropriate Health/Regulatory Authorities, without written 
permission from the sponsor-investigator and BTCRC AHQ. After the initial publication, the 
complete data set will be available to all BTCRC institutions. 
 
Trials that use the Lurie Cancer’s DSMP are not permitted to publish trial data in any capacity 
until the data has been approved by the DMC.  If a PI anticipates that he or she will publish data 
prior to three months after the Clinicaltrials.gov primary completion date, they must notify the 
assigned QAM as soon as possible.  QAMs can prepare the data summary for DMC approval upon 
PI request, but must have a minimum six weeks’ notification. 


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14.2. Record Retention 
To enable evaluations and/or audits from Health Authorities/BTCRC AHQ, the investigator agrees 
to keep records, including the identity of all participating subjects (sufficient information to link 
records; e.g., hospital records), all original signed informed consent forms, copies of all source 
documents, and detailed records of drug disposition in compliance with local and federal 
regulations. 
 
During data entry, range and missing data checks will be performed on-line.  The checks to be 
performed will be documented in the Data Monitoring Plan for the study.  A summary report (QC 
Report) of these checks together with any queries resulting from manual review of the eCRFs will 
be generated for each site and transmitted to the site and the site monitor.  Corrections will be 
made by the study site personnel.  This will be done on an ongoing basis. 
 
14.3. Confidentiality 
There is a slight risk of loss of confidentiality of subject information.  All records identifying the 
subject will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available.   
 
Information collected will be maintained on secure, password protected electronic systems. Paper 
files that contain personal information will be kept in locked and secure locations only accessible 
to the study team. Samples that are collected will be identified by a subject study number assigned 
at the time of registration to the trial.  Any material issued to collaborating researchers will be 
anonymized and only identified by the subject study number. 
 
Subjects will be informed in writing that some organizations, including the sponsor-investigator 
and his/her research associates, BTCRC AHQ, Merck, IRB, or government agencies, like the 
FDA, may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
14.4. Changes to the Protocol and Informed Consent 
Study procedures will not be changed without the mutual agreement of the sponsor-investigator, 
BTCRC AHQ, and Merck. 
 
If it is necessary for the study protocol to be amended, the amendment or a new version of the 
study protocol (amended protocol) will be generated by BTCRC AHQ and must be approved by 
the sponsor-investigator and Merck in addition to each site’s IRB, and if applicable, also the local 
regulatory authority.  Local requirements must be followed. 
 
If a protocol amendment requires a change to the informed consent form sites must notify their 
local IRB.  Approval of the revised informed consent form by the local IRB is required before the 
revised form is used.  
 


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The local investigator is responsible for the distribution of amended documents to his or her IRB, 
and to the staff at his or her center.  The distribution of these documents to the regulatory authority 
will be handled according to local practice. 
 
Merck’s willingness to supply study drug is predicated upon the review of the protocol.  BTCRC 
AHQ agrees to provide written notice to Merck of any modifications to the protocol. 
 
15. ETHICS 
 
15.1. Ethics Review 
The final study protocol, including the final version of the informed consent form, must be 
approved or given a favorable opinion in writing by an IRB.  The local investigator must submit 
written approval to the BTCRC AHQ office before he or she can enroll any subject into the study.   
 
The local investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements.  In addition, the IRB must approve all advertising used to 
recruit subjects for the study.  The protocol must be re-approved by the IRB annually, as local 
regulations require.  
 
Progress reports and notifications of serious unexpected adverse drug reactions will be provided to 
the IRB according to local regulations and guidelines. 
 
The local investigator is also responsible for providing the IRB with reports of any serious adverse 
drug reactions from any other study conducted with the investigational product.  Merck will 
provide this information to the sponsor-investigator and BTCRC AHQ.  These reports will be 
reviewed by the sponsor-investigator and will be forwarded to participating sites every 2 weeks for 
submission to their Institutional Review Boards per their guidelines.   
 
15.2. Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the Declaration 
of Helsinki, which are consistent with ICH Good Clinical Practice, and applicable regulatory 
requirements. 
 
15.3. Informed Consent Process 
The informed consent will adhere to IRB requirements, applicable laws and regulations, and 
funder requirements. The initial informed consent form, any subsequent revised written informed 
consent form and any written information provided to the subject must receive the IRB’s 
approval/favorable opinion prior to use.  The subject or his/her legally authorized 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.  
 
Each site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study prior to 
participating in the clinical trial. Subjects must also be notified they are free to discontinue from 
the study at any time.  The subject should be given the opportunity to ask questions and allowed 
time to consider the information provided. 
 


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The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study.  The investigator must store the original, signed written 
informed consent form.  A copy of the signed informed consent form must be given to the subject. 
 
15.4. Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the sponsor-investigator 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. The sponsor-
investigator has delegated responsibility for registering the trial and posting trial results on 
clinicaltrials.gov to BTCRC AHQ. 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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