Clinical trial NCT02630823
Conditions: Endometrial Cancer Endometrial Carcinoma Neoplasms, Endometrial
Sponsor: Washington University School of Medicine
Start date: 2016-02-05; Completion date: 2020-10-03
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Due to the high expression of PD-L1 in endometrial cancers as well as in ovarian cancers which are molecularly similar to uterine serous cancers, using pembrolizumab should be beneficial in this patient population. Since the investigators are able to get a pre-treatment research- related endometrial biopsy as well as the surgical specimen post two cycles of pembrolizumab, the investigators will be able to evaluate the mechanism of action of this drug on the endometrial cancer tumor environment.

Detailed description:

Arms: arm 1: * Patients will undergo endometrial biopsy followed by 2 doses of MK-3475 3 weeks apart. 3-4 weeks after the second dose of MK-3475, the standard of care surgical resection will take place, followed by standard of care adjuvant therapy. Tissue and blood will be collected at the time of surgical resection for immune analysis. For patients whose pathology confirms high-risk features and advanced stage, MK-3475 will be given every 3 weeks starting 4 -6 weeks after completion of adjuvant therapy for a maximum of 4 doses post-surgery.
* MK-3475 will be given intravenously at a dose of 200 mg over the course of 30 minutes.
* The standard of care chemotherapy will consist of 6 cycles of paclitaxel and carboplatin AUC 5 every 3 weeks for 6 cycles.
* The decision to administer radiation therapy will be per the treating physician. If the patient does not receive radiation therapy, then the patient will start MK-3475 every 3 weeks x 4 doses after the completion of chemotherapy.
Interventions: intervention 1: MK-3475 intervention 2: Surgical resection (standard of care) intervention 3: Paclitaxel (standard of care) intervention 4: Carboplatin (standard of care) intervention 5: Radiation (standard of care) intervention 6: Endometrial biopsy intervention 7: Peripheral blood draw
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version: 04/09/18 Amendment 4 
 
Page 1 of 56 
 
 
 
Immunotherapy with MK-3475 in surgically resectable endometrial carcinoma 
 
Washington University School of Medicine 
Department of OB/GYN Oncology 
660 South Euclid Avenue, Campus Box 8064 
St. Louis, MO  63110 
 
Protocol #: 201601062 
Version Date: 04/09/18 
 
Principal Investigator: 
 
Premal H. Thaker, M.D., MSc. 
Phone: (314) 362-1740 
E-mail: thakerp@wustl.edu  
 
Sub-Investigators 
 
 
 
Modality 
Katherine Fuh, M.D., Ph.D.  
 
Gynecologic Oncology 
Andrea R. Hagemann, M.D.  
 
Gynecologic Oncology 
Ian Hagemann, M.D.  
 
 
Anatomic and Molecular Pathology 
Lindsay Kuroki, M.D. 
 
 
Gynecologic Oncology 
L. Stewart Massad, M.D. 
 
 
Gynecologic Oncology 
Carolyn McCourt, M.D. 
 
 
Gynecologic Oncology 
David G. Mutch, M.D. 
 
 
Gynecologic Oncology 
Stephen T. Oh, M.D., Ph.D.  
 
Hematology/Oncology 
Russell Pachynski, M.D. 
 
 
Medical Oncology/Immunology 
Matthew A. Powell, M.D. 
 
 
Gynecologic Oncology 
Ningying Wu, Ph.D.  
                        Biostatistics 
 
Ancillary Personnel 
Lynne Lippmann 
 
 
 
Regulatory 
Kacie Gebhardt 
 
 
 
Regulatory 
Chrisann Winslow, R.N. 
 
 
Research Nurse 
Lorri Dewitt, Pharm.D. 
 
 
Investigational Pharmacist 
 
Study Drug:  
 
MK-3475 (pembrolizumab, Keytruda) 
IND #: 
128997 
Clinical Trials.gov #: 
NCT02630823 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to obtain 
informed consent, may not be disclosed to another party unless law or regulations require such disclosure.  Persons 
to whom the information is disclosed must be informed that the information is confidential and may not be further 
disclosed by them 
 
 


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Immunotherapy with MK-3475 in surgically resectable endometrial carcinoma 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
01/15/16 
Amendment #1 Version 
 
 
 
 
 
 
09/09/16 
Amendment #2 Version 
 
 
 
 
 
 
03/02/17 
Amendment #3 Version (QASMC only) 
 
 
 
 
12/04/17 
Amendment #3 Version 
 
 
 
 
 
 
03/07/18 
Amendment #4 Version  
 
 
 
 
 
 
04/09/18 
 
 


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Immunotherapy with MK-3475 in surgically resectable endometrial carcinoma 
 
 
SCHEMA 
 
 
Patients must have a FIGO grade 3 endometrioid cancer, serous, clear cell, or mixed high grade 
endometrial cancer and stage III or IV by radiographic imaging 
 
 
 
An endometrial biopsy will be obtained after enrollment in trial 
 
 
 
Receive two doses of MK-3475 200mg q 3 weeks pre-operatively and have a blood draw prior to 
each dose of MK-3475 
 
 
 
Surgery for endometrial cancer staging 3-4 weeks after last dose of MK-3475. Blood and tumor 
samples will be obtained at surgical procedure 
 
 
Complete adjuvant chemotherapy of Paclitaxel 175mg/m2 intravenously over 3 hours on day 1 
and Carboplatin AUC 5 intravenously on day 1 +/- radiation therapy. Collect blood sample prior 
to re-administering MK-3475 4-6 weeks post completion of adjuvant therapy. 
 
 
 
Receive MK-3475 every 3 weeks x 4 cycles 
 
 
Collect blood prior to 2nd and 4th cycle of MK-3475 
 
 


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Glossary of Abbreviations 
AE/irAE 
Adverse event/immune-related adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
CBC 
Complete blood count 
CMP 
Complete metabolic panel 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DM 
Distant metastases 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
ECI/irECI 
Event of clinical interest/immune-related event of clinical interest 
FDA 
Food and Drug Administration 
GOG 
Gynecologic Oncology Group 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IULN 
Institutional upper limit of normal 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NSAID 
Nonsteroidal anti-inflammatory drug 
NSCLC 
Non-small cell lung cancer 
OHRP 
Office of Human Research Protections  
PBMC 
Peripheral blood mononuclear cell 
PI 
Principal investigator 
PT 
Prothrombin time 
PTT/aPTT 
Partial thromboplastin time 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SUSAR 
Suspected unexpected serious adverse reaction 
TSH 
UPN 
Thyroid stimulating hormone 
Unique patient number 
 
 
 


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Table of Contents 
SCHEMA ................................................................................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE .................................................................................. 7 
1.1 
Endometrial Adenocarcinoma ................................................................................................ 7 
1.2 
MK-3475 ................................................................................................................................ 7 
1.3 
Study Rationale ...................................................................................................................... 9 
1.4 
Correlative Studies Background .......................................................................................... 11 
2.0 
OBJECTIVES ...................................................................................................................... 13 
2.1 
Primary Objective ................................................................................................................ 13 
2.2 
Secondary Objective ............................................................................................................ 13 
2.3 
Exploratory Objective .......................................................................................................... 13 
3.0 
PATIENT SELECTION ...................................................................................................... 13 
3.1 
Inclusion Criteria .................................................................................................................. 13 
3.2 
Exclusion Criteria ................................................................................................................. 14 
3.3 
Inclusion of Women and Minorities .................................................................................... 15 
4.0 
REGISTRATION PROCEDURES ...................................................................................... 17 
4.1 
Confirmation of Patient Eligibility....................................................................................... 17 
4.2 
Patient Registration in the Siteman Cancer Center Database .............................................. 17 
4.3 
Assignment of UPN ............................................................................................................. 17 
5.0 
TREATMENT PLAN .......................................................................................................... 17 
5.1 
Premedication Administration ............................................................................................. 17 
5.2 
Agent Administration ........................................................................................................... 18 
5.3 
Evaluability .......................................................................................................................... 18 
5.4 
General Concomitant Medication and Supportive Care Guidelines .................................... 19 
5.5 
Women of Childbearing Potential ........................................................................................ 20 
5.6 
Duration of Therapy ............................................................................................................. 22 
5.7 
Duration of Follow-up.......................................................................................................... 23 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS ...................................................................... 23 
6.1 
MK-3475 Dose Modifications ............................................................................................. 23 
6.2 
Dose Modifications for Chemotherapy ................................................................................ 26 
7.0 
REGULATORY AND REPORTING REQUIREMENTS .................................................. 28 
7.1 
Adverse Events (AEs) .......................................................................................................... 29 
7.2 
Unanticipated Problems ....................................................................................................... 30 
7.3 
Noncompliance .................................................................................................................... 30 
7.4 
Serious Noncompliance ....................................................................................................... 30 
7.5 
Protocol Exceptions ............................................................................................................. 30 
7.6 
Reporting to the Human Research Protection Office (HRPO) and the Quality Assurance 
and Safety Monitoring Committee (QASMC) at Washington University ........................................... 30 
7.7 
Reporting to the FDA ........................................................................................................... 31 
7.8 
Reporting to Merck & Co., Inc. ........................................................................................... 31 
7.9 
Timeframe for Reporting Required Events .......................................................................... 34 
8.0 
PHARMACEUTICAL INFORMATION ............................................................................ 34 
8.1 
MK-3475 .............................................................................................................................. 34 
8.2 
Paclitaxel .............................................................................................................................. 36 
8.3 
Carboplatin (Paraplatin®) .................................................................................................... 37 
9.0 
CORRELATIVE STUDIES................................................................................................. 37 
9.1 
Tumor Tissue ....................................................................................................................... 37 


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9.2 
Peripheral Blood for Biomarkers ......................................................................................... 39 
10.0 
STUDY CALENDAR .......................................................................................................... 41 
10.1 
Calendar for All Participants ................................................................................................ 41 
10.2 
Calendar for Participants who Receive Adjuvant MK-3475 ............................................... 41 
11.0 
DATA SUBMISSION SCHEDULE.................................................................................... 42 
12.0 
MEASUREMENT OF EFFECT .......................................................................................... 42 
12.1 
Antitumor Effect – Solid Tumors ........................................................................................ 42 
12.2 
Disease Parameters ............................................................................................................... 43 
12.3 
Methods for Evaluation of Measurable Disease .................................................................. 43 
12.4 
Response Criteria ................................................................................................................. 47 
13.0 
DATA AND SAFETY MONITORING .............................................................................. 49 
14.0 
STATISTICAL CONSIDERATIONS ................................................................................. 50 
14.1 
Study Design ........................................................................................................................ 50 
14.2 
Study Endpoints ................................................................................................................... 50 
14.3 
Data Analysis ....................................................................................................................... 50 
14.4 
Power Analysis and Sample Size ......................................................................................... 50 
14.5 
Accrual ................................................................................................................................. 50 
14.6 
Toxicity and Plans for Data and Safety Monitoring (Stopping Rule) .................................. 50 
15.0 
REFERENCES ..................................................................................................................... 51 
APPENDIX A: ECOG Performance Status Scale ................................................................................... 53 
APPENDIX B: Carboplatin Dose Calculation Instructions .................................................................... 54 
APPENDIX C: General Chemotherapy Guidelines ................................................................................ 56 
 
 


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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Endometrial Adenocarcinoma 
 
Endometrial adenocarcinomas are the most common gynecologic malignancy in developed 
countries.  Although current therapies result in a five-year survival of 80-90% for low risk 
patients with Stage I disease, patients with high-risk (serous or clear cell – any stage or Stage III 
grade 2 or 3 endometrioid histology) disease have poor survival ranging from 18-74% with 
Stage I-IV disease. For those who recur, multi-modality treatment options are not successful.  
Thus, there is a pressing need for development of novel therapeutics for high-risk endometrial 
cancer (1). 
 
Standard of care treatment for locally advanced disease includes surgical resection followed by 
adjuvant radiation, and for advanced, metastatic disease, the standard of care includes surgical 
resection followed by chemotherapy with or without adjuvant radiation. Despite the addition of 
these modalities, a portion of locally advanced and metastatic disease patients will suffer disease 
specific mortality and could benefit from novel therapeutic approaches.  
 
Endometrial cancer has distinct features that make it ideal for checkpoint blockade based 
immunotherapeutic approaches.  First, there has been positive PD-L1 immunohistochemical 
expression detected in 83% of primary, 67% of recurrent, and 100% of metastatic endometrial 
cancers (2). As seen in the MK-3475 melanoma and NSCLC trials, tumors with PD-L1 
expression had better progression-free survival compared to PD-L1 negative tumors.  
Additionally, the genomic landscape of these cancers has shown at least 48 genes with 
differential mutation frequencies that can lead to an array of antigenic targets for immune based 
therapeutics (3). Such high mutational frequencies in tumors have been hypothesized to be a 
factor in patient response to checkpoint inhibitors, as in the case of lung and bladder cancers. 
Thus, we believe that anti-PD1 therapy will have signal in endometrial carcinoma. 
 
1.2 
MK-3475 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (4).  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies (5-9) .  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4, which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) (10, 11).  The 
structure of murine PD-1 has been resolved (12).  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for 
ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 


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molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based 
switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases 
SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in 
the CD3 T-cell signaling cascade (11, 13-15).  The mechanism by which PD-1 down modulates 
T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an 
overlapping set of signaling proteins (7, 16).  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer 
cells (17, 18).  Expression has also been shown during thymic development on CD4-CD8- 
(double negative) T-cells as well as subsets of macrophages and dendritic cells (19).  The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety 
of cell types, including non-hematopoietic tissues as well as in various tumors (4-8).  Both 
ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs.  
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably 
on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is 
thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to 
dampen unwarranted T-cell function in peripheral tissues (18).  Although healthy organs express 
little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this 
T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell expansion in 
subjects with melanoma (MEL) (20) .  This suggests that the PD-1/PD-L1 pathway plays a 
critical role in tumor immune evasion and should be considered as an attractive target for 
therapeutic intervention. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated 
for the treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.   
 
Please refer to the IB for preclinical and clinical data. 
 
1.2.1 Rationale for Dosing 
 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475.  The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 
weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were well 
tolerated and no dose-limiting toxicities were observed.  This first in human study of 
MK-3475 showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been 
identified to date.  10.0 mg/kg Q2W, the highest dose tested in PN001, will be the dose 
and schedule utilized in Cohorts A, B, C and D of this protocol to test for initial tumor 
activity.  Recent data from other clinical studies within the MK-3475 program has 


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shown that a lower dose of MK-3475 and a less frequent schedule may be sufficient for 
target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement 
is durable (>21 days).  This early PK and pharmacodynamic data provides scientific 
rationale for testing a Q2W and Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration 
time data from 476 patients. Within the resulting population PK model, clearance and 
volume parameters of MK-3475 were found to be dependent on body weight. The 
relationship between clearance and body weight, with an allometric exponent of 0.59, is 
within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  MK-3475 has been found to 
have a wide therapeutic range based on the melanoma indication.  The differences in 
exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based 
regimen are anticipated to remain well within the established exposure margins of 0.5 – 
5.0 for MK-3475 in the melanoma indication. The exposure margins are based on the 
notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed 
dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population 
PK evaluation revealed that there was no significant impact of tumor burden on 
exposure. In addition, exposure was similar between the NSCLC and melanoma 
indications. Therefore, there are no anticipated changes in exposure between different 
indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of 
pembrolizumab in solid tumors is based on: 1) similar efficacy and safety of 
pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 
2) the flat exposure-response relationships of pembrolizumab for both efficacy and 
safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of 
tumor burden or indication on distribution behavior of pembrolizumab (as assessed by 
the population PK model) and 4) the assumption that the dynamics of pembrolizumab 
target engagement will not vary meaningfully with tumor type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab 
showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are 
optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will 
maintain individual patient exposures in the exposure range established in melanoma as 
associated with maximal efficacy response and 3) will maintain individual patients 
exposure in the exposure range established in melanoma that are well tolerated and safe.  
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors.  A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage. 
 
1.3 
Study Rationale 


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Women with early stage and FIGO grade 1 and 2 endometrial cancer have a relatively good 
prognosis with surgery alone or surgery plus radiation (21). However, 10-15% of patients are 
diagnosed with stage III disease at the time of surgery, and have an estimated 5 year survival 
rate of 40-70% (22). Lastly, the remaining 10-15% of patients are diagnosed with stage IV 
disease and have a very poor 5 year survival of 0-10% (23). 
 
Those patients with advanced disease are unlikely to be cured by surgery, chemotherapy and/or 
radiation alone. In addition, the prognosis for recurrent disease is even more dismal, with 
expected overall survival of only 14-15 months. It is well-known that more aggressive 
histologies such as serous and clear cell carcinoma cause a disproportionate amount of recurrent 
cases and ultimately deaths therefore requiring more aggressive treatment even in early stage 
disease. 
 
The Cancer Genome Atlas Research Network published that uterine serous carcinomas and 
approximately 25% of high-grade endometrioid cancers had extensive copy number alterations 
and frequent TP53 mutations. Additionally, there were frequent mutations in PTEN, CNNB1, 
PIK3CA, ARID1A, ARID5B and KRAS. Uterine serous carcinomas shared genomic features 
with ovarian serous carcinomas (3). 
 
Much work needs to be done with regards to managing patients with advanced stage or recurrent 
disease. The current standard is systemic treatment with paclitaxel and carboplatin. A large 
phase III non-inferiority study performed by the Gynecologic Oncology Group (GOG) 
compared paclitaxel/carboplatin versus a three drug regimen of paclitaxel, doxorubicin and 
cisplatin (TAP) and showed that paclitaxel/carboplatin was not inferior to TAP in terms of PFS 
and OS. 
 
Overall, paclitaxel and carboplatin also had a favorable toxicity profile (24, 25).  According to 
the Surveillance, Epidemiology and End Results (SEER) study of cases diagnosed from 1998-
2001, the five-year survival rate (26): 
• Among women with stage III cancers, it was 33, 48, 48 for serous, clear cell, and grade 3 
endometrioid cancers respectively. 
• Among women with stage IV cancer, it was 18, 18, 37 percent for serous, clear cell, and 
grade 3 endometrioid respectively. 
Thus no other adjuvant therapies have been identified to improve this dismal statistic of survival 
for patients with stages III/IV endometrial cancer. 
 
Vanderstraeten et al. used a composite immunohistochemistry scoring which included the 
subparts of the percentage of total tumor cells showing expression and the intensity of the 
staining to evaluate indoleamine 2,3 dioxygenase, PD-L1, and PD-L2 in mainly grade 3 
endometrioid, clear cell and papillary serous uterine cancers.  Eighty-three percent of primary 
endometrial tumors showed high expression of PD-L1, and there was a trend to improved 
overall survival in patients with high expression of PD-L1. Sixty-seven and one hundred percent 
of recurrent and metastatic endometrial cancers had high expression of PD-L1 (2). Gatalica and 
colleagues surveyed several common cancer types and confirmed in 16 cases of endometrial 
cancer that there was 88% PD-L1 expression in tumor cells and concurrent PD-1 and PD-LI 
expression in 79% (27). Interferon-gamma and CD8+ T cells cause upregulation of PD-L1. 
Therefore, PD-L1 expression could be viewed as a result of ongoing endogenous anti-tumor 


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immune response and may represent a negative feedback loop dependent on an infiltrating 
immune response (2).   
 
Due to the high expression of PD-L1 in endometrial cancers as well as in ovarian cancers which 
are molecularly similar to uterine serous cancers, using pembrolizumab should be beneficial in 
this patient population. Since we are able to get a pre-treatment research- related endometrial 
biopsy as well as the surgical specimen post two cycles of pembrolizumab, we will be able to 
evaluate the mechanism of action of this drug on the endometrial cancer tumor environment. 
Please see below for more details. 
 
1.4 
Correlative Studies Background 
     
The goal of the correlative work will be to determine if there is any correlation between the 
primary endpoint and biomarkers within peripheral blood or in the tumor specimens. The key 
advantage of this study is the availability of not only matched pre- and post-treatment peripheral 
blood but also pre- and post-treatment tumor tissue from treatment naïve patients. Existing data 
suggest that tumor expression of PD-L1 correlates with patient responses.  However, the 
understanding of predictive biomarkers is incomplete.  Thus, we propose to not only incorporate 
PD-L1 tumor staining on the neoadjuvant biopsies of pre- and post-treatment tumors, but to also 
analyze molecular signatures in peripheral blood and tumor tissues. RNA profiling of the pre- 
and post- pembrolizumab treated specimens will also be performed using either FFPE tumors or 
flash frozen tumors. Together, these data will lead to an improved understanding of those 
endometrial cancer patients who may benefit most from MK-3475 therapy. 
  
We hypothesize that MK-3475 will result in increased T cell responses in peripheral blood as 
detected by multiparameter analysis and will define a unique biomarker molecular signature of 
MK-3475 activity (28).  MK-3475 treatment will reveal an intratumoral signature of an immune 
response to advanced stage endometrial cancer. The goal will be to determine if there is any 
correlation between the primary endpoint and biomarkers within peripheral blood or in the 
tumor specimens. The key advantage of this study is the availability of not only matched pre- 
and post-treatment peripheral blood but also pre- and post-treatment tumor tissue from treatment 
naïve patients.  In addition to standard IHC methodology, we will aim to generate biomarkers 
that will be linked to patient outcomes identified in the primary endpoint. Using our 
immunomonitoring core, we will apply CyTOF or FACS based multiparameter analysis of 
PBMCs pre- and post- MK-3475 treatment to delineate immune cell subsets and cell surface 
activation markers.  Additionally, pre-treatment tumor tissue is available, FACS or CyTOF will 
also be applied to tumor infiltrating immune cells.   
 
A next generation of single-cell analysis technology called mass cytometry overcomes 
limitations of flow cytometry of measuring a maximum of ten markers per panel. The CyTOF 
(Cytometry of Time Of Flight) is a mass spectrometer-flow cytometer hybrid instrument that 
uses stable isotopes instead of fluorophores as reporters.  Due to the discrete read-outs of mass 
cytometry, use of isotopes as reporters enables a significant increase in the number of 
measurable parameters per cell.  CyTOF will be used to detect changes in immune populations 
and markers.  Additionally panels can be designed with up to 45 antibodies focused completely 
on surface markers to delineate cellular hierarchy and intracellular signaling molecules.  This 
will allow us to focus on the activation states of intracellular signaling pathways (29). 
 


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Additionally, T cell immune repertoire diversity based on the detection of V-J arrangements of 
the T cell receptor (TCR) will allow monitoring of immune diversity in blood or tumors (30). 
 
 
 


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2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
To determine the safety of treatment with MK-3475 in women with advanced endometrial 
adenocarcinoma. 
 
2.2 
Secondary Objective 
 
To determine progression-free survival of women with endometrial adenocarcinoma treated 
with MK-3475. 
 
2.3 
Exploratory Objective 
 
To compare the anti-endometrial tumor immune response before and after treatment with MK-
3475 as measured by PD-L1 IHC expression, immune function in blood and tumor tissue, and 
immune correlates. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Diagnosis of FIGO grade 3 endometrioid cancer, serous, clear cell, or mixed high grade 
endometrial cancer with confirmation on research-related endometrial biopsy. 
 
2. Radiographically confirmed endometrial adenocarcinoma of stages III-IV requiring adjuvant 
therapy. If stage III disease is suspected, there should be multiple pelvic and/ and or lymph 
nodes involved. 
 
3. Measurable disease defined as lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >10 mm with CT scan, as >20 mm by chest 
x-ray, or >10 mm with calipers by clinical exam by RECIST 1.1. 
 
4. Treatment plan must include primary site biopsy followed by resection of the primary tumor 
site and any metastatic sites at time of surgery. 
 
5. At least 18 years of age. 
 
6. GOG performance status ≤ 2 (see Appendix A). 
 
7. Normal bone marrow and organ function as defined below: 
a. Absolute neutrophil count ≥ 1,500/mcl 
b. Platelets ≥ 100,000/mcl 
c. Hemoglobin ≥ 9 g/dL  
d. Total bilirubin ≤ 1.5 x IULN OR direct bilirubin ≤ IULN for patients with total bilirubin 
> 1.5 x IULN 


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e. AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN (or ≤ 5 x IULN for patients with liver 
metastases) 
f. Serum creatinine ≤ 1.5 x IULN OR creatinine clearance by Cockcroft-Gault ≥ 60 
mL/min/1.73 m2 for patients with creatinine levels > 1.5 x IULN 
g. INR or PT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR 
or PTT is within therapeutic range of intended use of anticoagulants 
h. aPTT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or 
PTT is within therapeutic range of intended use of anticoagulants 
 
8. Sexually active women of childbearing potential must agree to contraceptive methods as 
described in Section 5.5 prior to study entry, for the duration of pre-operative study 
participation and until definitive hysterectomy/bilateral salpingo-oophorectomy.  Should a 
woman become pregnant or suspect she is pregnant while participating in this study, she 
must inform her treating physician immediately. 
 
9. Ability to understand and willingness to sign an IRB approved written informed consent 
document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. FIGO grade 1 or 2 endometrioid cancer. 
 
2. Radiographic imaging demonstrating uterine cancer that is probably stage I or II. 
 
3. Prior treatment for endometrial cancer.  
 
4. Prior treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
 
5. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to first dose of MK-3475 
or has not recovered (i.e., to ≤ grade 1 or baseline) from adverse events due to agents 
administered more than 4 weeks earlier. 
 
6. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks 
prior to the first dose of MK-3475 or has not recovered (i.e., to ≤ grade 1 or baseline) from 
adverse events due to a previously administered agent.  Note, subjects with ≤ grade 2 
neuropathy are an exception to this criterion and may qualify for the study.  Note, if a 
subject received major surgery, she must have recovered adequately from the toxicity and/or 
complications from the intervention prior to starting therapy. 
 
7. Received a live vaccine within 30 days prior to the first dose of MK-3475. Examples of live 
vaccines include, but are not limited to, the following: measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist) are live 
attenuated vaccines and are not allowed. 
 
8. A history of other malignancy ≤ 5 years previous with the exception of basal cell or 
squamous cell carcinoma of the skin which were treated with local resection only. 


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9. Known active central nervous system 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 4 weeks prior to the first dose of MK-3475 
and any neurologic symptoms have returned to baseline), have no evidence of new or 
enlarging brain metastases, and are not using steroids for at least 7 days prior to trial 
treatment.  This exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability. 
 
10. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing 
exceeding 10 mg daily of prednisone or equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of MK-3475. 
 
11. Currently receiving any other investigational agents or has participated in a study of an 
investigational agent or using an investigational device within 4 weeks of the first dose of 
MK-3475. 
 
12. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to MK-3475 or other agents used in the study. 
 
13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
requiring systemic therapy, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, immunosuppression, autoimmune conditions, underlying pulmonary 
disease, or psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
14. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).  
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
 
15. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. 
 
16. Pregnant and/or breastfeeding.  Patient must have a negative serum or urine pregnancy test 
within 72 hours of study entry. 
 
17. 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). 
 
18. Known history of HIV (HIV 1/2 antibodies). 
 
19. Known history of active TB. 
 
3.3 
Inclusion of Women and Minorities 
 
Women and members of all races and ethnic groups are eligible for this trial. 
 


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4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center Database 
 
All patients must be registered through the Siteman Cancer Center database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data will 
be recorded with this identification number on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN 
 
Patients will undergo endometrial biopsy followed by two doses of neoadjuvant MK-3475 three weeks 
apart.  Three to four weeks after the second dose of MK-3475, the standard of care surgical resection 
will take place, followed by standard of care adjuvant therapy (chemotherapy ± radiation).  Tissue and 
blood will be collected at the time of surgical resection for immune analysis.  Patients confirmed to 
have high-risk endometrial cancer will begin additional treatment with adjuvant MK-3475 4 to 6 weeks 
after the end of adjuvant chemotherapy +/- radiation for a total of 4 doses and will undergo evaluations 
for toxicity and response. 
 
5.1 
Premedication Administration 
 
No premedications are required for MK-3475, but antiemetics will be given as per institutional 
practice for the adjuvant chemotherapy with or without radiation. 
 
 


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5.2 
Agent Administration 
 
MK-3475 will be given intravenously at a dose of 200 mg over the course of 30 minutes (-5 
min/+10 min) on an outpatient basis.  MK-3475 will be given twice prior to surgery at three 
week intervals, with the second dose given 3 to 4 weeks pre-op.  After surgery, all patients will 
receive standard of care adjuvant therapy (chemotherapy ± radiation).  For patients whose 
pathology confirms high-risk features and advanced stage, MK-3475 will be given every 3 
weeks starting 4 to 6 weeks after completion of adjuvant therapy for a maximum of 4 doses 
post-surgery.   
 
5.2.1 Post-operative Chemotherapy Regimen 
 
This will consist of 6 cycles of paclitaxel 175mg/m2 and carboplatin AUC 5 every 3 
weeks if patient has adequate blood and chemistry values for 6 cycles. Docetaxel can be 
substituted for paclitaxel per institutional guidelines if a patient suffers a hypersensitivity 
reaction. Chemotherapy cycles may be delayed per treating physician’s discretion.  
 
Paclitaxel will be infused over approximately 3 hours. 
 
Carboplatin will be infused over approximately 30 minutes, following paclitaxel. 
 
For all cycles 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), an anti-
histamine H1 (diphenhydramine 25-50 mg IV or orally, or an equivalent dose of an 
alternate H1blocker such as loratadine or fexofenadine), and a standard dose of 
antihistamine H2 IV (Famotidine is preferred, but ranitidine can also be used). The 
preparative regimen can be altered at the discretion of the treating physician. 
 
Dosing of Carboplatin: See Appendix B for Carboplatin Dose Calculation Instructions. 
 
Chemotherapy administration: See Appendix C for General Chemotherapy Guidelines. 
 
5.2.2 Post-operative Radiation Therapy 
 
The decision to administer radiation therapy will be per the treating physician. If the 
patient does not receive radiation therapy, then the patient will start MK-3475 every 
three weeks x four doses after the completion of chemotherapy. 
 
5.3 
Evaluability 
 
All patients who receive any treatment with MK-3475 are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 30-day follow up after the conclusion of 
treatment or death. 
 
All patients are evaluable for disease response unless they discontinue treatment due to 
treatment related adverse events(s) before any disease assessment.  Patients will be followed 


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every 3 months post-completion of MK-3475 adjuvant therapy for two years and every 6 
months for three additional years (unless patient recurs sooner). 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
All treatments that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. 
 
Patients are prohibited from receiving the following therapies while in screening for and 
enrolled in this trial: 
• Antineoplastic systemic chemotherapy other than as dictated in the post-operative setting 
or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than MK-3475 
• Radiation therapy other than as dictated in the post-operative setting 
• Live vaccines within 30 days prior to the first dose of 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. 
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  Steroids may be used as 
anti-emetics around the time of chemotherapy delivery, which may occur more than 10 
weeks after the pre-operative single dose MK-3475 and 4 weeks before post-operative 
dosing. In the immediate perioperative period patients receive steroids to help with 
wound edema from surgery. The use of physiologic doses of corticosteroids may be 
approved. 
 
Patients may receive myeloid growth factors either filgrastim or pegfilgrastim) can be used per 
institutional guidelines. This may only be used during administration of chemotherapy + 
radiation therapy and not during the pre-operative or post-adjuvant therapy of MK-3475. 
 
5.4.1 Supportive Care Guidelines for Infusion Reactions 
 
Pembrolizumab may cause severe or life-threatening reactions including severe 
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion.  
 
The table below shows treatment guidelines for patients who experience an infusion 
reaction associated with MK-3475. 
 
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 


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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 2 
Requires infusion interruption but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for < =24 
hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but is 
not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the opinion 
of the investigator. 
If symptoms resolve within one hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g. from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms resolve and 
the subject should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further trial treatment administration. 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of MK-3475 with: 
 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is 
not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the opinion 
of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further trial 
treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 
 
5.5 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that precludes 
withdrawal bleeding, and women who have had a tubal ligation) are required to have a negative 
serum or urine pregnancy test within 72 hours prior to the first dose of MK-3475.   
 
Pembrolizumab may have adverse effects on a fetus in utero. 
 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).  Women in the following categories are not considered of 
childbearing potential: 
 


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• Premenarchal 
• Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
 
• Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
 A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.  
o Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
 
Contraception Requirements 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study subjects of childbearing potential must adhere to the contraception requirement (described 
below) from the day of study medication initiation (or 14 days prior to the initiation of study 
medication for oral contraception) throughout the study period up to 120 days after the last dose 
of trial therapy.  If there is any question that a subject of childbearing potential will not reliably 
comply with the requirements for contraception, that subject should not be entered into the 
study. 
 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in the table 
below during the protocol-defined timeframe.  
 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of < 1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen-containing ) hormonal contraception b, c 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b, c 
○ Oral  
○ Injectable  
Highly 
Effective 
Methods 
That 
Have 
Low 
User 
Dependency 
Failure rate of <1% per year when used consistently and correctly. 


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● Progestogen- only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has 
been confirmed.  If not, an additional highly effective method of contraception should 
be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for
participants of clinical studies.  
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and
correctly).  
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment,
condoms must be used in addition to the hormonal contraception during the treatment period and for at 
least [X days, corresponding to time needed to eliminate study treatment plus 30 days for study 
treatments with genotoxic potential] after the last dose of study treatment. 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable
hormonal contraceptives are limited to those which inhibit ovulation.  
 
Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.  
 
Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected, after the last dose of study 
treatment, and as required locally. 
 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
 
5.6 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the patient’s 
health and/or the patient no longer wishes to continue protocol therapy, the protocol therapy 
should be discontinued and the reason(s) for discontinuation documented in the case report 
forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue for up to 4 
doses of MK-3475 in the adjuvant setting following surgery plus adjuvant chemotherapy +/- 
radiation therapy or until one of the following criteria applies: 
 
• Documented and confirmed disease progression 


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• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious non-compliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as indicated in 
the study calendar. 
 
5.7 
Duration of Follow-up 
 
All patients will be followed for at least 5 years for cancer surveillance following completion of 
postoperative treatment with MK-3475 (i.e. up to 5 years after surgery) or for 5 years after 
surgery for patients who did not receive post-op MK-3475 or until death, whichever occurs first. 
Patients removed from study for unacceptable adverse events will be followed until resolution 
or stabilization of the adverse event or up to 5 years as dictated by the treating physician. Case 
report forms will be filled in every 3 months for the first 24 months post-completion of therapy 
and then every 6 months for the following 3 years until progression. 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
6.1 
MK-3475 Dose Modifications 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption.  In case any toxicity listed below does not resolve to grade 0-1 within 12 
weeks after last infusion, trial treatment should be discontinued.  However  patients with a 
laboratory adverse event still at grade 2 after 12 weeks may continue treatment in the trial only 
if asymptomatic and controlled and with PI approval.  For information on the management of 
adverse events, see the table below. 
   
Patients 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 trial 
treatment. 
 
Pembrolizumab will be withheld for drug-related toxicities and severe or life-threatening AEs as 
per the table below. 
 
 


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General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. 
Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤ 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 1-2mg/kg 
prednisone or equivalent) 
followed by taper 
 
• 
Monitor participants for signs and symptoms of 
pneumonitis 
• 
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment 
• 
Add prophylactic antibiotics for opportunistic 
infections 
Grade 3 or 4, or recurrent 
grade 2 
Permanently discontinue 
Diarrhea / colitis  
Grade 2 or 3 
Withhold 
• Administer corticosteroids 
(initial dose of 1-2mg/kg 
prednisone or equivalent) 
followed by taper 
 
• 
Monitor participants for signs and symptoms of 
enterocolitis (i.e. diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (i.e. 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- 1mg/kg 
prednisone or equivalent) 
followed by taper 
• 
Monitor with liver function tests (consider weekly 
or more frequently until liver enzyme value 
returned to baseline or is stable 
Grade 3 or 4  
Permanently discontinue 
• Administer corticosteroids 
(initial dose of 1-2mg/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 β-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic 
in participants with 
hyperglycemia  
• 
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated.   
• 
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)  
Grade 3 or 4  
Withhold or permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (e.g. 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 (e.g. 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 1-2mg/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 or 
exclude other causes 
Grade 3 or 4 
Permanently discontinue 
All Other 
immune-related 
AEs 
Intolerable/ persistent 
Grade 2 
Withhold 
• Based on severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm etiology 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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6.2 
Dose Modifications for Chemotherapy 
 
In order to maintain dose-intensity and cumulative dose-delivery on this study, reasonable 
efforts will be made to minimize dose reduction and treatment delays as specified. Any patient 
whose treatment is delayed must be evaluated on a weekly basis until adequate hematologic and 
non-hematologic parameters have been met. No dose escalation is planned for this study. 
 
6.2.1 Individual Dose Modification Levels 
 
All modifications are relative to the actual starting doses for the specific Regimen. For 
application of individual dose modifications, see specific guidelines below. 
 
Allowable drug dose levels and instructions are summarized in Tables A, B, and C. 
 
General Guidelines for Hematologic Toxicity 
• Hematologic Nadirs, Table A 
• Delayed Hematologic Recovery, Table B 
• Non-Hematologic Toxicity, Table C 
 
6.2.2   General Guidelines for Hematologic Toxicity 
 
Initial treatment modifications will consist of cycle delay and/or dose reduction as 
directed. Treatment decisions will be based on the absolute neutrophil count (ANC) 
rather than the total white cell count (WBC). 
 
6.2.3 Lower Limits for ANC and Platelet Count 
 
Subsequent courses of treatment which contain any cytotoxic chemotherapy 
(carboplatin, paclitaxel) will not begin (day 1 of each cycle) until the ANC is ≥1,500 
cells/ mcl and the platelet count is ≥ 100,000/ mcl. Such treatment will be delayed for a 
maximum of three weeks until these values are achieved. Patients who fail to recover 
adequate counts within a three-week delay will no longer receive any protocol-directed 
therapy. 
 
Exceptions: 
Patients who received filgrastim or pegfilgrastim prior to the current cycle may begin 
(day 1 of cycle) with ANC ≥ 1000 cells/mcl, if clinically appropriate, to allow for 
transient reductions in ANC after discontinuation of myeloid growth factors. Patients 
who are delayed more than 7 days may begin with ANC ≥ 1000 cells/ mcl, if clinically 
appropriate; and if they will receive filgrastim or pegfilgrastim with subsequent therapy. 
 
6.2.4 Modifications for Hematologic Toxicity (Nadirs) 
 
Initial occurrence of dose-limiting neutropenia (defined in 6.15) or dose limiting 
thrombocytopenia (defined in 6.16) will be handled according to Table A. 
 
Dose-Limiting Neutropenia (DLT-ANC) is defined by the occurrence of febrile 


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neutropenia or prolonged Grade 4 neutropenia persisting ≥ 7 days. There will be no 
modifications for uncomplicated Grade 4 neutropenia lasting less than 7 days. Febrile 
neutropenia is defined as a disorder characterized by an ANC <1000/mm3 and a single 
temperature of >38.3°C (101°F) or a sustained temperature of ≥ 38°C (100.4°F) for more 
than one hour. Dose reductions will be handled according to Table A. 
 
Dose-limiting thrombocytopenia (DLT-PLT) is defined by any occurrence of Grade 4 
thrombocytopenia or bleeding associated with Grade 3 thrombocytopenia. There will be 
no modifications for uncomplicated Grade 3 thrombocytopenia. Dose reductions will be 
handled according to Table A. 
 
Table A: Modification Instructions for Dose-Limiting Hematologic Toxicity 
DLT 
ANC 
DLT 
PLT 
First Occurrence 
Second Occurrence 
Third Occurrence 
Yes± 
No 
Reduce paclitaxel 
one dose level 
Reduce carboplatin 
one AUC unit* 
Discontinue protocol-directed 
cytotoxic chemotherapy 
Yes± 
Yes 
Reduce paclitaxel 
one dose level 
and carboplatin 
one AUC unit* 
Reduce paclitaxel 
one dose level 
Discontinue protocol-directed 
cytotoxic chemotherapy 
No 
Yes 
Reduce 
carboplatin one 
Reduce paclitaxel 
one dose level 
Discontinue protocol-directed 
cytotoxic chemotherapy 
*Minimum carboplatin dose = AUC 4. 
±Myeloid growth factors (either filgrastim or pegfilgrastim) can be used (it is recommended that ASCO, 
NCCN and/or your institutional guidelines be consulted). 
 
6.2.5 Modifications for Delayed Hematologic Recovery: 
 
Delay on the basis of neutropenia (Delay-ANC) is defined if the ANC is less than 1,500 
cells/mcl within 24 hours prior to scheduled day 1 therapy, or less than 1,000 cells/mcl, 
if the patient received filgrastim or pegfilgrastim during the previous cycle. 
 
Delay on the basis of thrombocytopenia (Delay-PLT) is defined if the platelet count is 
less than 100,000/mcl within 24 hours prior to scheduled day 1 therapy. 
 
Modifications noted below are only required for management of delays in the absence of 
dose reductions stipulated by nadir DLT-ANC and/or DLT-PLT (as noted above). In 
other words, if the patient experiences DLT-ANC and Delay-ANC, make the 
modifications as indicated for the nadir counts without additional modifications based on 
delayed recovery. 
 
Table B: Modifications for Delayed Hematologic Recovery 
Category 
Delay (days) Modification 
Delay - 
ANC† 
1-7 
No Change mandated 
8-21 
Decrease paclitaxel one dose level 
>21 
Discontinue Protocol Directed Cytotoxic Chemotherapy 
Delay-PLT 
1-7 
No Change 
8-21 
Decrease carboplatin one AUC unit* 
>21 
Discontinue Protocol Directed Cytotoxic Chemotherapy 
*Minimum carboplatin dose = AUC 4. 
†Myeloid growth factors (either filgrastim or pegfilgrastim) can be used (it is recommended that ASCO, 


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NCCN and/or your institutional guidelines be consulted). 
 
6.2.6 Adjustments for Non-Hematologic Toxicity 
 
Table C: Adjustments for Non-Hematologic Toxicity 
Drug 
Regimen -2 
Level 
Regimen -1 
Level 
Regimen 
Starting Dose 
Paclitaxel 
110 mg/m2 
135 mg/m2 
175 mg/m2 
Carboplatin Discontinue 
AUC = 4 
AUC = 5 
 
The development of Grade 2 (or greater) peripheral neuropathy requires reduction of one 
dose level in paclitaxel. If CTCAE Grade 3 or 4 peripheral neuropathy occurs then 
subsequent doses of paclitaxel will be delayed for a maximum of three weeks until 
recovered to CTCAE Grade ≤2. If peripheral neuropathy fails to recover to Grade ≤2 by 
a maximum delay of three weeks from time therapy is due, then all paclitaxel should be 
withheld from all subsequent chemotherapy cycles. 
 
Renal toxicity (associated with reduction in GFR) is not expected as a direct 
complication of chemotherapy in this chemotherapy naive patient population using the 
prescribed dose and schedule of each regimen.  See Appendix C (Carboplatin Dose 
Calculation Instructions).  
 
Hepatic toxicity is not expected as a direct complication of chemotherapy in this 
chemotherapy naive patient population using the prescribed dose and schedule for each 
regimen. However, the development of Grade 3 (or greater) elevations in AST, ALT, 
alkaline phosphatase or bilirubin requires reduction of one dose level in paclitaxel and 
delay in subsequent therapy for a maximum of three weeks until recovered to Grade 1. 
 
There will be no dose modifications for alopecia or controllable nausea, vomiting, 
constipation, or diarrhea. It is recommended that routine medical measures be employed 
to manage nausea, vomiting, constipation, and diarrhea. 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as outline 
below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as outlined in 
Section 7.2. 
 
The FDA requires that all serious and unexpected adverse events be reported as outlined in Section 7.4.  
In addition, any fatal or life-threatening adverse experiences where there is a reasonable possibility of 
relationship to study intervention must be reported. 
 
Merck requires that all SAEs or SUSARs be reported as outlined in Section 7.5. 
 
 


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7.1 
Definitions 
 
7.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all 
toxicity reporting.  A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health and 
Human Services’ Office for Human Research Protections (OHRP).  A copy of this 
guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
7.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any of the 
following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption of a 
person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above 
 
All unexpected SAEs must be reported to the FDA. 
 
7.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
Events that are both serious AND unexpected must be reported to the FDA.  
 
7.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that, had it occurred in a more severe form, might have caused death. 
 


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Life-threatening adverse experiences must be reported to the FDA. 
 
7.1.5 Unanticipated Problems 
 
Definition: 
 
• unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
7.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate choice to 
ignore regulations, institutional policies, or determinations of the IRB. 
 
7.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 
7.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the research 
team’s control. Exceptions apply only to a single participant or a singular situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event. 
 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
• Any unanticipated problems involving risks to participants or others which occur at WU, 
any BJH or SLCH institution, or that impacts participants or the conduct of the study. 
• Noncompliance with federal regulations or the requirements or determinations of the 
IRB. 


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• Receipt of new information that may impact the willingness of participants to participate 
or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies as a 
reportable event should be reported within 1 working day of the occurrence of the event or 
notification to the PI of the event. 
 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) 
at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or any 
BJH or SLCH institution that has been reported to and acknowledged by HRPO as reportable.  
(Unanticipated problems reported to HRPO and withdrawn during the review process need not 
be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to a 
QASMC auditor. 
 
7.4 
Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  PLEASE 
NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER FROM 
REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the responsibility of the 
investigator to report any unanticipated problem to the FDA as follows: 
 
• Report any unexpected fatal or life-threatening adverse experiences (Section 7.1.4) 
associated with use of the drug (i.e., there is a reasonable possibility that the experience 
may have been caused by the drug) by telephone or fax no later than 7 calendar days 
after initial receipt of the information.   
• Report any serious, unexpected adverse experiences (Section 7.1.2), as well as results 
from animal studies that suggest significant clinical risk within 15 calendar days after 
initial receipt of this information.   
 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at the 
following address or by fax: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Oncology Drug Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 1-800-FDA-0178 
 
7.5 
Reporting to Merck & Co., Inc. 
 
The PI shall forward to Merck’s Global Safety group (FAX 215-661-6229) any SAE and 
SUSAR information, including, but not limited to, all initial and follow-up information 


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involving any study subject in the study within 2 business days or 3 calendar days (whichever 
comes first) of learning of the SAE or SUSAR. 
 
 “Adverse Event” or “AE” shall mean any untoward medical occurrence in a Study subject who 
is administered the Study Drug regardless of whether or not a causal relationship with the Study 
Drug exists.  By way of example and without limitation, an AE can be any unfavorable and 
unintended sign (for example, an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of the Study Drug. 
  
“Serious Adverse Event” or “SAE” shall mean any untoward medical occurrence in a Study 
subject who is administered the Study Drug that results in death, a life-threatening drug 
experience, requires inpatient hospitalization or prolongation of existing hospitalization, results 
in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect, cancer, 
or is a new cancer if the cancer is the condition of the study, or overdose.  Other important 
medical events that may jeopardize the patient or may require intervention to prevent one of the 
outcomes listed previously should also be considered “serious.” 
 
“Suspected Unexpected Serious Adverse Reaction” or “SUSAR” shall mean any Serious 
Adverse Event, the nature, severity or frequency of which is not consistent with information in 
the most current investigator’s brochure, or with respect to a marketed product the most current 
Summary of Product Characteristics (SPC) or Package Insert. 
 
7.5.1 Reporting Overdose 
 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 
1,000 mg or greater (≥5 times the indicated dose).  No specific information is available 
on the treatment of overdose of pembrolizumab. Appropriate supportive treatment 
should be provided if clinically indicated. In the event of overdose, the subject should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be 
provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck 
product, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology 
“accidental or intentional overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 
hours to the Sponsor and within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 661-6229) 
 
7.5.2 Reporting Pregnancy and Lactation 
 
Although pregnancy and infant exposure during breastfeeding are not considered 
adverse events, it is the responsibility of investigators or their designees to report any 


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pregnancy or lactation in a subject (spontaneously reported to them) that occurs during 
the trial. 
 
Pregnancies and infant exposures during breastfeeding that occur after the consent form 
is signed but before treatment allocation/randomization must be reported by the 
investigator if they cause the subject to be excluded from the trial, or are the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation 
of usual therapy, diet, placebo treatment or a procedure.   
 
Pregnancies and infant exposures during breastfeeding that occur from the time of 
treatment allocation/randomization through 120 days following cessation of Sponsor’s 
product, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, must be reported by the investigator.  All 
reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform 
mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be 
reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported. 
 
Such events must be reported within 24 hours to the Sponsor and within 2 working days 
to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 661-6229) 
 
7.5.3 Reporting Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported within 2 working days to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX 215 661-6229) 
 
Events of clinical interest for this trial include: 
1. an overdose of Merck product that is not associated with clinical symptoms or 
abnormal laboratory results.  
2. an elevated AST or ALT lab value that is ≥ 3 x IULN and an elevated total 
bilirubin lab value that is ≥ 2 x IULN and, at the same time, an alkaline 
phosphatase lab value that is < 2 x IULN, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.  
 
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 to Merck Global Safety 
within 2 working days. 


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7.6 
Timeframe for Reporting Required Events  
 
Adverse events will be tracked for 30 days following the last day of study treatment.  For the 
purposes of this protocol, reportable adverse events are events thought to be possibly, probably, 
or definitely related to MK-3475.  Events thought to be probably or definitely related to surgery 
or adjuvant therapy need not be recorded.  Please note that patients must be followed for events 
of clinical interest for 90 days following the last day of study treatment. 
 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
MK-3475 
 
8.1.1 MK-3475 Description 
 
MK-3475 is a potent humanized IgG4 mAb with high specificity of binding to the PD-1 
receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, MK-3475 has high affinity and potent receptor blocking activity for PD-1. 
MK-3475 has an acceptable preclinical safety profile and is being advanced for clinical 
development as an IV immunotherapy for advanced malignancies. 
 
8.1.2 Clinical Pharmacology 
 
Refer to Section 5.2 of the IB. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
Refer to Section 5.2 of the IB. 
 
8.1.4 Supplier 
 
MK-3475 will be provided free of charge by Merck & Co., Inc. 
 
8.1.5 Dosage Form and Preparation 
 
Merck will provide MK-3475 as a liquid drug product. 
 
8.1.6 Storage and Stability 
 
MK-3475 should be stored under refrigerated conditions (2°C - 8°C). 
 
If not used immediately, vials and/or IV bags may be stored at 2-8 °C for up to a 
cumulative time of 20 hours. If refrigerated, the vials and/or IV bags should be allowed 
to equilibrate to room temperature prior to subsequent use. MK-3475 solutions may be 
stored at room temperature for a cumulative time of up to 4 hours. 
 
8.1.7 Administration 


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MK-3475 will be given intravenously over the course of 30 minutes (-5 min/+10 min) on 
an outpatient basis.   
 
 


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8.2 
Paclitaxel  
 
8.2.1 Formulation 
 
Paclitaxel is supplied as a 6mg/mL non-aqueous solution in multi-dose vials containing 
30mg/5mL, 100mg/16.7mL, or 300mg/50mL of paclitaxel In addition to 6mg of 
paclitaxel, each mL of sterile nonpyrogenic solution contains 527mg of purified 
Cremophor® EL (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, 
USP. 
 
8.2.2 Storage 
 
Unopened vials of paclitaxel are stable to the date indicated on the package when stored 
between 20 to 25°C (68 to 77°F). Protect from light. 
 
8.2.3 Stability 
 
Commercially available paclitaxel will be labeled with an expiration date. All solutions 
of paclitaxel exhibit a slight haziness directly proportional to the concentration of drug 
and the time elapsed after preparation, although when prepared as described below, 
solutions of paclitaxel (0.3-1.2 mg/ml) are physically and chemically stable for 27 hours. 
 
8.2.4 Preparation 
 
Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% Sodium 
Chloride for Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% 
Sodium Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a final 
concentration of 0.3 to 1.2mg/mL. The solutions are physically and chemically stable for 
up to 27 hours at ambient temperature (approximately 25°C / 77°F) and room lighting 
conditions. 
 
NOTE: In order to minimize patient exposure to the plasticizer DEHP, which may be 
leached from PVC infusion bags or sets, diluted paclitaxel solutions should be stored in 
bottles (glass, polypropylene) or plastic (polypropylene, polyolefin) bags and 
administered through polyethylene lined administration sets. 
 
Paclitaxel should be administered through an inline filter with a microporous membrane 
not greater than 0.22 microns. Use of filter devices such as IVEX-2® or IVEX-HP®, 
which incorporate short inlet and outlet PVC-coated tubing has not resulted in 
significant leaching of DEHP. 
 
All patients should be premedicated with corticosteroids, diphenhydramine, and H2 
antagonists prior to paclitaxel administration in order to prevent severe hypersensitivity 
reactions. Patients who experience severe hypersensitivity reactions to paclitaxel should 
not be re-challenged with the drug. 
 
8.2.5 Supplier/ How Supplied 
 


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Commercially available both from Bristol-Myers Squibb Oncology as well as generic 
manufacturers. Consult the American Hospital Formulary Service Drug Information 
guide, Facts and Comparisons, or the package insert for additional information.  
 
8.3 
Carboplatin (Paraplatin®) 
 
8.3.1 Formulation 
 
Carboplatin is supplied as a sterile, pyrogen-free, 10mg/mL aqueous solution in multi-
dose vials containing 50mg/5mL, 150mg/15mL, 450mg/45mL, or 600mg/60mL of 
carboplatin. 
 
8.3.2 Storage 
 
Unopened vials of carboplatin are stable to the date indicated on the package when 
stored at 25°C (77°F). Excursions from 15 to 30°C (59 to 86°F) are permitted. Protect 
from light. Carboplatin multi dose vials maintain microbial, chemical, and physical 
stability for up to 14 days at 25°C following multiple needle entries. 
 
8.3.3 Preparation 
 
Carboplatin aqueous solution can be further diluted to concentrations as low as 
0.5mg/mL with 5% Dextrose in Water or 0.9% Sodium Chloride for Injection, USP. 
When prepared as directed, carboplatin aqueous solutions are stable for 8 hours at room 
temperature (25°C / 77°F). Since no antibacterial preservative is contained in the 
formulation, it is recommended that carboplatin solutions be discarded 8 hours after 
dilution. 
 
NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss of 
potency; therefore, needles or intravenous sets containing aluminum parts that may come 
in contact with the drug must NOT be used for the preparation or administration of 
carboplatin. 
 
8.3.4 Supplier 
 
Commercially available both from Bristol-Myers Squibb Oncology as well as generic 
manufacturers.  Consult the American Hospital Formulary Service Drug Information 
guide, Facts and Comparisons, or the package insert for additional information. 
 
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Tumor Tissue 
 
9.1.1 Collection of Specimens 
 
An endometrial biopsy will be performed at baseline for research purposes only since 
majority of patients will have already had either an endometrial biopsy or dilatation and 


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curettage performed to confirm diagnosis prior to seeing the gynecologic oncologist.  At 
least 1 ml of tissue will be needed and placed in saline.  We will try to collect metastatic 
disease if possible for research purposes if the treating clinician decides to get a biopsy 
of a metastatic site prior to initiation of any therapy.  Dr. Ian Hagemann will confirm the 
histology, tumor presence and viability of the research endometrial biopsy and if there is 
a metastatic site.  Tissue from the surgical resection of both primary uterine tumor and a 
metastatic site will also be harvested for analysis of intratumoral changes.  Routinely a 
pathology resident or fellow comes to the operating room intraoperatively to evaluate the 
uterus for viable tumor and will provide the samples of both the primary uterine tumor 
and metastatic site. Dr. Hagemann will then confirm the tumor histology, cellularity and 
viability of these samples by H&E.  
 
In the event that the research biopsy does not yield sufficient tissue to be able to perform 
the correlative studies required, the FFPE archival block from the original diagnostic 
procedure will be requested. Consent and release of records will be utilized to obtain the 
block which is required from the pathology department of origin. Laboratory personnel 
will use to block to cut up to 10 slides to include 1 slide for H&E staining and the rest 
(5µm, charged slides) to be used to complete the correlative studies.  The block will then 
be returned to the originating pathology department. Additionally, RNA will be obtained 
from FFPE slides or fresh frozen tumors for RNA profiling of pre- and post-
pembrolizumab treated tumors.  
 
Up to 10 additional tissue samples from patients with either advanced stage endometrial 
or ovarian cancer, and some normal endometrium or ovarian  tissue samples will be 
requested from our Gynecologic Oncology Tissue Bank (IRB#:201105400) at 
Washington University in St. Louis.  
 
In addition, up to 10 samples of whole blood from patients with either advanced stage 
endometrium or ovarian cancer, and some normal pathology will also be requested from 
our tissue bank.   
 
Both the blood and tissue samples will have been collected under the tissue bank consent 
for that study, and per division policy, a request for these samples will be made to the 
bank and approval received by the appropriate faculty before they are used. These 
samples will be de-identified prior to submission to Dr. Fuh’s lab and no identifying 
except some minimal clinical data to confirm histology and advanced stage cancer will 
be associated with the samples. These matched blood and tissue samples will be used as 
controls for the CyTof testing as well as optimization as described below.  
 
9.1.2 Handling of Specimens  
 
The specimens will be taken to the laboratory of Katherine Fuh, MD, PhD. and tissue 
digestion will be performed in preparation for CyTof.  Paired pre- and post-treatment 
blood will be analyzed by multiparameter CyTOF mass cytometer based analysis in 
CHiiPS for changes in immune populations and markers including ICOS and PD-1. 
CD3+ infiltrates in tumors and TCR repertoire expansion, and antibody arrays will also 
be performed. IHC on pre-and post-treatment tumor samples to examine for immune cell 
infiltrates will be performed which include but are not limited to T cells: CD3, CD4, 


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CD8, CD25, Foxp3; B cells: CD19, CD20, MDSC: Siglec-3/CD33, Lineage negative, 
HLA-DR negative, CD14+; DC: CD11c HLA-DR lineage +/- CD123 +/- CD8; NK: 
CD16, CD5, CD107, CD3-; Macrophages/TAMs: CD11b+, CD11c-, CD68.  
IHC intensity will be graded by 2 blinded reviewers for both intensity and frequency of 
staining by microscopy.  IHC staining for PD-L1 will be performed PD-L1 assessment 
with the prototype assay as developed by Merck.  The following scoring system will be 
used as performed in the pembrolizumab paper in NSCLC.  The intensity of the 
infiltrates will be graded by using a proportion score (PS), defined as the percentage of 
cells with membranous PD-L1 staining at any intensity. A proportion score of 2+ or 3+ 
(P2S) is defined as the percentage of cells with membranous PD- L1 staining at 
moderate (2+) or strong (3+) intensity.  A proportion score 3+ (P3S) is defined as the 
percentage of cells with membranous PD-L1 staining at strong intensity (3+).  A 
modified H-score (HS) provides a numerical value that accounts for the proportion of 
cells staining for PD-L1 at each of the 3 intensities.  
In addition to standard IHC methodology, we will be applying approaches for biomarker 
generation that can be linked to patient outcomes through next-generation sequencing 
and CyTOF. Using the immunomonitoring core of ChiiPs, we will apply CyTOF multi 
parameter analysis of endometrial cells pre- and post-MK-3475 treatment to delineate 
immune cell subsets and cell surface activation markers. Tissue samples requested from 
the tissue bank of the Division of Gynecologic Oncology will be used as controls. 
CyTOF will also be applied to analyze the tumor infiltrating immune cells (eg. 
CD3+TIL). The breadth of the immune response will be evaluated by TCR repertoire 
expansion (for the cellular arm), and antibody array (for the humoral response).  
 
9.2 
Peripheral Blood for Biomarkers 
 
9.2.1 Collection of Specimens 
 
Blood samples (10-15 mL) will be collected and fixed using a fixation/stabilization 
buffer (Smart Tube Inc.) within 30 min of phlebotomy and stored at −80°C. Collection 
will be performed prior to first dose of MK-3475, prior to second dose of MK-3475, day 
of surgery, after adjuvant therapy and prior to resuming first dose of MK-3475 after 
adjuvant therapy, and every other administration of MK-3475 in adjuvant setting (pre-
dose 2 and 4 of MK-3475). 
 
9.2.2 Handling of Specimens 
 
Samples will be thawed on the day of processing. Red blood cells will be lysed using a 
hypotonic buffer (Smart Tube Inc.). Peripheral blood leukocytes will be washed and 
resuspended in cell staining medium. This will be performed in the laboratory of 
Katherine Fuh, MD, PhD.  Using the immunomonitoring core of CHiiPs, we will apply 
CyTOF multiparameter analysis of PBMCs pre- and post- MK-3475 treatment to 
delineate immune cell subsets and cell surface activation markers (similar markers as 
was performed for the endometrial tumors as for blood). Blood samples from the tissue 
bank of the Division of Gynecologic Oncology will be used as controls. CyTOF will also 
be applied to analyze the tumor infiltrating immune cells (e.g. CD3+ TIL). The breadth 


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of immune response will be evaluated by TCR repertoire expansion (for the cellular 
arm), and antibody array (for the humoral response). 
 
 
 


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10.0 
STUDY CALENDAR 
 
10.1 
Calendar for All Participants 
 
There is a +/- 2-day window for all assessments with the exception of surgery. 
 
Screening11 
Baseline12 
Day 1 
Day 
22 
Days 42-46 
(Surgery) 
Adj. 
Tx4 
Maint. 
MK-3475 
Follow-
Up3 
Informed consent 
X 
 
 
 
 
 
 
 
H&P, ECOG PS, wt 
X 
 
X 
X 
 
 
 
 
Vital signs (HR, BP, temp) 
X 
 
X 
X 
 
 
 
 
CBC 
X 
 
X13 
X14 
 
 
 
 
CMP 
X 
 
X13 
X14 
 
 
 
 
aPTT and PT/INR 
X 
 
 
 
 
 
 
 
Pregnancy test 
X1 
 
 
 
 
 
 
 
TSH 
X 
 
 
X14 
 
 
X8 
 
Chest imaging (X-ray or CT) 
X 
 
 
 
X2,10 
X5 
 
X9,10 
CT or MRI of abdomen/pelvis 
X 
 
 
 
X2,10 
X5 
 
X9,10 
Endometrial biopsy10 
 
X 
 
 
X 
 
 
 
Peripheral blood10 
 
X 
 
X 
X 
X6 
X7 
 
MK-3475 
 
 
X 
X 
 
 
 
 
AE assessment 
 
X 
Pts will be followed for AEs for 90 days following the last dose 
of MK-3475. AE assessment at each cycle of MK-3475. 
1. 
Women of childbearing potential only.  To be performed no more than 72 hours prior to start of treatment 
2. 
Within a week of surgery but post-second dose of neoadjuvant MK-3475 
3. 
Follow-up will be performed as per routine care of every 3 months for the first 2 years after surgery and every 6 months for the next 3 years 
until progression occurs.  Data on progression and survival will be recorded. 
4. 
Adjuvant therapy should typically begin between 4 and 6 weeks following surgery.  Laboratory assessments will be performed as per routine 
care and will not be dictated by this research protocol. 
5. 
Radiographic imaging will be considered standard of care after completing chemotherapy +/- radiation therapy 
6. 
Peripheral blood draw at completion of adjuvant therapy 
7. 
Blood draw at Cycles 2 and 4 of MK-3475 
8. 
TSH to be draw in adjuvant setting if elevated in neoadjuvant setting 
9. 
Imaging post completion of MK-3475 Cycle 4 in adjuvant setting. Imaging should be done within 30 days of completing treatment. 
10. Research-related assessment 
11. Chest imaging and CT or MRI abd/pelvis within 28 days of treatment; all other procedures within 14 days of treatment 
12. Within 14 days of enrollment. 
13. Screening labs can be used if within 14 days of Day 1. 
14. Drawn within 3-5 days of treatment 
 
10.2 
Calendar for Participants Who Receive Adjuvant MK-3475 
 
Only patients whose pathology shows high risk features will receive further treatment with MK-
3475.  This treatment will start 4 to 6 weeks after the end of standard of care adjuvant treatment. 
 
Dose #1 
Dose #2 
Dose #3 
Dose #4 
Post-dose #4 
H&P, ECOG PS, wt 
X 
X 
X 
X 
 
CBC1 
X 
X 
X 
X 
 
CMP1 
X 
X 
X 
X 
 
TSH1 
X 
 
X 
 
 
MK-3475 
X 
X 
X 
X 
 
Blood draw 
 
X 
 
X 
 
Imaging2 
 
 
 
 
X 
AE assessment 
X ----------------------------------- X 
 
1. Drawn within 3-5 days before treatment 
2. Within 30 days of completing dose #4 


Protocol Version: 04/09/18 Amendment 4 
 
Page 42 of 56 
 
 
11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the schedule 
listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Pre-Treatment Summary Form 
Prior to starting treatment 
MK-3475 Treatment Form 
Every dose of MK-3475 (Neoadjuvant and adjuvant)  
Surgery Form 
Time of surgery 
Correlatives Form 
Prior to starting treatment 
Day 22 
Surgery 
Adjuvant therapy 
Maintenance Dose #2 
Maintenance Dose #4 
RECIST Form 
irRECIST Form 
Prior to starting treatment 
Surgery 
Adjuvant therapy 
Post-Maintenance Dose #4 
Toxicity Form 
Continuous 
Adjuvant Treatment Summary Form Adjuvant therapy 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
Q 3 months for first two years and then Q 6 months for 
additional 3 years until progression occurs 
MedWatch Form 
See Section 7.0 for reporting requirements 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response per table 10.1 and 
per the treating physician’s discretion if there is a concern of progression sooner   In addition to 
a baseline scan, confirmatory scans should also be obtained 4 weeks following initial 
documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
 


Protocol Version: 04/09/18 Amendment 4 
 
Page 43 of 56 
12.2 
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 
mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
12.3 
Methods for Evaluation of Measurable Disease 
 


Protocol Version: 04/09/18 Amendment 4 
 
Page 44 of 56 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, 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 which may bias an investigator if it is not routinely or serially 
performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 


Protocol Version: 04/09/18 Amendment 4 
 
Page 45 of 56 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian 
cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 
2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
• FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
  


Protocol Version: 04/09/18 Amendment 4 
 
Page 46 of 56 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
 


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Page 47 of 56 
12.4 
Response Criteria 
 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
12.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short 
axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not 
a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
12.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria. 


Protocol Version: 04/09/18 Amendment 4 
 
Page 48 of 56 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported 
as “symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised 
 
 
12.4.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started). 
 


Protocol Version: 04/09/18 Amendment 4 
 
Page 49 of 56 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
12.4.5 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually beginning 
six months after accrual has opened (if at least five patients have been enrolled) or one year after 
accrual has opened (if fewer than five patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least monthly (or before each dose-escalation if 
occurring sooner than monthly), and provide a semi-annual report to the Quality Assurance and Safety 
Monitoring Committee (QASMC).  This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date of 
HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, error, or 
breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date  
• Objectives of protocol with supporting data and list the number of participants who have met 
each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have met the 
early stopping rules 
• Summary of toxicities 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious toxicities on 
an ongoing basis. Once the principal investigator or Research Patient Coordinator becomes aware of an 
adverse event, the AE will be reported to the HRPO and QASMC according to institutional guidelines. 


Protocol Version: 04/09/18 Amendment 4 
 
Page 50 of 56 
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Study Design 
 
This single arm, phase I study will investigate the safety of treatment with MK-3475 in women 
with advanced endometrial adenocarcinoma. 
 
14.2 
Study Endpoints 
 
The primary endpoint is safety as measured by treatment related adverse events. Secondary 
endpoints include 2-year progression-free survival (PFS) for all the endometrial 
adenocarcinoma patients treated with MK-3475, as well as the anti-endometrial tumor immune 
response before and after treatment with MK-3475 as measured by PD-L1 IHC expression, 
immune function in blood and tumor tissue, and immune correlates. 
 
14.3 
Data Analysis 
 
Demographic and clinical characteristics will be summarized using descriptive statistics. PFS 
will be analyzed by Kaplan-Meier (KM) method. Paired t-test and/or paired-sample Wilcoxon 
Signed Rank test will be used to compare the anti-endometrial tumor immune response before 
and after treatment with MK-3475.  
 
14.4 
Power Analysis and Sample Size 
 
 
Approximately 9 evaluable patients will be enrolled. The proposed sample size was chosen to 
allow assessment of safety and was not based on either statistical modeling or methods to obtain 
adequate power for any endpoint analysis. 
 
14.5 
Accrual 
 
The rate of accrual for the study is expected to be about 1 patient per 1-3 month. It is estimated 
6-9 patients will be enrolled within one year.  
 
14.6 
Toxicity and Plans for Data and Safety Monitoring (Stopping Rule) 
 
Toxicity will be reviewed on a continuous basis. Early stopping of this trial will be based on the 
excessive MK-3475-related adverse events (AE). Assuming a maximum-tolerated toxicity rate 
is 30% and a toxicity rate of 25% and or less is acceptable, based on the repeated significance 
testing (using R function toxbdry) with 80% power and 0.05 overall Type I error, the study will 
be halted if excessive MK-3475-related adverse events occur in the first patients, or 2 of the first 
3 patients, or 3 of the first 5, or 4 of the first 7, or if the 5th unacceptable toxicity is observed 
before the last evaluable  patient has completed the trial. 
 
 


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Page 51 of 56 
 
 
15.0 
REFERENCES 
 
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7. 
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Adults: U.S. SEER Program, 1988-2001, Patient and Tumor Characteristics. NCI, SEER Program, 
National Cancer Institute; Bethesda, MD 2007.  
27.       Gatalica Z, Snyder C, Maney T, Ghazalpour A, Holterman DA, Xiao N, et al. Programmed Cell 
Death 1 (PD-1) and Its Ligand (PD-L1) in Common Cancers and Their Correlation with Molecular 
Cancer Type. Cancer Epidemiol Biomarkers Prev 2014;23:2965-70. 
28.       Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting 
adaptive immune resistance.  Nature 2014;515:568-71. 
29.       Bjornson ZB, Nolan GP, Fantl WJ. Single-cell mass cytometry analysis of immune system 
functional states. Curr Opin Immunol 2013;25:484-494. 
30.       Tanneau I, Nonde A, Courtier A, et al. ImmunTraCkeR as a reliable TCR repertoire profiling 
tool to understand immune response and to explore immunotherapy biomarkers.  J for Immunotherapy 
Cancer 2013; 1(Suppl1): P112. 
 


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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 


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APPENDIX B: Carboplatin Dose Calculation Instructions 
 
• The Cockcroft-Gault formula will be used in this trial. 
• Conversion of IDMS creatinine levels to “non-IDMS” values will not be permitted. 
• The carboplatin calculation tool is available on the GOG website (Web Menu, Tools). 
 
1) 
Dosing of Carboplatin: 
 
2) The carboplatin dose will be calculated to reach a target area under the curve (AUC) according to 
the Calvert formula using an estimated glomerular filtration rate (GFR) from the Cockcroft-Gault 
formula. 
 
3) The initial dose of carboplatin must be calculated using GFR. In the absence of renal toxicity 
greater than or equal to CTCAE Grade 2 (serum creatinine >1.5 x ULN) or toxicity requiring dose 
modification, the dose of carboplatin will not need to be recalculated for subsequent cycles, but 
will be subject to dose modification for toxicity as noted in the protocol. 
 
4) Carboplatin doses are required to be recalculated if the patient has a weight change of greater than 
or equal to 10%. Patients are permitted to have chemotherapy doses recalculated for < 10% 
weight changes. 
 
5) At the time of dose modification, if the patient’s age had changed (the patient has had a 
birthday), the site can use the current age. 
 
6) In patients with an abnormally low serum creatinine (less than 0.7 mg/dl), the creatinine 
clearance should be estimated using a minimum value of 0.7 mg/dl. For trials where 
patients enter and are treated within less than or equal to 12 weeks of surgery: If a more 
appropriate (higher) baseline creatinine value is available from the pre-operative period 
(within 4 weeks of surgery date), that value may also be used for the initial estimation of 
GFR. 
 
CALVERT FORMULA: 
Carboplatin dose (mg) = target AUC x (GFR + 25) 
 
NOTE: the GFR used in the Calvert formula should not exceed 125 ml/min. 
 
Maximum carboplatin dose (mg) = target AUC (mg/ml x min) x 150 ml/min. 
The maximum allowed doses of carboplatin are: 
AUC 6 = 900 mg 
AUC 5 = 750 mg 
AUC 4 = 600 mg 
 
 
For the purposes of this protocol, the GFR is considered to be equivalent to the estimated 
creatinine clearance. The estimated creatinine clearance (ml/min) is calculated by the method of 
Cockcroft-Gault using the following formula: 
 


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Creatinine Clearance (mL/min) = [140-Age (years)] x Weight (kg) x 0.85 
72 x serum creatinine (mg/dl) 
 
Notes: 
1) Weight in kilograms (kg): 
a. Body Mass Index (BMI) should be calculated for each patient. A BMI calculator is 
available at the following link: http://www.nhlbisupport.com/bmi/ 
b. Actual weight should be used for estimation of GFR for patients with BMI of less than 25. 
c. Adjusted weight should be used for estimation of GFR for patients with BMI of greater 
than or equal to 25. 
d. Adjusted weight calculation: 
Ideal weight (kg) = (((Height (cm)/2.54) – 60) x 2.3) + 45.5 
Adjusted weight (kg) = ((Actual weight – Ideal weight) x 0.40) + Ideal weight 
 
2) The Cockcroft-Gault formula above is specifically for women (it includes the 0.85 factor). 
 
At the time of a dose modification for toxicity: If the creatinine at the time of a dose 
modification is lower than the creatinine used to calculate the previous dose, use the previous 
(higher) creatinine; if the creatinine at the time of a dose modification is higher than the 
creatinine used to calculate the previous dose, use the current (higher) creatinine. This will 
ensure that the patient is actually receiving a dose reduction. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX C: General Chemotherapy Guidelines 
 
• For 21 or 28 day cycles, a patient will be permitted to have a new cycle of chemotherapy 
delayed up to 7 days (without this being considered to be a protocol violation) for major 
life events (e.g., serious illness in a family member, major holiday, vacation which is 
unable to be re-scheduled). Documentation to justify this decision should be provided. 
 
• It will be acceptable for individual chemotherapy doses to be delivered within a “24-
hour window before and after the protocol-defined date” for “Day 1” treatment of 21 or 
28 day cycles. If the treatment due date is a Friday, and the patient cannot be treated on 
that Friday, then the window for treatment would include the Thursday (1 day earlier 
than due) through the Monday (day 3 past due). 
 
• For weekly regimens, it will be acceptable for individual chemotherapy doses to be 
delivered within a “24-hour window,” for example; “Day 8 chemotherapy” can be 
delivered on Day 7, Day 8, or Day 9 and “Day 15 chemotherapy” can be given on Day 14, 
Day 15, or Day 16. 
 
• Chemotherapy doses can be “rounded” according to institutional standards without 
being considered a protocol violation (most institutions use a rule of approximately 
+/- 5% of the calculated dose). 
 
• Chemotherapy doses are required to be recalculated if the patient has a weight change 
of greater than or equal to 10%. Patients are permitted to have chemotherapy doses 
recalculated for < 10% weight changes. 
 
• Maximum body surface area used for chemotherapy dose calculations will be 2.0 m2. For 
chemotherapy dose calculations that use mg/kg, there will be no maximum kilogram 
amount used (doses will be calculated on actual weight in kg).