Clinical trial NCT02375672
Conditions: Colorectal Cancer
Keywords: Pembrolizumab MK-3475
Sponsor: Hoosier Cancer Research Network
Start date: 2015-05-28; Completion date: 2020-10-08
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multi-institutional, single arm, open-label, phase II study, including a safety run-in cohort. No randomization or blinding involved.

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

INVESTIGATIONAL TREATMENT:

mFOLFOX6 Treatment D1 and D15 (Cycle = 28 days)

* Oxaliplatin 85 mg/m2 IV with
* Leucovorin 400 mg/m2 IV followed by
* 5FU 400 mg/m2 bolus and then 2400 mg/m2 via continuous infusion

Pembrolizumab (MK-3475) IV over 30 minutes every 3 weeks

SAFETY RUN-IN COHORT:

The safety run-in cohort will include 6 subjects treated with 200 mg (fixed) IV infusion of pembrolizumab (MK-3475) every 3 weeks plus standard-dose mFOLFOX6 given every 2 weeks. These first 6 subjects will be followed for 4 weeks for dose limiting toxicities (DLT) before enrolling an additional 24 patients. If a DLT is observed in no more than 1 of 6 subjects, the trial will continue with enrolling subjects to the remainder of the phase II portion of the study. Otherwise, 6 additional subjects will be enrolled at dose level -1. If no more than one DLT is observed, then phase II will enroll subjects at dose level -1 for the total expected number of accrual.

Disease evaluation every 8 weeks or after every 2 cycles

Demonstrate adequate organ function as defined by the following laboratory values at study entry. All screening labs should be performed within 14 days prior to registration for protocol therapy.

Hematopoietic:

* Hemoglobin ≥ 9 g/dL (transfusions are acceptable)
* Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L
* Platelets ≥ 100 × 10\^9/L

Renal:

* Serum creatinine ≤ 1.5 × upper limit of normal (ULN), or measured or calculated creatinine clearance (estimated by Cockcroft-Gault formula below or measured) ≥ 50 mL/min

Hepatic:

* Serum total bilirubin ≤ 1.5 × ULN
* Aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, SGPT) ≤ 3 × ULN, unless evidence of liver metastases, then AST/ALT ≤ 5 x ULN

Arms: arm 1: Following the safety run-in cohort:

mFOLFOX6 Treatment D1 and D15 (every 2 weeks); Pembrolizumab (MK-3475) IV over 30 minutes (every 3 weeks)
Interventions: intervention 1: Pembrolizumab intervention 2: mFOLFOX6
Intervention descriptions: intervention 1: Pembrolizumab (MK-3475) 200mg IV over 30 minutes every 3 weeks intervention 2: mFOLFOX6 Treatment D1 and D15 (Cycle = 28 days)

* Oxaliplatin 85 mg/m\^2 IV with
* Leucovorin 400 mg/m\^2 IV followed by
* 5FU 400 mg/m\^2 bolus and then 2400 mg/m\^2 via continuous infusion

Protocol documents:
Prot_SAP_000.pdf: 
HCRN GI14-186 
Clinical Study Protocol  
 
 
 
Protocol Title 
A Multi-Center, Single Arm, Phase II study of Pembrolizumab (MK-3475) in Combination 
with Chemotherapy for Patients with Advanced Colorectal Cancer: HCRN GI14-186 
 
Sponsor-Investigator 
Kathy D Miller, M.D. 
Indiana University School of Medicine 
 
Statistician 
Ziyue Liu, PhD 
Indiana University, Schools of Public Health and Medicine 
 
Trial Management Provided by  
Hoosier Cancer Research Network, Inc. 
 
Funding Support and Pembrolizumab Provided By 
Merck Sharp & Dohme Corp. 
 
Investigational New Drug (IND) Application 
Exempt per FDA 24FEB2015 
 
 
 
Initial Protocol Version Date: 23FEB2015 
Amended Protocol Version Date: 
06JUL2015  
30SEP2015  
26FEB2016 
02AUG2016 
10NOV2016 
29APR2019 
 
 
 


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PROTOCOL SIGNATURE PAGE 
A Multi-Center, Single Arm, Phase II study of Pembrolizumab (MK-3475) in Combination 
with Chemotherapy for Patients with Advanced Colorectal Cancer:  
Hoosier Cancer Research Network GI14-186 
 
VERSION DATE: 29APR2019 
 
I confirm I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable guidelines for good clinical practices, or the applicable laws and regulations of 
the country of the study site for which I am responsible, whichever provides the greater 
protection of the individual. I will accept the monitor’s overseeing of the study. I will 
promptly submit the protocol to applicable ethical review board(s). 
 
 
 
 
 
 
 ___________________________________  
 _______________________  
 Signature of Investigator 
 
 
 
 
Date 
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 Investigator Name (printed) 
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 Investigator Title 
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 Name of Facility 
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 Location of Facility (City and State) 
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 Not Submitting to IRB 
 Expected IRB Approval Date 
 
 
PLEASE COMPLETE AND EMAIL COPY TO HCRN 
 
Instructions to the Investigator: Please SIGN and DATE this signature page. 
PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date. Scan and email 
the completed form to HCRN and keep a record for your files. 
 


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SYNOPSIS 
TITLE 
A Multi-Center, Single Arm, Phase II study of Pembrolizumab (MK-
3475) in Combination with Chemotherapy for Patients with Advanced 
Colorectal Cancer: HCRN GI14-186 
SHORT TITLE 
Phase II study of Pembrolizumab (MK-3475) in combination with 
Chemotherapy for patients with advanced colorectal cancer  
PHASE  
II 
OBJECTIVES 
Primary Objective 
Estimate median progression free survival (mPFS) and compare to 
historical standard 
 
Primary Endpoint   
Median progression free survival as measured from the time of 
registration to the time of progression per RECIST v1.1 or subject death  
 
Secondary Objectives 
1- Objective response rate (ORR)  
2- Disease control rate (DCR)  
3- Delayed response  
4- Overall Survival (OS)  
5- Toxicity of the combination of Pembrolizumab plus mFOLFOX6  
6- Response Criteria per established Immune Related Response 
Criteria 
 
Secondary Endpoints 
1- ORR will be calculated with combining the number of subjects 
who achieve complete response and partial response per irRC 
criteria 
2- Disease control rate; defined as the sum of subjects with complete 
response, partial response and stable disease.  
3- Delayed response will be evaluated in subjects who achieve stable 
disease on first tumor assessment but they exhibit an objective 
response on subsequent tumor evaluations per irRC.  
4- Overall Survival will be calculated from the time of registration 
till the time of subject death  
5- Toxicity of therapy will be assessed per CTCAE v4 
6- Response rate per Immune Related Response Criteria (irRC) 
 
Exploratory Objectives 
1. Assess the association between TLR4, MyD88, NF-kB expression 
by IHC and response rate 
2. Assess Microsatellite status by IHC


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3. Assess the association between HMGB1 blood level and response 
rate 
4. Assess the association between PD-L1 expression and response 
rate 
5. Blood samples will be stored in the HCRN Biorepository for 
future correlatives. 
6. Tissue samples will be stored in the HCRN Biorepository for 
future correlatives.
STUDY DESIGN 
Multi-institutional, single arm, open-label, phase II study, including a 
safety run-in cohort. No randomization or blinding involved. 
ESTIMATED 
NUMBER OF 
SUBJECTS  
N = 30 
ELIGIBILITY 
CRITERIA  
Inclusion Criteria 
1. Be willing and able to provide written informed consent for the 
trial and HIPAA authorization for release of personal health 
information. 
NOTE: HIPAA authorization may be included in the informed 
consent or obtained separately. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Have a performance status of 0 or 1 on the ECOG Performance 
Scale within 14 days prior to registration. 
4. Have histological or cytological evidence of colorectal 
adenocarcinoma with confirmation of metastatic disease either by 
pathologic or radiologic findings.  
5. Have identified tissue from an archival tissue sample (preferably 
from a metastasis, but sample from primary tumor allowable) or 
newly obtained core or excisional biopsy of a tumor lesion. 
6. Have had no prior systemic therapy for advanced or metastatic 
disease. Prior adjuvant therapy should have been completed at 
least 9 months from documentation of metastatic disease. 
7. Have measurable disease according to RECIST v1.1 obtained by 
imaging within 28 days prior to registration.  
8. Hemoglobin ≥ 9 g/dL (transfusions are acceptable) 
9. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
10. Platelets ≥ 100 × 109/L 
11. Serum creatinine ≤ 1.5 × upper limit of normal (ULN), or 
measured or calculated creatinine clearance (estimated by 
Cockcroft-Gault formula below or measured) ≥ 50 mL/min  
12. Serum total bilirubin ≤ 1.5 × ULN  
13. Aspartate aminotransferase (AST, SGOT) and alanine 
aminotransferase (ALT, SGPT) ≤ 3 × ULN, unless evidence of 
liver metastases, then AST/ALT ≤ 5 x ULN 
 


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14. International Normalized Ratio (INR) or Prothrombin Time (PT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy as 
long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
15. Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN 
unless subject is receiving anticoagulant therapy as long as PT or 
PTT is within therapeutic range of intended use of anticoagulants  
16. Female subject of childbearing potential should have a negative 
urine or serum pregnancy within 14 days prior to study 
registration. If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required. Subjects of 
childbearing potential (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) are 
those who meet the following criteria: 
• Has not undergone a hysterectomy or bilateral 
oophorectomy; or 
• Has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the 
preceding 12 consecutive months). 
17. Female subjects of childbearing potential should be willing to use 
2 methods of birth control or be surgically sterile, or abstain from 
heterosexual activity for the course of the study through 120 days 
after the last dose of study medication.  
 
Exclusion Criteria 
1. Has clearly resectable colon cancer liver metastases (CCLM), for 
example oligometastatic disease involving only one lobe of the 
liver. Subjects with suspected resectable CCLM should undergo 
evaluation by a liver surgeon prior to enrollment to document the 
incurable nature of their disease. 
2. Is currently participating in or has participated in a study of an 
investigational agent or using an investigational device within 4 
weeks of registration. Subjects are not permitted to participate in 
another investigational drug study while being treated on this 
protocol. 
3. Is unable to receive a port or peripherally inserted central catheter 
(PICC). 
4. Has a diagnosis of immunodeficiency or is receiving chronic 
steroid therapy of prednisone ≥ 10 mg daily or any equivalent dose 
of corticosteroids. 
 
5. Has previously undergone organ or bone marrow transplantation 
and is on immunosuppressive therapy 
6. Has had major surgery or significant traumatic injury within 4 
weeks of study registration. Subject must have recovered 
adequately from the toxicity and/or complications from the 
intervention prior to starting therapy. A diagnostic or research 


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biopsy does not exclude subjects from enrollment. Placement of a 
vascular access device such as a Port-A-Cath is not considered 
major surgery 
7. Has baseline peripheral neuropathy/paresthesia grade ≥ 1. 
8. Has a known additional malignancy within the past 3 years. 
Exceptions include treated localized basal cell or squamous cell 
carcinoma of the skin, in situ cervical or vulvar carcinoma that has 
undergone potentially curative therapy, superficial bladder tumors 
(Ta, Tis & T1), ductal carcinoma in situ (DCIS) of the breast and 
low grade prostate cancer (Gleason sore 6). Any cancer curatively 
treated > 3 years prior to registration with no clinical evidence of 
recurrence is permitted 
9. Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. Subjects with previously treated brain 
metastases may participate provided they are stable (without 
evidence of progression by imaging for at least four weeks prior to 
trial registration 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 
registration.  
10. Has an active autoimmune disease requiring systemic treatment 
within the past 3 months or a documented history of clinically 
severe autoimmune disease, or a syndrome that requires systemic 
steroids or immunosuppressive agents. Exceptions to the rule: 
• Subjects with vitiligo  
• Subjects with resolved childhood asthma/atopy.  
• Subjects that require intermittent use of bronchodilators or 
local steroid injections.  
• Subjects with hypothyroidism stable on hormone 
replacement or  
• Sjögren’s syndrome  
11. Has a history of pneumonitis that required steroids or current 
pneumonitis. 
12. Has known history of active tuberculosis. 
13. Has an active infection requiring systemic therapy (≥ grade 2) for 
more than 3 days within 1 week of enrollment. 
14. Is pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the 
pre-screening or screening visit through 120 days after the last 
dose of Pembrolizumab. 
15. Has known hypersensitivity to fluorouracil (5FU), oxaliplatin, or 
other platinum agents. 
16. Known hypersensitivity to pembrolizumab or any of its excipients. 
17. Has known dihydropyrimidine dehydrogenase deficiency (DPD) 
deficiency (testing not required) 
18. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-


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PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated 
antigen-4 (CTLA-4) antibody (including ipilimumab or any other 
antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways). 
19. Has known active Hepatitis B unless patient subject has been on 
antiviral agents for at least 2 months (baseline testing not required) 
20. Has a known history of Human Immunodeficiency Virus (HIV) or 
Hepatitis C (baseline testing is not required). 
21. Has received a live vaccine within 30 days prior to trial 
registration.  
22. Has a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, 
interfere with the subject’s participation for the full duration of the 
trial, or is not in the best interest of the subject to participate, in the 
opinion of the site investigator.  
23. Has known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
24. Has any other psychological, familial, sociological or geographical 
condition potentially hampering compliance with the study 
protocol and follow-up schedule. Those conditions should be 
discussed with the subject before registration in the trial. 
STATISTICAL 
CONSIDERATIONS 
 
This is a multi-institutional, single arm, open-label, phase II study, 
including a safety run-in cohort, of the combination of pembrolizumab 
plus FOFLOX in subjects with untreated locally advanced or metastatic 
colorectal cancer. After a safety run-in cohort of 6 subjects at the tolerated 
dose level, 24 additional subjects will be enrolled. These 30 subjects will 
be analyzed as a single cohort for subsequent efficacy and safety analyses. 
PFS and OS will be estimated by Kaplan-Meier method. Median PFS 
(mPFS) and OS (mOS) will be estimated with 80% confidence intervals 
(CIs). The response rates will be estimated with their Agresti-Coull 95% 
CIs. Duration of response will be summarized by descriptive statistics. 
Frequencies and proportions will be used to describe toxicities. Common 
Terminology Criteria for Adverse Events (CTCAE) v4 will be used for 
assessment of acute and late toxicities during the follow-up period. 
Logistic regressions will be used for the exploratory objectives studying 
potential predictors of responses. 
 
Historically, first line FOLFOX achieves an mPFS of 9-months. If there 
are moderate evidences that adding Pembrolizumab will increase mPFS 
from 9- to around 14-months, a full scale randomized Phase II study will 
be considered to formally test whether the improvement is meaningful and 
statistically significant.  
 
The sample size N=30 is determined based on budget/recruitment 
considerations and precision of estimation. We expect that these 30 


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subjects will be uniformly accrued within 12-months with an additional 
24-months follow up. Kaplan-Meier method will be used to estimate PFS. 
mPFS and its two-sided 80% CI will be calculated. Consequently, the 
half-width of the CI from the lower bound to the point estimate of mPFS 
will be around 4.5-months, which is smaller than the difference between 
14- and 9-months. We consider this precision level will allow a decision 
to be made whether to pursue further studies. 
 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated months: 12 months 
ESTIMATED STUDY 
DURATION  
Estimated months: 24 months 
 
 


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TABLE OF CONTENTS 
 
SCHEMA ........................................................................................................................................... 10 
1. 
BACKGROUND AND RATIONALE ............................................................................ 11 
2. 
STUDY OBJECTIVES .................................................................................................... 15 
3. 
ELIGIBILITY CRITERIA .............................................................................................. 16 
4. 
SUBJECT REGISTRATION .......................................................................................... 17 
5. 
TREATMENT PLAN ...................................................................................................... 19 
6. 
TREATMENT DISCONTINUATION ........................................................................... 34 
7. 
STUDY SCHEDULE OF EVENTS ................................................................................ 35 
8. 
CRITERIA FOR DISEASE EVALUATION ................................................................. 41 
9. 
BIOLOGICAL SPECIMEN PARAMETERS FOR CORRELATIVES ..................... 49 
10. 
STUDY DRUG INFORMATION ................................................................................... 50 
11. 
ADVERSE EVENTS ........................................................................................................ 55 
12. 
STATISTICAL METHODS ............................................................................................ 59 
13. 
TRIAL MANAGEMENT ................................................................................................ 62 
14. 
DATA HANDLING AND RECORD KEEPING .......................................................... 63 
15. 
ETHICS ............................................................................................................................. 65 
16. 
REFERENCES ................................................................................................................. 66 
17. 
APPENDIX ....................................................................................................................... 69 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14 days prior to registration 
Medical and laboratory testing 
Disease progression  
suspected 
Sustained CR or PR, SD 
Continue treatment for 24 
months then observe 
radiographically  
See Section 7.4 
Informed consent
Pathologically confirmed untreated, advanced unresectable 
or metastatic adenocarcinoma of the colon. ECOG 0-1. 
28 days prior to registration: 
• 
Radiological assessment/tumor measurements 
• 
Identify available archived samples of tumor 
(preferably from a metastatic lesion 
mFOLFOX6 Treatment D1 and D15 
(Cycle = 28 days) 
• 
Oxaliplatin IV over 2 hrs 
• 
Leucovorin IV over 2 hrs 
• 
5FU IV over 46 hrs 
 
Pembrolizumab IV over 30 minutes 
every 3 weeks 
Disease evaluation every 8 weeks or after every 2 cycles 
If archival tissue is not identified the 
patient will undergo a new biopsy 
prior to treatment if other eligibility 
criteria are met. 


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1. 
BACKGROUND AND RATIONALE 
 
1.1. 
Background 
Human cancers harbor numerous genetic and epigenetic alterations, generating neo-antigens 
that are potentially recognizable by the immune system. Cancer evolves when intrinsic and 
extrinsic aberrations occur. Intrinsic genetic errors lead to oncogenic activation and evasion 
of apoptosis, and an extrinsic aberration involves complex microenvironment interactions, 
and escaping immune surveillance [1] and immune mediated death [2]. Although an 
endogenous immune response to cancer is observed in preclinical models and patients, this 
response is commonly ineffective to eliminate the tumor [3]. This is based on the hypothesis 
that cancer develops multiple resistance mechanisms, including local immune suppression, 
induction of tolerance, and systemic dysfunction in T-cell signaling. Additionally, there is a 
collective evidence that the innate immune system can play a role as an extrinsic tumor 
suppressor, and in some cases, promote tumor growth [4]. This complex function of innate 
and adaptive immune system is commonly referred to as immunoediting [5]. The presence 
of tumor infiltrating lymphocytes (TIL) in the tumor microenvironment is associated with 
improved outcome in patients with several malignancies including colon cancer [6-10]. 
Additionally, the concentration of TILs in colorectal liver metastases is associated with 
improvement in progression free survival, and better response to chemotherapy [11]. The 
immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) that is present in the tumor 
microenvironment is associated with decreased CD3 tumor infiltrating cells, and higher risk 
of developing liver metastases from colon cancer tumors[12]. Programmed death 1 (PD-1) is 
a key immune checkpoint receptor expressed by activated T cells, and it mediates 
immunosuppression [13]. PD-1, in addition to several inhibitory and stimulatory key 
immune modulators, regulates the activity and function of T cells. When PD-1 is unbound, 
the T cells on which it is expressed can engage and kill target cells, but when bound to its 
ligands PD-L1 and PD-L2, it acts as a brake that inhibits T cell activities particularly during 
their cytotoxic attack in the tumor itself. Its ligands are overexpressed directly on cancer 
cells, and their interaction with PD-1 prevents tumor-infiltrating T cells from recognizing 
their quarry [14].  
 
1.2. 
Immunotherapy and Cancer  
The concept of reprogramming the immune system to recognize cancer as a “foreign entity” 
has been explored for decades. In fact, BCG was one of the first local immunotherapies used 
to treat early stage superficial bladder cancer [15]. Since then a tremendous effort has been 
made to explore several ways of stimulating the immune system and reprogram it to fight 
cancer. Early studies with interleukin 2 in melanoma and renal cell carcinoma exhibited low 
response rate, but was associated with first long durable responses in patients with 
metastatic disease [16]. Sipuleucel-T consists of autologous peripheral blood mononuclear 
cells, including APCs, that have been activated during a defined period in cell culture with 
recombinant human PAP–GM-CSF decreased risk of death for men with castrate resistant 
prostate cancer [17]. While some tumors appear to be more immunogenic than others, recent 
data supported the potential promise of vaccine therapy in patients with gastrointestinal 
malignancies such as pancreatic adenocarcinoma [18, 19]. 
 


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The human immune system is under a complex regulatory structure. Several key factors 
work as inhibitory checkpoints and others are immune stimulatory [20]. Perhaps the 
antibody targeting the negative immune checkpoint inhibitors are the most advanced in 
clinical trials amongst other immune modulatory agents. CTLA4, PD-1, PD-L1 and PD-L2 
antagonists have already been evaluated in advanced melanoma with promising results [21-
23]. Ipilimumab (CTLA4 antagonist) is the first immune checkpoint inhibitor to be granted 
FDA approval for the treatment of advanced melanoma. Combination checkpoint inhibitors 
have demonstrated a promising new era of cancer immune therapy [21]. Proposals to 
evaluate whether combining a checkpoint inhibitor with an immune stimulatory compound 
will be safe and effective are underway.  
 
1.3. 
Pembrolizumab  
Pembrolizumab is a highly selective, humanized monoclonal IgG4–kappa isotype antibody 
against PD-1 that is designed to block the negative immune regulatory signaling of the PD-1 
receptor expressed by T cells. The IgG4 immunoglobulin subtype does not engage Fc 
receptors or activate complement, thus avoiding cytotoxic effects of the antibody when it 
binds to the T cells that it is intended to activate [24]. In a phase I dose escalation study, 9 
patients were enrolled at three different dose levels: 1mg/kg, 3 mg/kg and 10 mg/kg with no 
observed dose limiting toxicity of the compound with evidence of response in a patient with 
melanoma [23]. As a result, 135 patients with advanced melanoma were treated with 
pembrolizumab and experienced a high rate of sustained tumor regression, even in patients 
who received prior CTLA4 inhibitor [24].  
 
Toxicity associated with pembrolizumab were mainly grade 1 and 2 per the CTCAE, 
however 13% of patients experienced grade 3 and 4. The most commonly reported treatment 
emergent AEs experienced are fatigue (43.8%), nausea (26.7%), cough (25.3%), pruritus 
(24.6%), diarrhea (22.3%), and rash (21.5%). Immune-related adverse events were reported 
in 21.4% of melanoma patients; most of these events (15.8%) were considered drug-related 
by the investigator. The most commonly reported immune-related adverse events across the 
dose-schedules are rash (3.2%), pruritus (2.9%), vitiligo (2.9%), hypothyroidism (2.7%), 
arthralgia (2.2%), diarrhea (2.2%), and pneumonitis (1.9%).  
 
1.3.1 Pembrolizumab Dose 
Available PK results in subjects with melanoma, NSCLC, and other solid tumor types 
support a lack of meaningful difference in PK exposures obtained at a given dose among 
tumor types. An open-label Phase 1 trial (PN001) in melanoma subjects is being conducted 
to evaluate the safety and clinical activity of single agent pembrolizumab. The dose 
escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, 
administered every 2 weeks (Q2W) in subjects with advanced solid tumors. All three-dose 
levels were well tolerated and no dose-limiting toxicities were observed. This first in human 
study of pembrolizumab showed evidence of target engagement and objective evidence of 
tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No 
maximum tolerated dose (MTD) has been identified. 
 
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed. The 


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clinical efficacy and safety data demonstrate a lack of clinically important differences in 
efficacy response or safety profile at these doses. For example, in Cohort B2, advanced 
melanoma subjects who had received prior ipilimumab therapy were randomized to receive 
pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W.  The overall response rate (ORR) was 
26% (21/81) in the 2mg/kg group and 26% (25/79) in the 10 mg/kg group (full analysis set 
(FAS)). The proportion of subjects with drug-related adverse events (AEs), grade 3-5 drug-
related AEs, serious drug-related AEs, death or discontinuation due to an AE was 
comparable between groups or lower in the 10 mg/kg group.   
 
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid 
tumor types support a lack of meaningful difference in pharmacokinetic exposures obtained 
at a given dose among tumor types. Population PK analysis has been performed and has 
confirmed the expectation that intrinsic factors do not affect exposure to pembrolizumab to a 
clinically meaningful extent. Taken together, these data support the use of lower doses (with 
similar exposure to 2 mg/kg Q3W) in all solid tumor indications. 2 mg/kg Q3W is being 
evaluated in NSCLC in PN001, Cohort F30 and PN010, and 200 mg Q3W is being 
evaluated in head and neck cancer in PN012, which are expected to provide additional data 
supporting the dose selection. 
 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on 
simulation results indicating that 200 mg will provide exposures that are reasonably 
consistent with those obtained with 2 mg/kg dose and importantly will maintain individual 
patient exposures within the exposure range established in melanoma as associated with 
maximal clinical response. A population PK model, which characterized the influence of 
body weight and other patient covariates on exposure, has been developed using available 
data from 476 subjects from PN001. The distribution of exposures from the 200 mg fixed 
dose are predicted to considerably overlap those obtained with the 2 mg/kg dose, with some 
tendency for individual values to range slightly higher with the 200 mg fixed dose. The 
slight increase in PK variability predicted for the fixed dose relative to weight-based dosing 
is not expected to be clinically important given that the range of individual exposures is well 
contained within the range of exposures shown in the melanoma studies of 2 and 10 mg/kg 
to provide similar efficacy and safety. 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 tumor types and indication settings.   
 
1.4. 
Rationale for this Combination 
Until recently, a commonly held opinion was that chemotherapy and immunotherapy should 
not be combined because of the myelosuppressive effect of most cytotoxic agents. However, 
it has now become evident that chemotherapeutics can exert several beneficial effects on the 
immune system. Several studies demonstrated an “immunogenic cancer death” associated 
with certain cytotoxic chemotherapies. In particular, it has been demonstrated that 
oxaliplatin (OXP), but not cisplatin, induces immunogenic death of cancer cells [25]. Cancer 
cells undergo immunogenic apoptosis in response to OXP, meaning that their corpses are 
engulfed by dendritic cells (DC) and that tumor cell antigens are presented to tumor-specific 
CD8+ T cells, which then control residual tumor cells. One of the peculiarities of 


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immunogenic apoptosis is the early cell surface exposure of calreticulin (CRT). Pioneering 
work by Zitvogel et al. has shown that OXP induces immunogenic cell death, as upon 
treatment with OXP, tumor cells transport CRT to their cell surface. The exposure of CRT 
provides a signal that is recognized by DCs and ultimately results in phagocytosis of tumor 
cells [26]. Exposure of tumor cells to OXP also results in the release of high mobility group 
box 1 (HMGB1) protein [27], which activates DCs in a toll-like receptor-4 (TLR4)-
dependent manner. This in turn activates DC and leads to cytotoxic T-lymphocyte (CTL) 
infiltration of the tumor [28]. OXP also reduces expression of PD-L2 resulting in enhanced 
antigen-specific proliferation and Th1 cytokine secretion [29].  
 
Additionally, releasing antigens following effective therapy increases the cross presentation 
of these antigens, leading to increase in functional T lymphocytes activity in vivo [30]. 
Several mechanisms on how antigen presenting cells and other T cell inhibitory/stimulatory 
factors can interact following chemotherapy have been previously explored and discussed in 
detail [31]. Constant antigen presentation by APC, may lead to the upregulation of CTL 
stimulatory factors leading to activation of the immune response to antigen release [32]. 
 
While early phase studies [14, 22] included patients with colorectal cancer with no evidence 
of objective response, our proposal differs in the concept that it is evaluating the 
immunogenic effect of OXP on cell death leading to a magnified response when combined 
with pembrolizumab. Since mFOLFOX6 can induce an objective response (>30% tumor 
shrinkage per RECIST criteria) in nearly 50% of patients with metastatic colorectal cancer 
(mCRC) [33], this might lead to stimulating the immune response through OXP mediated 
immune cell death in addition to massive release of intracellular antigens from dying cancer 
cells leading to APCs chain activation.  
 
The combination of OXP and 5FU (mFOLFOX6) represents a widely accepted standard of 
care for the treatment of patients with metastatic colorectal cancer, and is commonly used in 
the first line setting with or without biologic agents [34, 35]. Oxaliplatin demonstrated 
synergic effect in combination with 5FU and represented a paradigm shift in the 
management of patients with advanced colorectal cancer leading to superior response rate, 
progression free survival, and overall survival. Given the previous data referenced, there is a 
substantial rationale to combine pembrolizumab with mFOLFOX6 in patients with untreated 
locally advanced or metastatic colorectal cancer. Here we propose a phase II study of 
pembrolizumab plus mFOLFOX6 in subjects with untreated locally advanced or metastatic 
colorectal cancer.  
 
 
 
 
 


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2. 
STUDY OBJECTIVES 
 
2.1. 
Primary Objective 
• Estimate median progression free survival (mPFS) and compare to historical standard 
 
• Primary Endpoint   
o Median progression free survival as measured from the time of registration to the 
time of progression per RECIST v1.1 or subject death  
 
2.2. 
Secondary Objectives 
• Objective response rate (ORR)  
• Disease control rate (DCR)  
• Delayed response  
• Overall Survival (OS)  
• Toxicity of the combination of pembrolizumab plus mFOLFOX6  
• Response Criteria per established Immune Related Response Criteria 
 
• Secondary Endpoints 
o ORR will be calculated with combining the number of subjects who achieve 
complete response and partial response per irRC criteria. 
o Disease control rate; defined as the sum of subjects with complete response, 
partial response and stable disease.  
o Delayed response will be evaluated in subjects who achieve stable disease on 
first tumor assessment but they exhibit an objective response on subsequent 
tumor evaluations per irRC.  
o Overall Survival will be calculated from the time of registration till the time of 
subject death  
o Toxicity of therapy will be assessed per CTCAE V4 
o Response rate per Immune Related Response Criteria (irRC) 
 
2.3. 
Exploratory Objectives 
• Assess the association between TLR4, MyD88, NF-kB expression by IHC and response 
rate. 
• Assess Microsatellite status by IHC. 
• Assess the association between HMGB1 blood level and response rate. 
• Assess the association between PD-L1 expression and response rate. 
• Blood samples will be stored in the HCRN Biorepository for future correlatives.  
• Tissue samples will be stored in the HCRN Biorepository for future correlatives 
 


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3. 
ELIGIBILITY CRITERIA 
 
3.1. 
Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent for the trial and HIPAA 
authorization for release of personal health information. 
• NOTE: HIPAA authorization may be included in the informed consent or 
obtained separately. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Have a performance status of 0 or 1 on the ECOG Performance Scale within 14 days 
prior to registration. 
4. Have histological or cytological evidence of colorectal adenocarcinoma with 
confirmation of metastatic disease either by pathologic or radiologic findings.  
5.  Have identified tissue from an archival tissue sample (preferably from a metastasis, 
but sample from primary tumor allowable) or newly obtained core or excisional 
biopsy of a tumor lesion.  See Section 9 for more details. 
6. Have had no prior systemic therapy for advanced or metastatic disease. Prior 
adjuvant therapy should have been completed at least 9 months from documentation 
of metastatic disease.  Prior palliative radiotherapy allowed if toxicities resolved to 
grade 1 or baseline.  
7. Have measurable disease according to RECIST v1.1 obtained by imaging within 28 
days prior to registration.  
8. Hemoglobin ≥ 9 g/dL (transfusions are acceptable) 
9. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
10. Platelets ≥ 100 × 109/L 
11. Serum creatinine ≤ 1.5 × upper limit of normal (ULN), or measured or calculated 
creatinine clearance (estimated by Cockcroft-Gault formula below or measured) ≥ 50 
mL/min  
• Males: (140 – Age in years) × Actual Body Weight in kg 
                                        72 × Serum Creatinine (mg/dL) 
• Females: Estimated creatinine clearance for males × 0.85 
12. Serum total bilirubin ≤ 1.5 × ULN  
13. Aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, 
SGPT) ≤ 3 × ULN, unless evidence of liver metastases, then AST/ALT ≤ 5 x ULN 
14. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless 
subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
15. Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is 
receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants  
16. Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 14 days prior to study registration. If the urine test is positive 
or cannot be confirmed as negative, a serum pregnancy test will be required. Subjects 
of childbearing potential (regardless of sexual orientation, having undergone a tubal 
ligation, or remaining celibate by choice) are those who meet the following criteria: 
• Has not undergone a hysterectomy or bilateral oophorectomy; or 


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• Has not been naturally postmenopausal for at least 24 consecutive months 
(i.e., has had menses at any time in the preceding 12 consecutive months). 
17. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication.  
 
3.2. 
Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has clearly resectable colon cancer liver metastases (CCLM), for example 
oligometastatic disease involving only one lobe of the liver. Subjects with suspected 
resectable CCLM should undergo evaluation by a liver surgeon prior to enrollment 
to document the incurable nature of their disease. 
2. Is currently participating in or has participated in a study of an investigational agent 
or using an investigational device within 4 weeks of registration. Subjects are not 
permitted to participate in another investigational drug study while being treated on 
this protocol. 
3. Is unable to receive a port or peripherally inserted central catheter (PICC). 
4. Has a diagnosis of immunodeficiency or is receiving chronic steroid therapy of 
prednisone ≥ 10 mg daily or any equivalent dose of corticosteroids. 
5. Has previously undergone organ or bone marrow transplantation and is on 
immunosuppressive therapy 
6. Has had major surgery or significant traumatic injury within 4 weeks of study 
registration. Subject must have recovered adequately from the toxicity and/or 
complications from the intervention prior to starting therapy. A diagnostic or 
research biopsy does not exclude subjects from enrollment. Placement of a vascular 
access device such as a Port-A-Cath is not considered major surgery. 
7. Has baseline peripheral neuropathy/paresthesia grade ≥ 1. 
8. Has a known additional malignancy within the past 3 years. Exceptions include 
treated localized basal cell or squamous cell carcinoma of the skin, in situ cervical or 
vulvar carcinoma that has undergone potentially curative therapy, superficial bladder 
tumors (Ta, Tis & T1), ductal carcinoma in situ (DCIS) of the breast and low grade 
prostate cancer (Gleason sore 6). Any cancer curatively treated > 3 years prior to 
registration with no clinical evidence of recurrence is permitted 
9. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to trial registration 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 registration.  
10. Has an active autoimmune disease requiring systemic treatment within the past 3 
months or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents. Exceptions 
to the rule: 
• Subjects with vitiligo  
• Subjects with resolved childhood asthma/atopy  


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• Subjects that require intermittent use of bronchodilators or local steroid 
injections 
• Subjects with hypothyroidism stable on hormone replacement  
• Subjects with Sjögren’s syndrome  
11. Has a history of pneumonitis that required steroids or current pneumonitis. 
12. Has known history of active tuberculosis. 
13. Has an active infection requiring systemic therapy (≥ grade 2) for more than 3 days 
within 1 week of enrollment. 
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of pembrolizumab. 
15. Has known hypersensitivity to fluorouracil (5FU), oxaliplatin, or other platinum 
agents. 
16. Known hypersensitivity to pembrolizumab or any of its excipients. 
17. Has known dihydropyrimidine dehydrogenase deficiency (DPD) deficiency (testing 
not required) 
18. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation 
or checkpoint pathways). 
19. Has known active Hepatitis B unless subject has been on antiviral agents for at least 
2 months (baseline testing not required) 
20. Has a known history of Human Immunodeficiency Virus (HIV) or Hepatitis C 
(baseline testing is not required). 
21. Has received a live vaccine within 30 days prior to trial registration.  
22. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the subject’s 
participation for the full duration of the trial, or is not in the best interest of the 
subject to participate, in the opinion of the site investigator.  
23. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
24. Has any other psychological, familial, sociological or geographical condition 
potentially hampering compliance with the study protocol and follow-up schedule. 
Those conditions should be discussed with the subject before registration in the trial. 
 
4. 
SUBJECT REGISTRATION 
All subjects must be registered through Hoosier Cancer Research Network (HCRN) 
electronic data capture OnCore prior to starting protocol therapy. A subject is considered to 
be registered to the protocol when an “On Study” date has been entered into OnCore.   
 
Subjects must begin therapy within five business days of the “On Study” date. 
 
 
 


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5. 
TREATMENT PLAN 
 
5.1 
Drug Administration 
 
The treatment to be used in this trial is outlined below in Table 1 and will consist of: 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion, with a window of -
5 and +10 minutes.  
 
mFOLFOX6 premedications and chemotherapy will be administered 30 minutes after 
pembrolizumab.  mFOLFOX is to be given at each site per their guidelines.  Administration 
of mFOLFOX6 outside the suggested time will not be considered a deviation. 
• Oxaliplatin 85 mg/m2 IV with  
• Leucovorin 400 mg/m2 IV followed by  
• 5FU 400 mg/m2 bolus and then 2400 mg/m2 via continuous infusion  
 
See Section 5.2.3 for premedications recommendations for mFOLFOX6. Standard 
supportive care should be followed at each site per their guidelines. Subjects should receive 
full supportive care, including transfusions of blood and blood products, antibiotics, 
antiemetics, etc., when appropriate. The use of epoetin products is not allowed. 
 
NOTE: Chemotherapy (mFOLFOX6) dose re-calculation on Day 1 is necessary for subjects 
who have >10% weigh change (gain or loss) from baseline. All BSA-based doses should use 
actual, not adjusted, weight.  
 
Table 1: Drug Administration Schedule 
Cycle = 28 days 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Duration 
Pembrolizumab  
200 mg 
every 3 weeks 
30-minute IV 
infusion 
up to 24 
months 
mFOLFOX6 premeds and chemo will be administered 30 minutes after pembrolizumab  
Oxaliplatin 
85 mg/m2 
every 2 weeks 
IV 
Leucovorin 
400 mg/m2 
every 2 weeks 
IV 
5FU 
400 mg/m2 bolus, 
then 2400 mg/m2 
every 2 weeks 
IV continuous 
infusion 


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5.2 
Safety run-in cohort 
The safety run-in cohort will include 6 subjects treated with 200 mg (fixed) IV infusion of 
pembrolizumab every 3 weeks plus standard-dose mFOLFOX6 given every 2 weeks. These 
first 6 subjects will be followed for 4 weeks for dose limiting toxicities (DLT) before 
enrolling an additional 24 subjects. If a DLT is observed in no more than 1 of 6 subjects, the 
trial will continue with enrolling subjects to the remainder of the phase II portion of the 
study. If 2 or more subjects experience DLT, 6 additional subjects will be enrolled at dose 
level -1. If no more than 1 DLT is observed, then phase II will enroll subjects at DL-1 for 
the total expected number of accrual. Otherwise, accrual will stop and the funder and 
sponsor-investigator will re-evaluate continuation of the trial. 
 
Number of subjects with DLT 
Action 
≤1 of 6 subjects 
Proceed with remainder of Phase II 
≥2 of 6 subjects 
MTD has been exceeded.  Enroll 6 subjects at dose 
level -1 and re-evaluate. 
 
A given dose cohort may be expanded up to a total of 12 subjects if further evaluation of the 
frequency of a given toxicity is warranted, based upon the observed safety profile in the 6 
subjects already recruited in the cohort, and where the incidence of the confirmed DLT does 
not exceed 33%.   
 
5.2.1 Dose limiting toxicity definition:  
Dose limiting toxicity (DLT) is defined as one of the following treatment-related events 
occurring during the first 4 weeks of treatment: 
• Any Grade 3-4 toxicity other than:  
o fatigue, or 
o nausea, vomiting, or diarrhea lasting less than 72 hours;  
• Grade 3-4 thrombocytopenia or neutropenia that leads to treatment delays for > 14 
days.  
• Grade 4 febrile neutropenia if DPD deficiency is ruled out and subject requires delay 
for the next cycle >14 days 
• Grade 3-4 Nausea, vomiting or diarrhea lasting 72 hours or longer despite maximal 
supportive care including anti emetics, intravenous hydration, anti-diarrhea agents 
and short term steroid use, if indicated.  
• Asymptomatic grade 3-4 laboratory abnormalities will be discussed between the site 
investigator and sponsor-investigator before being assigned as DLT.   
 
 
 


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5.2.2 Dose Level -1 
Pembrolizumab: 200 mg IV 
Oxaliplatin: 65 mg/m2 IV; Leucovorin: 400 mg/m2 IV; 5FU: 320 mg/m2 IV bolus then 5FU: 
1920 mg/m2 continuous infusion over 46 hours 
Cohort 
Pembrolizumab  
Oxaliplatin 
Leucovorin 
5FU 
0 (start) 
200 mg IV 
85 mg/m2 IV 
400 mg/m2 IV 
400 mg/m2 IV bolus 
then 2400 mg/m2 
-1 
200 mg IV 
65 mg/m2 IV 
400 mg/m2 IV 
320 mg/m2 IV bolus 
then 1920 mg/m2 
 
5.3 
Phase II 
If dose-limiting toxicity is observed in no more than 1 out of 6 subjects in the safety run-in 
cohort, the remainder of the subjects will be enrolled and treated at the current doses of 
pembrolizumab and mFOLFOX6. 
 
All subjects will continue study treatment for up to 24 months, until disease progression (as 
defined below at Section 8) or unacceptable treatment-related toxicity occurs. Subjects will 
continue to be followed until progression of disease or death. Subjects with sustained CR, 
PR or SD at 24 months will stop therapy and be observed per study imaging schedule. 
 
5.4 
Treatment Schedules 
Trial treatment should be administered on Day 1 of each cycle after all procedures/ 
assessments have been completed as detailed on the Study Schedule of Events (Section 7). 
Trial treatment may be administered up to 3 days before or after (±3 days) the scheduled 
Day 1 of each cycle due to administrative reasons.  All trial treatments will be administered 
on an outpatient basis. 
 
Pembrolizumab will be administered as a 30 minute IV infusion (treatment cycle intervals 
may be increased due to toxicity as described in Section 5.4). Sites should make every effort 
to target infusion timing to be as close to 30 minutes as possible. However, given the 
variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is 
permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
Please refer to the Study Procedures Manual (SPM) for specific instructions for 
pembrolizumab, reconstitution, preparation of the infusion fluid, and administration. 
mFOLFOX6 will be given per institutional standard of care.  Below are recommendations 
for pre-medication of mFOLFOX6. 
 
 


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Recommended pre-medications, hydration and prophylactic medications 
for mFOLFOX6 
Agent 
Dose/Precautions 
 
Route 
Schedule 
Ondansetron (or 
formulary 
equivalent).May 
consider use of 
palonosetron or 
addition of  
neurokinin receptor 
antagonist for D1 
24 mg Instruct subject 
to avoid exposure to 
cold (food, liquids, 
air) for 5 days 
following 
oxaliplatin 
PO 30 minutes prior 
to oxaliplatin 
Days 1 
  Prochlorperazine 
10 mg 
PO/IV q6h PRN 
for nausea or 
vomiting 
Days 1-14 
D5W 
100 cc/h 
IV during treatment 
for infusions in D5W 
and to flush lines 
between 
medications. 
Days 1 
Dexamethasone 
12 mg 
PO for nausea and 
vomiting unresponsive 
to above medications 
per site 
investigator 
discretion 
Loperamide (home 
instructions)1 
 
4 mg at onset of 
diarrhea, then 2mg q2h 
prn until diarrhea stops 
for at least 12 hours 
PO 
Days 1-14 
1For symptoms of diarrhea and/or abdominal cramping that occur at any time during a treatment cycle, 
subjects will be instructed to begin taking loperamide. Loperamide should be started at the earliest 
sign of (1) a poorly formed or loose stool or (2) the occurrence of 1 to 2 more bowel movements than 
usual in 1 day or (3) an increase in stool volume or liquidity. Loperamide should be taken in the 
following manner: 4 mg at the first onset of diarrhea, then 2 mg every 2 hours around the clock 
until diarrhea-free for at least 12 hours. Subjects may take loperamide 4 mg every 4 hours during 
the night. The maximum daily dose of loperamide is 16 mg/day. Subjects should be advised to obtain 
loperamide at the initial treatment visit so that they have sufficient supply on hand in case 
antidiarrheal support is required. Additional antidiarrheal measures may be used at the discretion of 
the site investigator. Subjects should be instructed to increase fluid intake to help maintain fluid and 
electrolyte balance during episodes of diarrhea. 
 
5.5 
Dose Modifications 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v4 will be used to 
grade adverse events. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and 
adverse events requiring study drug interruption or discontinuation at each study visit for the 
duration of their participation in the study. 
 
 
 
 


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5.5.1 Pembrolizumab Dose Modifications and Toxicity Management 
The starting dose amount required to prepare the pembrolizumab infusion solution is a fixed 
dose of 200 mg and does not require calculation.  On days when both chemotherapy and 
pembrolizumab are administered, if chemotherapy is held due to toxicity, pembrolizumab 
should also be held.  
 
Pembrolizumab will be held for the following hematologic AEs if related: 
• Hematologic toxicities  
o Any Grade 4  
o Grade 3 except neutropenia, anemia, thrombocytopenia and lymphopenia   
 
Pembrolizumab will be held for the following non-hematologic AEs if related:  
o Site investigators should consider holding pembrolizumab for Grade 2 toxicities with 
persistent symptoms unless specified in Table 2 below. 
o Any ≥ Grade 3 toxicities including laboratory abnormalities.  Exceptions include 
AST, ALT and bilirubin; Table 2 below should be followed in those instances. 
 
Table 2: Dose modification guidelines for drug-related non-hematological adverse 
events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 
mg or less of prednisone or equivalent per day 
within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 3-
4 hyperglycemia associated with 
evidence of beta cell failure.  
Resume pembrolizumab when subjects are 
clinically and metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 
mg or less of prednisone or equivalent per day 
within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 
mg or less of prednisone or equivalent per day 
within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
2-4 
Therapy with pembrolizumab can be 
continued while treatment for the 
thyroid disorder is instituted
Therapy with pembrolizumab can be continued 
while treatment for the thyroid disorder is 
instituted. 
Infusion Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
 
 


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Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 
mg or less of prednisone or equivalent per day 
within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 
mg or less of prednisone or equivalent per day 
within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity2 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 
mg or less of prednisone or equivalent per day 
within 12 weeks. 
4 
Permanently discontinue
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For subjects with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal 
to 50% relative to baseline and lasts for at least 1 week then subjects should be discontinued. 
2 Subjects with intolerable or persistent Grade 2 drug-related AE may hold study medication at site investigator discretion.  
Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that 
do not recover to Grade 0-1 within 12 weeks of the last dose.  
 
Any delays will be recorded in the appropriate electronic case report form(s). If needed, a 
site investigator may consult with the sponsor-investigator by contacting the HCRN Project 
Manager.  
 
If the toxicity does not resolve to Grade 0-1 within 4 weeks after last infusion, trial treatment 
should be discontinued per protocol guidelines.  With site investigator and sponsor-
investigator agreement, subjects with a laboratory adverse event still at Grade 2 after 4 
weeks may continue treatment in the trial only if asymptomatic and controlled.  See Section 
11 for information on the management of adverse events. 
 
Subjects who experience a recurrence of the same severe or life-threatening event at the 
same grade or greater with re-challenge of pembrolizumab should be discontinued from trial 
treatment. 
 
If a subject discontinues mFOLFOX6 treatment completely or any portion of this therapy 
(i.e. oxaliplatin) due to toxicity, the subject may elect to continue pembrolizumab with any 
portion of the original chemotherapy regimen or as a single-agent every 3 weeks per the 
protocol schedule for a total of 24 months, or may discontinue all study treatment and be 
treated at site investigator’s discretion. If all therapy is discontinued, it is recommended that 
subjects not be treated with a second-line chemotherapy regimen until disease progression 
has been documented.  Such subjects may continue to be imaged per the study guidelines 
until progression or complete withdrawal from the study. 
 
5.5.2 mFOLFOX6 Dose Modifications and Toxicity Management  
Missed doses of mFOLFOX6 will not be made up. Dose delays and treatment restarts will 
be made at the discretion of the site investigator according to institutional guidelines. Dose 
reduction of 5-FU and/or oxaliplatin is allowed and is recommended for grade 3 toxicities.   
 
Subjects will receive mFOLFOX6 per institutional guidelines. Below are optional guidelines 
for dose modification and toxicity management.  Subjects receiving oxaliplatin on this study 


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should be counseled to avoid cold drinks, chewing of ice chips, and exposure to cold water 
or air because the neurotoxicity often seen with oxaliplatin appears to be exacerbated by 
exposure to cold. The period of time during which the subject is at risk for these cold-
induced sensory neuropathies is not well documented. Subjects should exercise caution 
regarding cold exposure during the treatment period. Peripheral sensory neuropathies can 
occur at any time after receiving oxaliplatin therapy. 
• 
If a dose reduction beyond Level -3 is required for oxaliplatin, oxaliplatin will be 
discontinued. Continue 5-FU/leucovorin and pembrolizumab. 
• 
If a dose reduction beyond level -3 is required for 5-FU, discontinue 
m FOLFOX6. Continue pembrolizumab. 
• 
If more than one dose reduction applies, use the most stringent (i.e., the greatest dose 
reduction.) 
• 
If mFOLFOX6 is delayed due to toxicity for ≥ 4 weeks, counting from the originally 
scheduled day of treatment that was held, consider 2 level dose reductions. 
Continue pembrolizumab at the same dose level. 
• 
If pembrolizumab held due to toxicity not deemed related to mFOLFOX6, 
continue mFOLFOX6 therapy as scheduled. 
• 
Missed doses of any of the drugs are not made up. 
 
Dose Levels based on toxicity beyond DLT assessment period: 
Agent 
Level 0 
Level –1 
Level –2 
Level –3 
Oxaliplatin 
85 mg/m2 
65 mg/m2 
50 mg/m2 
40 mg/m2 
5-FU Bolus 
400 mg/m2 
320 mg/m2 
270 mg/m2 
230 mg/m2 
5-FU 
Infusion 
2400 mg/m2 
over 46-48 hrs 
1920 mg/m2 over 
46-48 hrs 
1600 mg/m2 
over 46-48 hrs 
1360 mg/m2 
over 46-48 hrs 
Leucovorin dose is always 400 mg/m
2. If 5-FU is skipped, leucovorin must also be skipped. 
 
 
Hematologic toxicities 
• Dose modifications for hematologic toxicities are based on CBC on Day 1 of 
each cycle of m FOLFOX6. CBC may be collected within 72 hours of treatment (or 
96 hours if due to holidays). 
• For ANC 1000-1199: Delay mFOLFOX6 until ANC ≥ 1200, then resume at the 
previous doses of oxaliplatin and 5-FU. 
• For ANC < 1000: Delay mFOLFOX6 until ANC ≥ 1200, then resume with one 
dose level reduction of oxaliplatin and 5-FU for all subsequent cycles. 
• For febrile neutropenia (defined as ANC < 1000 and T ≥ 38.5°C): Delay 
mFOLFOX6 until fever has resolved and ANC ≥ 1200, then resume mFOLFOX6 
with one dose level reduction of oxaliplatin and 5-FU for all subsequent cycles. 
• For platelets 50,000 – 74,999: Delay mFOLFOX6 until platelets ≥ 75,000, then 
resume at the previous dose levels of oxaliplatin and 5-FU. 
• 
For platelets < 50,000: Delay mFOLFOX6 until platelets ≥ 75,000, then resume 
with one dose level reduction of oxaliplatin and 5-FU for all subsequent cycles. 
 
 


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Gastrointestinal toxicities 
• For ≥ grade 2 diarrhea: Delay mFOLFOX6 until diarrhea improves to < grade 2. 
Hold pembrolizumab until diarrhea improves to < grade 2. 
• Following grade 2 diarrhea at any time during a cycle: Continue mFOLFOX6 
at the previous dose levels of oxaliplatin and 5-FU. 
• Following grade 3 diarrhea at any time during a cycle: Continue mFOLFOX6 
with one dose level reduction of 5-FU for all subsequent cycles and the previous 
dose level of oxaliplatin. 
• Following grade 4 diarrhea at any time during a cycle: Continue mFOLFOX6 
with one dose level reduction of oxaliplatin and 5-FU for all subsequent cycles. 
 
 
Oral Mucositis 
• For ≥ grade 2 oral mucositis present on Day 1 of a cycle, delay mFOLFOX6 
until mucositis improves to < grade 2. Continue pembrolizumab. 
• For grade 2 oral mucositis, at any time during a cycle, resume/continue 
mFOLFOX6 at the previous dose level. 
• For grade 3 or 4 oral mucositis, despite optimal management, at any time 
during a cycle, resume/continue mFOLFOX6 with one dose level reduction of 
5-FU and the previous dose level of oxaliplatin. 
 
Nausea or Vomiting  
• For grade ≥ 2 nausea or vomiting present on Day 1 of a cycle despite 
optimal antiemetic therapy, delay mFOLFOX6 until nausea and vomiting 
improve to < grade 2. Continue pembrolizumab. 
• For grade 2 nausea or vomiting, at any time during a cycle, 
resume/continue mFOLFOX6 at the previous dose levels. 
• For grade 3 nausea or vomiting, despite optimal antiemetic therapy, at any 
time during a cycle, resume/continue mFOLFOX6 with one dose level reduction of 
oxaliplatin and the previous dose level of 5-FU. 
• For grade 4 nausea or vomiting, despite optimal antiemetic therapy, at any 
time during a cycle, resume/continue mFOLFOX6 with one dose level reduction of 
oxaliplatin and 5-FU. 
 
Pulmonary Toxicities 
• For ≥ grade 3 cough, dyspnea, hypoxia, pneumonitis, or pulmonary infiltrates, 
skip oxaliplatin until interstitial lung disease is ruled out. Continue 5-
FU/leucovorin. Discontinue all protocol therapy if interstitial lung disease is 
confirmed. 
 
 
Thrombotic microangiopathy 
• 
For ≥ grade 3 hemolytic uremic syndrome (HUS): Discontinue oxaliplatin. Continue 
5- FU/leucovorin and pembrolizumab. 
 
 
 
 


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Neurotoxicity 
Toxicity Scale for the Sensory Neuropathies Associated with Oxaliplatin (using the Oxaliplatin 
Specific Neurotoxicity Scale) 
 
 
Symptoms 
Grade 1 
Paresthesias/dysesthesias* of short duration that resolve and do not 
interfere with function. 
Grade 2 
Paresthesias/dysesthesias* interfering with function, but not with 
activities of daily living (ADL) 
Grade 3 
Paresthesias/dysesthesias* with pain or with functional impairment that 
also interfere with ADL. 
Grade 4 
Persistent paresthesias/dysesthesias* that are disabling or life threatening. 
 
* May be cold-induced 
 
• For grade 2 neurotoxicity persisting between treatments: Continue mFOLFOX6 
with one dose level reduction of oxaliplatin for all subsequent cycles and the 
previous dose level of 5-FU. Continue pembrolizumab at the same dose level. 
• For grade 3 neurotoxicity resolving to ≤ grade 2 between treatments: Continue 
mFOLFOX6 with one dose level reduction of oxaliplatin for all subsequent 
cycles and the previous dose level of 5-FU. Continue pembrolizumab at the same 
dose level. 
• For grade 3 neurotoxicity persisting between treatments: Discontinue 
oxaliplatin. Continue 5-FU/leucovorin and pembrolizumab at the same dose level. 
• For grade 4 neurotoxicity: Discontinue oxaliplatin. Continue 5-FU/leucovorin 
and pembrolizumab at the same dose level. 
• For pharyngolaryngeal dysesthesia: Increase the duration of oxaliplatin 
infusion to 6 hours for all subsequent cycles.  
 
Extravasation 
Extravasation of oxaliplatin has been associated with necrosis; if extravasation is suspected, 
the infusion should be stopped and the drug administered at another site. Extravasation 
should be treated according to institutional guidelines. 
 
Allergic Reactions 
• For grade 1 allergic reactions: Decrease the infusion rate by 50% until symptoms 
resolve, then resume at the initial planned rate. 
• For grade 2 allergic reactions: Stop infusion. Administer H1 and/or H2 blockers, 
and/or steroids according to institutional policy. Restart the infusion when 
symptoms resolve and pretreat before all subsequent doses. Treat according to 
institutional policy. 
• For grade 3 or grade 4 allergic reactions or anaphylaxis: Stop the infusion. 
Discontinue oxaliplatin (if timing consistent with oxaliplatin hypersensitivity). 
Continue 5-FU and leucovorin and pembrolizumab. If grade 3 or 4 allergic reactions 
or anaphylaxis with first or second cycle, consider leucovorin as offending agent. 
Discontinue leucovorin and continue mFOLFOX6 (without leucovorin) and 
pembrolizumab. 


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Oxaliplatin-induced pharyngolaryngeal dysesthesia 
Should a subject develop oxaliplatin-induced pharyngolaryngeal dysesthesia, her/his oxygen 
saturation should be evaluated via a pulse oximeter; if abnormal, an anxiolytic agent may 
be given and the subject observed in the clinic until the episode has resolved. Increase 
the duration of oxaliplatin to 6 hours for all subsequent treatments. Some overlap may 
exist between the manifestations of pharyngolaryngeal dysesthesia and hypersensitivity 
reactions. A table comparing the two is presented below 
 
Comparison of the Symptoms and Treatment of Pharyngolaryngeal Dysesthesias and Platinum 
Hypersensitivity Reactions 
 
Clinical Symptoms 
Pharyngo-Laryngeal  Dysesthesias 
Platinum Hypersensitivity 
Dyspnea 
present
present 
Bronchospasm 
absent 
present 
Laryngospasm 
absent 
present 
Anxiety 
present 
present 
O2 saturation 
normal 
decreased 
Difficulty swallowing 
present (loss of sensation) 
absent 
Pruritus 
absent 
present 
Urticaria/rash 
absent 
present 
cold-induced symptoms 
yes 
no 
BP 
normal or increased 
normal or decreased 
Treatment 
anxiolytics, observation in a controlled 
clinical setting until symptoms abate or 
at the site investigator’s discretion 
oxygen, steroids, epinephrine, 
bronchodilators; fluids and 
vasopressors, if appropriate 
 
Cardiovascular toxicities 
• For grade 3 or 4 cardiac ischemia/infarction: Discontinue all protocol therapy 
(mFOLFOX6 and pembrolizumab). 
• For grade 3 or 4 cerebrovascular ischemia: Discontinue all protocol therapy 
(mFOLFOX6 and pembrolizumab). 
 
Other non-hematologic toxicities for mFOLFOX6 
For other grade 3 or 4 non-hematologic toxicities considered related to mFOLFOX6, delay 
mFOLFOX6 until toxicity resolves to ≤ grade 1, then resume mFOLFOX6 at one dose level 
reduction of oxaliplatin and 5-FU (if toxicity is hand-foot syndrome or stomatitis, dose 
reduction of only 5-FU bolus and continuous infusion of 5-FU is permitted). Continue 
pembrolizumab. 
 
Dose modifications for obese subjects 
There is no clearly documented adverse impact of treatment of obese subjects when 
dosing is performed according to actual body weight. Therefore, all dosing is to be 
determined solely by actual weight without any modification unless explicitly 
described in the protocol. This will eliminate the risk of calculation error and the possible 
introduction of variability in dose administration. Failure to use actual body weight in 
the calculation of drug dosages will be considered a major protocol deviation. Site 
investigators who are uncomfortable with calculating doses based on actual body weight 
should recognize that doing otherwise would be a protocol violation. 


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The actual weight on the day of registration or the first day of treatment may be used for 
cycle 1 unless the change in the weight results in a change in calculated dose ≥10%, in 
which case the weight on the day of treatment should be used. Over the course of treatment 
it is not required to change the doses of 5-FU, leucovorin or oxaliplatin due to changes 
in weight unless the calculated dose changes by ≥10%. 
 
5.6 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The site investigator should discuss any questions regarding 
this with the sponsor-investigator by contacting the HCRN project manager. The final 
decision on any supportive therapy or vaccination rests with the site investigator and/or the 
subject's primary physician. However, the decision to continue the subject on trial therapy or 
vaccination schedule requires the mutual agreement of the site investigator, the sponsor-
investigator, and the subject. Please contact the HCRN project manager in such cases. 
 
5.6.1 Acceptable Concomitant Medications 
All treatments that the site investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the site investigator in keeping with the community 
standards of medical care. All concomitant medication will be recorded on the case report 
form (CRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids.  If changes occur during the trial period, documentation of drug 
dosage, frequency, route, and date may also be included on the CRF. 
 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant 
medications administered 30 days after the last dose of trial treatment should be recorded if 
associated with SAEs and events of clinical interest (ECIs). 
 
5.6.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial. The Exclusion Criteria describes other medications that are 
prohibited in this trial. 
 
• Anti-cancer systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than Pembrolizumab 
• Radiation therapy  
 Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed after consultation with sponsor-investigator.  
• Live vaccines within 30 days prior to study registration and while participating in the 
trial. Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines 


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and are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist®) are live 
attenuated vaccines, and are not allowed.  Glucocorticoids for any purpose other than 
to modulate symptoms from an event of clinical interest of suspected immunologic 
etiology. The use of physiologic doses of corticosteroids may be approved after 
consultation with the sponsor-investigator. Please contact the HCRN project 
manager. 
 
Subjects who, in the assessment by the site investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial 
treatment. Subjects may receive other medications that the site investigator deems to be 
medically necessary off trial treatment. 
 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.7 
Supportive Care and Rescue Medications  
 
5.7.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
site investigator including but not limited to the items outlined below: 
 
Nausea/vomiting:  
Nausea and vomiting should be treated aggressively, and consideration should be given in 
subsequent cycles to the administration of prophylactic antiemetic therapy according to 
standard institutional practice. Subjects should be strongly encouraged to maintain liberal 
oral fluid intake. 
 
Antimicrobials:  
Subjects with a documented infectious complication should receive oral or IV antibiotics or 
other anti-infective agents as considered appropriate by the site investigator for a given 
infectious condition, according to standard institutional practice. 
 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
• All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
• For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
• For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
• When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 


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Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
• For T1DM or Grade 3-4 Hyperglycemia 
o Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
o Evaluate subjects with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
Hypophysitis: 
• For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
• For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor subjects for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
• Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
o In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested 
as initial therapy. 
o In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
• Grade 3-4 hyperthyroidism  
o Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones may 
be required as the steroid dose is tapered. 
 
Hepatic: 
• For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
o Treat with IV or oral corticosteroids 
• For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
• When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
Renal Failure or Nephritis: 
• For Grade 2 events, treat with corticosteroids. 
• For Grade 3-4 events, treat with systemic corticosteroids. 
• When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  


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Management of Infusion Reactions:  
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion.  
 
Table 3 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 
 
Table 3 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the site investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the site investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration.
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab 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 site 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. 
 
 
 
 


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5.8 
Diet/Activity/Other Considerations 
 
5.8.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting. 
 
5.8.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm. Women of child-
bearing potential may be enrolled if they are willing to use two methods of birth control or 
are considered highly unlikely to conceive. Highly unlikely to conceive is defined as: 
• 
Surgically sterilized, or  
• 
Postmenopausal (a woman who is ≥ 45 years of age and has not had menses for > 
one year will be considered postmenopausal), or  
• 
Not heterosexually active for the duration of the study.  
 
The two birth control methods can either be two barrier methods or a barrier method plus a 
hormonal method to prevent pregnancy. Subjects should start using birth control from the 
point of registration up to 120 days after the last dose of study drug.  
 
The following are considered adequate barrier methods of contraception: diaphragm, 
condom (by the partner), copper intrauterine device, sponge, or spermicide. Appropriate 
hormonal contraceptives will include any registered and marketed contraceptive agent that 
contains an estrogen and/or a progestational agent (including oral, subcutaneous, 
intrauterine, or intramuscular agents). 
 
Subjects should be informed that taking the study drug may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study they must adhere to the contraception requirement (described above) for the 
duration of the study and for 120 days after the last dose of study drug. If there is any 
question that a subject will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study. 
 
5.8.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on study, the subject will immediately be 
discontinued from protocol therapy. If treatment with pembrolizumab, the site will contact 
the subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated. The outcome of the pregnancy will be reported to HCRN 
immediately and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The site investigator will make every effort to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to HCRN. If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately 
and the pregnancy reported to HCRN and followed as described in the Adverse Event 
section 11. 
 


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5.8.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
 
6. 
TREATMENT DISCONTINUATION 
 
6.1. 
Reasons for Discontinuing Protocol Therapy 
A subject will be discontinued from the treatment under the following circumstances: 
• If there is evidence of progressive disease (based on immune related response 
criteria) as outlined in the Schedule of Events. Progression per RECIST 1.1 is NOT a 
criteria for removal from study, unless the site investigator determines that removal 
from protocol is in the subject’s best interest. 
• If a situation other than progression of disease arises and the site investigator 
determines a change of therapy would be in the best interest of the subject.  
• If the drug(s) exhibit(s) an unacceptable adverse event. 
• If a subject becomes pregnant or is unwilling to use appropriate birth control 
techniques as outlined in the inclusion criteria (See Section 3). 
• If there is a treatment interruption for greater than 4 weeks due to treatment related 
adverse event. 
• Subjects can stop participating at any time. However, if they decide to stop 
participating in the study, subjects will continue to be followed for disease 
progression and survival. 
• Twenty-four months of uninterrupted protocol therapy. 
 
6.2. 
Reasons for Withdrawal from Study  
• 
Subject withdraws consent for participation 
• 
Termination of the study 
• 
Lost to follow-up 
• 
Death 


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7. 
STUDY SCHEDULE OF EVENTS  
 
Footnotes on next page  
 
Cycle = 28 days 
Examination 
Screening 
Cycles 1–2 
Cycles 3–4 
Cycle 5+ 
Disease 
progression
End of 
Treatment 
Follow up 
-28 
days 
-14 
days 
Day 1 
(±3) 
Day 15 
(±3) 
Day 1 
(±3) 
Day 15 
(±3) 
Day 1 
(±3) 
Day 15 
(±3) 
 
30 days  
(± 7) 
after last 
dose
 
REQUIRED ASSESSMENTS 
Informed Consent and Eligibility 
 
X
 
Demographics, Medical History, Ht 
 
X
 
Physical Examination 
 
X
X
X
X
X 
X
Vital Signs (BP, wt) and ECOG PS11 
 
X
X
X
X
X
X 
X
 
X
 
AEs, Con Meds, ECI’s11 
 
X
X
X
X
X
X 
X
 
X
 
LABORATORY ASSESSMENTS 
Comprehensive Metabolic Panel1 
 
X
X1 
X
X
X
X 
X
 
X
 
Calculated Creatinine Clearance 
 
X
 
 
 
 
 
 
 
X
 
CBC with Differential and platelet2 
 
X
X2 
X
X
X
X 
X
 
X
 
PT, PTT, INR 
 
X
 
CEA9  
 
X
X
X 
CA19-9 
 
X
X10
 
TSH, T3 and T43 
 
X
X
X
X 
X
Pregnancy Test (Urine or Serum)4 
 
X
 
DISEASE ASSESSMENT 
CT or MRI of Chest, Abd and Pelvis5 
X 
X
X 
X
TREATMENT EXPOSURE 
mFOLFOX6 every 2 weeks 
X
X
X
X
X 
X
Pembrolizumab every 3 weeks11 
 
C1D1    C1D22    C2D15    C3D8    C4D1    C4D22    C5D15    C6D8; up to 24 months of treatment 
CORRELATIVE STUDIES 
MANDATORY serum collection 6 
 
X 
 
 
 
X
 
MANDATORY whole blood 
collection6 
 
 
X 
X 
X 
 
 
 
 
X 
 
Tissue sample for PD-LI and IHC 7 
 
X
 
X
 
FOLLOW-UP 
 
 
For progression, start of additional 
cancer treatment, and survival8 
 
 
 
 
 
 
 
 
 
 
X 
 


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Footnotes: 
1Comprehensive metabolic profile to include will include: serum chemistries (creatinine, glucose, total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2 or 
bicarbonate], albumin, total bilirubin, alkaline phosphatase, and aspartate transaminase [AST] and alanine transaminase [ALT]) and electrolytes (total calcium, chloride, 
potassium, sodium).  NOTE: For Cycle 1 Day 1 only, required tests do not need to be repeated if done within 7 days prior. 
 
2 Complete blood cell profile to include hemoglobin, hematocrit, red blood cell count, WBC [total and differential], absolute neutrophil count and platelet count. NOTE: 
For Cycle 1 Day 1 only, required tests do not need to be repeated if done within 7 days prior   
 
3 TSH, T3, T4 at screening then every 4 weeks during treatment with study medication through Cycle 5.  After cycle 5 thyroid testing will be done every other cycle 
(C7, C9, etc).  
 
4Women of child bearing potential ONLY 
 
5Chest/Abdomen/Pelvic CT scans to be done every 8 weeks starting C1D1. Screening CT scan done within 28 days from C1D1 is adequate as a baseline imaging.  For 
EOT visit, radiological assessment is needed if > 28 days from last assessment only if subject EOT due to toxicity. 
 
6 MANDATORY correlative serum samples are to be collected at pre-dose C1D1, pre-dose C2D1 and at End of Treatment. MANDATORY whole blood samples are to 
be collected at pre-dose C1D1, pre-dose C1D15, pre-dose C3D1 (after 2 cycles of treatment or at first response assessment) and at End of Treatment. Refer to the SPM 
for collection, processing, labeling and shipping instructions.  
 
7 MANDATORY: Have identified tissue from an archival tissue sample (preferably from a metastasis, but sample from primary tumor allowable) or newly obtained 
core or excisional biopsy of a tumor lesion. OPTIONAL biopsy for submission of unstained slides for IHC testing are requested at the time the subject progresses. 
OPTIONAL submission of tissue obtained from surgery for those subjects that have surgery during study treatment or follow up.  See Section 9 for more details.  See 
Study Procedures Manual for collection, labeling and shipping instructions. 
 
8Subjects who discontinue treatment without evidence of tumor progression will be followed for progression with imaging studies performed every three months (±7 
days), or until new treatment is initiated. Every effort should be made to perform the same imaging modality (e.g., CT or MRI) throughout the follow-up period.  In 
addition, the site investigator or designees will make every possible attempt to contact the subject or family every three months (±7 days) for two years from completion 
of protocol therapy, every six months (±7 days) for years 3-5, and annually thereafter (±2 weeks) to obtain the survival information of the subject and start date of 
additional anticancer treatment. 
 
9Subjects will have CEA done every 2months while on treatment. 
 
10Subjects will have CA19-9 at baseline and at the time of first scan while on treatment. 
 
11 On Days in which Pembrolizumab ONLY is given, the following assessments are required: Blood pressure, weight [kg] and ECOG performance status.  Adverse 
events and concomitant medications should also be recorded.  This includes ECI’s.   
 


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7.1 
Screening 
 
Within 28 days prior to registration for protocol therapy: 
• 
Radiological assessment (CT or MRI of chest, abdomen, and pelvis) with tumor 
measurements 
• 
Prior to the subject being registered to the study, an available archived tumor block 
(preferably from a metastasis, but sample from primary tumor is allowable) must be 
identified. If an archived tumor tissue sample is not available, subjects may consent 
to a newly obtained core or excisional biopsy of a tumor lesion prior to treatment 
C1D1 after all other eligibility criteria has been met. See SPM for collection, 
labeling and shipping instructions.  
 
Within 14 days prior to registration for protocol therapy unless otherwise noted: 
• 
Eligibility evaluation (review of inclusion and exclusion criteria) 
• 
Medical history and Height 
• 
Physical examination 
• 
Record Adverse Events and concomitant medications. Including ECI’s.  
• 
Vitals Signs (including blood pressure), Weight [kg] and ECOG PS 
• 
Laboratory Assessments: 
o Complete metabolic profile (CMP) will include: serum chemistries (creatinine, 
glucose, total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2 or 
bicarbonate], albumin, total bilirubin, alkaline phosphatase, and aspartate 
transaminase [AST] and alanine transaminase [ALT]) and electrolytes (total 
calcium, chloride, potassium, sodium). 
o CBC (hemoglobin, hematocrit, red blood cell count, WBC [total and 
differential], absolute neutrophil count and platelet count) 
o Calculated Creatinine Clearance 
o Urine pregnancy test for female subjects of childbearing potential (If urine 
pregnancy results cannot be confirmed as negative, a serum β-human chorionic 
gonadotropin test will be required) 
o PT, PTT and INR 
o TSH, T3, T4 
 
7.2. 
On Treatment 
 
Cycles 1 and Cycle 2 Day 1 (± 3 days) unless otherwise noted: 
On Day 1 of each treatment cycle, the following assessments/treatment administrations will 
occur: (NOTE: For Cycle 1 Day 1 only, required tests do not need to be repeated if done 
within 7 days prior) 
• 
Physical examination 
• 
Record Adverse Events and concomitant medications. Including ECI’s. 
• 
Vital signs, Weight [kg] and ECOG PS 
• 
Laboratory Assessments: 
o CMP will include: serum chemistries (creatinine, glucose, total protein, BUN, 
total CO2, albumin, total bilirubin, alkaline phosphatase, and AST and ALT) and 
electrolytes (total calcium, chloride, potassium, sodium) 


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o CBC (hemoglobin, hematocrit, red blood cell count, WBC [total and 
differential], absolute neutrophil count and platelet count) 
o CEA- prior to C1D1 ONLY 
o CA19-9- prior to C1D1 ONLY 
o TSH, T3, T4 
o MANDATORY serum samples are to be collected at pre-dose C1D1 and pre-
dose C2D1. Refer to the SPM for collection, processing, labeling and shipping 
instructions.  
o MANDATORY whole blood samples are to be collected at pre-dose C1D1.  
Refer to the SPM for collection, processing, labeling and shipping instructions.  
• 
Have provided tissue from an archival tissue sample (preferably from a metastasis, 
but sample from primary tumor allowable) or newly obtained core or excisional 
biopsy of a tumor lesion. 
• 
Pembrolizumab IV is given every 3 weeks.  First dose C1D1 
• 
mFOLFOX6 IV is given every 2 weeks.  First dose C1D1  
  
Cycles 1 and Cycle 2 Day 15 (± 3 days) unless otherwise noted: 
• 
Physical exam 
• 
Record Adverse Events and concomitant medications. Including ECI’s. 
• 
Vital signs, Weight [kg] and ECOG PS 
• 
Laboratory Assessments: 
o CMP will include: serum chemistries (creatinine, glucose, total protein, BUN, 
total CO2, albumin, total bilirubin, alkaline phosphatase, and AST and ALT) and 
electrolytes (total calcium, chloride, potassium, sodium) 
o CBC (hemoglobin, hematocrit, red blood cell count, WBC [total and 
differential], absolute neutrophil count and platelet count)  
o Mandatory whole blood samples are to be collected at pre-dose C1D15. Refer to 
the SPM for collection, processing, labeling and shipping instructions.  
• 
Pembrolizumab IV C2D15 
• 
mFOLFOX6 a IV 
 
Cycles 3 and Cycle 4 Day 1 (± 3 days) unless otherwise noted: 
On Day 1 of each treatment cycle, the following assessments/treatment administrations will 
occur:  
• Physical examination 
• Record Adverse Events and concomitant medications.  Including ECI’s. 
• Vital signs, Weight [kg] and ECOG PS 
• Laboratory Assessments 
o CMP will include: serum chemistries (creatinine, glucose, total protein, BUN, 
total CO2, albumin, total bilirubin, alkaline phosphatase, and AST and ALT) and 
electrolytes (total calcium, chloride, potassium, sodium) 
o CBC (hemoglobin, hematocrit, red blood cell count, WBC [total and 
differential], absolute neutrophil count and platelet count) 
o CEA- prior to C3D1 
o CA19-9- prior to C4D1 or with first set of scans while on treatment. 
o TSH, T3, T4 


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o MANDATORY whole blood samples are to be collected pre-dose C3D1 (after 2 
cycles of treatment or at first response assessment). Refer to the SPM for 
collection, processing, labeling and shipping instructions.  
• 
CT or MRI of chest, abdomen/pelvis: pre-dose C3D1 (after 2 cycles of treatment or 
at first response assessment). 
• CT or MRI of chest, abdomen/pelvis after 4 cycles (PRIOR to 5TH CYCLE) 
• Pembrolizumab IV C4D1 
• mFOLFOX6 IV 
 
Cycle 3 and Cycle 4 Day 15 (± 3 days) unless otherwise noted: 
• Record Adverse Events and concomitant medications. Including ECI’s. 
• Vital signs, Weight [kg] and ECOG PS 
• Laboratory Assessments 
o CMP will include: serum chemistries (creatinine, glucose, total protein, BUN, 
total CO2, albumin, total bilirubin, alkaline phosphatase, and AST and ALT) and 
electrolytes (total calcium, chloride, potassium, sodium) 
o CBC (hemoglobin, hematocrit, red blood cell count, WBC [total and 
differential], absolute neutrophil count and platelet count) 
• mFOLFOX6 IV 
 
Cycle 5 and subsequent Cycles Day 1 (± 3 days) unless otherwise noted: 
On Day 1 of each treatment cycle, the following assessments/treatment administrations will 
occur:  
• Physical examination 
• Record Adverse Events and concomitant medications. Including ECI’s. 
• Vital signs, Weight [kg] and ECOG PS 
• Laboratory Assessments  
o CMP will include: serum chemistries (creatinine, glucose, total protein, BUN, 
total CO2, albumin, total bilirubin, alkaline phosphatase, and AST and ALT) and 
electrolytes (total calcium, chloride, potassium, sodium) 
o CBC (hemoglobin, hematocrit, red blood cell count, WBC [total and 
differential], absolute neutrophil count and platelet count) 
o CEA 
• CT or MRI of chest, abdomen/pelvis after 4 cycles (PRIOR to 5TH CYCLE) 
• mFOLFOX6 IV 
 
Cycle 5 and subsequent Cycles Day 15 (± 3 days) unless otherwise noted: 
• Vital signs, Weight [kg] and ECOG PS 
• Record Adverse Events and concomitant medications.  Including ECI’s. 
• Laboratory Assessments 
o CMP will include: serum chemistries (creatinine, glucose, total protein, BUN, 
total CO2, albumin, total bilirubin, alkaline phosphatase, and AST and ALT) and 
electrolytes (total calcium, chloride, potassium, sodium) 
o CBC (hemoglobin, hematocrit, red blood cell count, WBC [total and 
differential], absolute neutrophil count and platelet count) 


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• mFOLFOX6 IV 
 
Pembrolizumab ONLY infusion days:  
• Record Adverse Events and concomitant medications.  Including ECI’s. 
• Vital signs[kg] and ECOG PS 
• Pembrolizumab IV every 3 weeks 
 
7.3. 
Restaging Evaluations 
A restaging CT or MRI of the chest, abdomen, and pelvis will be performed after every two 
cycles of treatment (i.e., approximately every 8 weeks). For subjects on an increased dosing 
interval (every four weeks) due to pneumonitis (as per section 5.2.3), the frequency of 
restaging imaging studies should be discussed with the sponsor-investigator by contacting 
the HCRN project manager. Every effort should be made to perform the same imaging 
modality (e.g., CT or MRI) throughout the study. 
 
7.4. 
Determination of Progression/Post-progression imaging 
irRC will be adapted as follows to account for the unique tumor response seen in this class 
of therapeutics. 
 
After the first documentation of progression per irRC, if the subject is clinically stable, 
confirmatory scans should be performed 4-6 weeks later. It is at the discretion of the site 
investigator to keep a clinically stable subject on study therapy or to stop study therapy until 
repeat imaging performed.  
 
Clinical Stability is defined as: 
1. Absence of symptoms and signs indicating clinically significant progression of 
disease (including worsening of laboratory values) indicating disease progression. 
2. No decline in ECOG PS  
3. Absence of rapid progression of disease or progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention. 
 
Subjects who are deemed clinically unstable are not required to have repeat imaging for 
confirmation of progression.  
 
If progression is confirmed, the subject will be discontinued from study therapy. If 
progression is not confirmed, the subject should resume/continue study therapy and have 
their next scan approximately eight weeks from the date of the scan that first showed 
progression.  
 
When feasible, subjects should not be discontinued until progression is confirmed. 
 
7.5. 
Progression/End of Treatment (EOT) 
Treatment will be discontinued if there is evidence of disease progression per irRC (after 
confirmatory CT scan) or unacceptable toxicity or if the subject stops participating or 
withdraws from the study.  
 


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At least 30 days (+7) of last dose of study drug 
• 
Physical examination 
• 
Vital signs including Blood pressure, Weight [kg] and ECOG PS 
• 
Laboratory assessments 
o CMP will include: serum chemistries (creatinine, glucose, total protein, BUN, 
total CO2, albumin, total bilirubin, alkaline phosphatase, and AST and ALT) 
and electrolytes (total calcium, chloride, potassium, sodium)  
o CBC (hemoglobin, hematocrit, red blood cell count, WBC [total and 
differential], absolute neutrophil count and platelet count) 
o Calculated Creatinine Clearance 
o MANDATORY serum samples are to be collected at end of treatment. Refer 
to the SPM for collection, processing, labeling and shipping instructions.  
o MANDATORY whole blood samples are to be collected at End of 
Treatment. Refer to the SPM for collection, processing, labeling and shipping 
instructions.  
o OPTIONAL biopsy for submission of unstained slides from Time of 
Progression. In addition, subjects that undergo surgery for tumor resection at 
any time during study treatment or follow up will be asked to provide tissue 
for research.  Refer to the SPM for collection, labeling and shipping 
instructions.  
• 
Record Adverse Events and concomitant medications.  Including ECI’s. 
• 
Subjects will continue to be followed until resolution or stabilization of any 
treatment-related toxicities.  
• 
Radiological assessments (only if > 28 days since last assessment) for subjects taken 
off study due to toxicity ONLY.   
 
7.6. 
Follow-up 
• Subjects who discontinue treatment without evidence of tumor progression will be 
followed for progression with imaging studies performed every three months (±7 
days), or until new treatment is initiated. Every effort should be made to perform the 
same imaging modality (e.g., CT or MRI) throughout the follow-up period.  
• The site investigator or designees will make every possible attempt to contact the 
subject or family every three months (±7 days) for two years from completion of 
protocol therapy, every six months (±7 days) for years 3-5, and annually thereafter 
(±2 weeks), to obtain the survival information of the subject and start date of 
additional anticancer treatment. 
 
8. 
CRITERIA FOR DISEASE EVALUATION 
Response assessments will be made both using the Immune Related Response Criteria, and 
using RECIST v1.1, allowing additional comparisons among these criteria for disease 
response assessment. The same measurable and non-measurable lesions will be followed by 
both RECIST v1.1 & irRC. RECIST v1.1 will be used in primary objective assessment. 
 
8.1. 
Immune Related Response Criteria 
This study will utilize the Immune Related Response Criteria (irRC) for secondary 
endpoints. These response criteria were developed to overcome the variable and unusual 


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patterns of response to immunotherapeutic agents, in particular, ipilimumab [1]. The 
development of the guidelines were prompted by observations, mostly in subjects with 
metastatic melanoma, of initial disease progression followed by later response, late 
responses, and mixed responses with an overall decrease in tumor burden. 
 
8.2. 
Antitumor response based on total measurable tumor burden 
For the irRC, only index and measurable new lesions are taken into account (in contrast to 
conventional WHO criteria, which do not require the measurement of new lesions, nor do 
they include new lesion measurements in the characterization of evolving tumor burden). At 
the baseline tumor assessment, the sum of the products of the two largest perpendicular 
diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions) is 
calculated. At each subsequent tumor assessment, the SPD of the index lesions and of new, 
measurable lesions (up to 5 new lesions per organ; 10 visceral lesions) are added together to 
provide the total tumor burden:  Tumor Burden = SPDindex lesions + SPDnew, measurable lesions  
 
Table 4: Comparison of WHO and irRC criteria 
 
WHO 
irRC
New, 
measurable 
lesions  
Always represent PD 
Incorporated into tumor burden 
New, non-
measurable 
lesions  
Always represent PD 
Do not define progression (but preclude 
irCR) 
Non-index 
lesions 
Changes contribute to defining BOR of CR, PR, SD, 
and PD 
Contribute to defining irCR (complete 
disappearance required) 
CR 
Disappearance of all lesions in two consecutive 
observations not less than 4 wk apart 
Disappearance of all lesions in two 
consecutive observations not less than 4 wk 
apart
PR 
≥50% decrease in SPD of all index lesions compared 
with baseline in two observations at least 4 wk apart, in 
absence of new lesions or unequivocal progression of 
non-index lesions  
≥50% decrease in tumor burden compared 
with baseline in two observations at least 4 
wk apart 
SD 
50% decrease in SPD compared with baseline cannot be 
established nor 25% increase compared with nadir, in 
absence of new lesions or unequivocal progression of 
non-index lesions  
50% decrease in tumor burden compared 
with baseline cannot be established nor 25% 
increase compared with nadir 
PD 
At least 25% increase in SPD compared with nadir 
and/or unequivocal progression of non-index lesions 
and/or appearance of new lesions (at any single time 
point)  
At least 25% increase in tumor burden 
compared with nadir (at any single time 
point) in two consecutive observations at 
least 4 wk apart  
 
8.3. 
Time-point response assessment using irRC 
Percentage changes in tumor burden per assessment time point describe the size and growth 
kinetics of both conventional and new, measurable lesions as they appear. At each tumor 
assessment, the response in index and new, measurable lesions is defined based on the 
change in tumor burden (after ruling out irPD). Decreases in tumor burden must be assessed 
relative to baseline measurements (i.e., the SPD of all index lesions at screening). The irRC 
were derived from WHO criteria and, therefore, the thresholds of response remain the same. 
However, the irRC response categories have been modified from those of WHO criteria as 
detailed in Tables 8 and 9.  
 


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8.4. 
Overall response using the irRC 
The sum of the products of diameters at tumor assessment using the immune-related 
response criteria (irRC) for progressive disease incorporates the contribution of new 
measurable lesions. Each net Percentage Change in Tumor Burden per assessment using 
irRC accounts for the size and growth kinetics of both old and new lesions as they appear. 
 
Definition of Index Lesions Response Using irRC 
• irComplete Response (irCR): Complete disappearance of all index lesions. This 
category encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 
• irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum 
of the products of the 2 largest perpendicular diameters of all index and all new 
measurable lesions (ie, Percentage Change in Tumor Burden). Note: the appearance of 
new measurable lesions is factored into the overall tumor burden, but does not 
automatically qualify as progressive disease until the SPD increases by ≥25% when 
compared to SPD at nadir. 
 
• irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of 
progressive disease. 
 
• irProgressive Disease (irPD): At least 25% increase Percentage Change in Tumor 
Burden (i.e., taking sum of the products of all index lesions and any new lesions) when 
compared to SPD at nadir. 
 
Definition of Non-Index Lesions Response Using irRC 
• irComplete Response (irCR): Complete disappearance of all non-index lesions. This 
category encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 
• irPartial Response (irPR) or irStable Disease (irSD): non-index lesion(s) are not 
considered in the definition of PR, these terms do not apply. 
 
• 
irProgressive Disease (irPD): Increases in number or size of non-index lesion(s) does 
not constitute progressive disease unless/until the Percentage Change in Tumor Burden 
increases by 25% (i.e., the SPD at nadir of the index lesions increases by the required 
amount). 
Impact of New Lesions on irRC 
New lesions in and by themselves do not qualify as progressive disease. However, their 
contribution to total tumor burden is included in the SPD which in turn feeds into the irRC 
criteria for tumor response. Therefore, new non-measurable lesions will not discontinue any 
subject from the study. 
 
Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria (see Table 9): 
 


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• Immune-Related Complete Response (irCR): Complete disappearance of all tumor 
lesions (index and non-index together with no new measurable/unmeasurable lesions) 
for at least 4 weeks from the date of documentation of complete response.  
 
• Immune-Related Partial Response (irPR): The sum of the products of the two largest 
perpendicular diameters of all index lesions is measured and captured as the SPD 
baseline. At each subsequent tumor assessment, the sum of the products of the two 
largest perpendicular diameters of all index lesions and of new measurable lesions are 
added together to provide the Immune Response Sum of Product Diameters (irSPD). A 
decrease, relative to baseline of the irSPD compared to the previous SPD baseline, of 
50% or greater is considered an immune Partial Response (irPR).  
 
• Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria 
for immune complete response or immune partial response, in the absence of progressive 
disease.  
• Immune-Related Progressive Disease (irPD): It is recommended in difficult cases to 
confirm PD by serial imaging. Any of the following will constitute progressive disease: 
− At least 25% increase in the sum of the products of all index lesions over nadir SPD 
calculated for the index lesions. 
 
− At least a 25% increase in the sum of the products of all index lesions and new 
measurable lesions (irSPD) over the baseline SPD calculated for the index lesions. 
 
Immune-Related Best Overall Response Using irRC (irBOR)  
irBOR is the best confirmed irRC overall response over the study as a whole, recorded 
between the date of first dose until the last tumor assessment before subsequent therapy 
(except for local palliative radiotherapy for painful bone lesions) for the individual subject in 
the study. For the assessment of irBOR, all available assessments per subject are considered. 
 
irCR or irPR determinations included in the irBOR assessment must be confirmed by a 
second (confirmatory) evaluation meeting the criteria for response and performed no less 
than 4 weeks after the criteria for response are first met. 
 
 


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Table 5: Derivation of irRC overall responses 
Measurable response 
Nonmeasurable response 
Overall 
response 
Index and new, measurable lesions (tumor 
burden),*% 
Non-index lesions 
New, nonmeasurable 
lesions 
Using irRC 
↓100 
Absent 
Absent 
irCR† 
↓100 
Stable 
Any 
irPR† 
↓100 
Unequivocal progression 
Any 
irPR† 
↓≥50 
Absent/Stable 
Any 
irPR† 
↓≥50 
Unequivocal progression 
Any 
irPR† 
↓<50 to <25↑ 
Absent/Stable 
Any 
irSD 
↓<50 to <25↑ 
Unequivocal progression 
Any 
irSD 
≥25 
Any 
Any 
irPD† 
*Decreases assessed relative to baseline (scan prior to start of any protocol therapy), including measurable 
lesions only  
†Assuming response (irCR) and progression (irPD) are confirmed by a second, consecutive assessment at least 
4 wk apart.  
 
8.5. 
Definitions Associated with Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1  
 
8.5.1. Measurable disease  
The presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
 
8.5.2. Measurable lesions  
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT 
scan, or >10 mm with calipers by clinical exam. All tumor measurements must be recorded 
in millimeters (or decimal fractions of centimeters). 
 
8.5.3 Non-measurable lesions  
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable.   
 
NOTE: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same subject, these are preferred for selection as target lesions. 


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8.5.4 Malignant lymph nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and 
followed. 
 
8.5.5 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, recorded, and 
measured at baseline. Target lesions should be selected based on 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 that can be measured reproducibly should be selected.  
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
 
8.5.6 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 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. 
 
8.6. 
Response Criteria 
 
8.6.1. 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).
 
 


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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
 
8.6.2. 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 
subject 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 site investigator should prevail in such circumstances, and the progression 
status should be confirmed later by the sponsor-investigator. 
 
8.6.3. Evaluation of best overall response 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
CR
No
CR 
CR 
Non-CR/ Non-PD
No
PR 
 
Not evaluated
No
PR 
PR 
Non-CR/ Non-PD/ not 
evaluated
No 
PR 
SD 
Non-CR/ Non-PD/ not 
evaluated
No 
SD 
PD 
Any
Yes or No
PD 
Any 
PD*
Yes or No
PD 
Any 
Any
Yes
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 


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“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete 
response status. 
 
8.7 
Definitions for Response Evaluation – RECIST version 1.1 
 
8.7.1 First Documentation of Response 
The time between initiation of therapy and first documentation of PR or CR. 
 
8.7.2 Confirmation of Response 
To be assigned a status of complete or partial response, changes in tumor measurements 
must be confirmed by repeat assessments performed no less than four weeks after the 
criteria for response are first met. 
 
8.7.3 Duration of Response 
Duration of overall response—the period measured from the time that measurement criteria 
are met for complete or partial response (whichever status is recorded first) until the date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since treatment started). 
 
8.7.4 Duration of Overall Complete Response 
The period measured from the time that measurement criteria are met for complete response 
until the first date that recurrent disease is objectively documented. 
 
8.7.5 Objective response rate  
The objective response rate is the proportion of all subjects with confirmed PR or CR 
according to RECIST v1.1, from the start of treatment until disease progression/recurrence 
(taking as reference for progressive disease the smallest measurements recorded since the 
start of treatment). 
 
8.7.6 Time to Progression: 
A measurement from the date of registration until the criteria for disease progression is met 
as defined by RECIST 1.1. Subjects who have not progressed or have died due to any cause 
will be right-censored at the date of the last disease evaluation or date of death. 
 
8.7.7 Progression Free Survival 
A measurement from the date of registration until the criteria for disease progression is met 
as defined by RECIST 1.1 or death occurs. Subjects who have not progressed will be right-
censored at the date of the last disease evaluation. 
 
8.7.8 Overall Survival 
Overall survival is defined by the date of registration to date of death from any cause. 


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9. 
BIOLOGICAL SPECIMEN PARAMETERS FOR CORRELATIVES 
As part of the correlative research we will assess the relationship between potential immune 
biomarker and response to the combination of pembrolizumab plus chemotherapy. 
 
Potential immune biomarkers include Toll-Like Receptor 4 (TLR4) pathway including the 
expression level of TLR4, MyD88 and NF-kB as well as PD-1/PD-L1 expression level in 
the tumor. 
 
9.1 
Unstained Slides for PD-L1 Testing 
9.1.1 MANDATORY: An archival tissue sample (preferably from a metastasis, but sample 
from primary tumor allowable) or newly obtained core or excisional biopsy of a 
tumor lesion will be used for PD-L1 testing.   
 
9.1.2 Archival tissue sample for submission must be identified during the screening 
process.  If not, available, the subject will undergo a new biopsy 
 
9.1.3 A fine needle aspirate, frozen sample, plastic embedded sample, cell block, clot, 
bone, bone marrow or cytologic specimen are not acceptable for PD-L1 analysis. 
 
9.1.4 A tissue sample from a pre-treatment biopsy will not be submitted until the subject is 
registered to the trial. 
 
9.1.5 Submission of unstained slides for PD-L1 expression will be analyzed at a central lab 
using a Merck-specified assay  
 
9.1.6  See SPM for collection, labeling and shipping instructions.  
 
9.2 
Unstained Slides for IHC Testing 
9.2.1 MANDATORY: An archival tissue sample (preferably from a metastasis, but sample 
from primary tumor allowable) or newly obtained core or excisional biopsy of a 
tumor lesion will be used for IHC testing.   
 
9.2.2 Archival tissue sample for submission must be identified during the screening 
process.  If not, available, the subject will undergo a new biopsy 
 
9.2.3 A tissue sample from a pre-treatment biopsy will not be submitted until the subject is 
registered to the trial.  
 
9.2.4 OPTIONAL AT PROGRESSION: Submission of unstained slides at time of 
progression for IHC testing. Potential immune biomarkers include Toll-Like 
Receptor 4 (TLR4) pathway including the expression level of TLR4, MyD88 and 
NF-Kb 
 
9.2.5 See SPM for collection, labeling and shipping instructions. 
 
9.3 
MANDATORY submission of Whole Blood and Serum Sample  


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9.3.1 MANDATORY serum samples are to be collected at pre-dose C1D1, pre-dose C2D1 
and at End of Treatment.  
 
9.3.2 MANDATORY whole blood samples are to be collected at pre-dose C1D1, pre-dose 
C1D15, pre-dose C3D1 (or at first response assessment; after 2 cycles of treatment) 
and at End of Treatment. 
 
9.3.3 See SPM for collection, labeling and shipping instructions. 
 
9.4 
OPTIONAL submission of tissue from Surgery 
If patients undergo surgical resection during study treatment or follow up, formalin fixed 
paraffin embedded tissue will be retrieved, or 10 unstained slides will be retrieved for 
correlative studies.  
 
10. 
DRUG INFORMATION 
 
10.1 
Drug Name 
Pembrolizumab (MK-3475), SCH 900475 (Anti-PD-1) 
Please see Investigator’s Brochure for detailed information regarding Pembrolizumab 
 
10.1.1 Chemical Name 
Humanized X PD-1_mAb (H409A11) IgG4 
 
10.1.2 Investigational Product 
The site investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution and usage 
of investigational product in accordance with the protocol and any applicable laws and 
regulations. 
 
Clinical Supplies will be provided by Merck as summarized below: 
Product Name & Potency 
Dosage Form 
Pembrolizumab (MK-3475) 100 mg/ 
4mL 
Solution for Injection 
 
10.1.3 Packaging and Labeling Information  
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
 
10.1.4 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the sponsor-
investigator and/or designee are not blinded to treatment. Drug identity (name, strength) is 
included in the label text; random code/disclosure envelopes or lists are not provided. 
 
 
 


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10.1.5 Returns and Reconciliation 
The site investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, the amount dispensed to and returned by the subjects and 
the amount remaining at the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the site investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 
10.1.6 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  Receipt and dispensing of trial medication must be 
recorded by an authorized person at the trial site.  Clinical supplies may not be used for any 
purpose other than that stated in the protocol. 
 
10.1.7 Adverse Events 
Please see Investigator’s Brochure for complete details regarding adverse events related to 
Pembrolizumab 
 
Pembrolizumab is generally well tolerated and demonstrates a favorable safety profile in 
comparison to chemotherapy. Pembrolizumab is an immunomodulatory agent, and based on 
this mechanism of action, immune mediated adverse events are of primary concern.  
Important identified risks for pembrolizumab are of an immune mediate nature, including: 
pneumonitis, colitis, thyroid disorders (hypothryoidism/hyperthyroidism), hepatitis, 
hypophysitis, Type I diabetes mellitis, uveitis, and nephritis. After a recent review of data, 
events newly characterized as identified risks also include pancreatitis, myositis, and severe 
skin reaction; these are included in the reference safety information in the current IB. The 
majority of immune-mediated adverse events were mild to moderate in severity, were 
manageable with appropriate care, and rarely required discontinuation of therapy. In 
addition to the previously noted identified risks, infusion-related reactions are a risk but are 
not considered immune mediated; these are also further described in the current IB. 
 
10.2 mFOLFOX6 
Qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe 
disposal of chemotherapeutic agents in a self-contained, protective environment. 
 
Discard unused portions of injectable chemotherapeutic agents that do not contain a 
bacteriostatic agent or are prepared with unpreserved diluents (i.e., Sterile Water for 
Injection USP or 0.9% Sodium Chloride for Injection USP) within eight hours of vial 
entry to minimize the risk of bacterial contamination. 
 


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The total administered dose of cytotoxic chemotherapy may be rounded up or down within 
a range of 5% of the actual calculated dose. 
 
It is not necessary to change the doses of 5-FU, leucovorin or oxaliplatin due to changes in 
weight unless the calculated dose changes by ≥10% from baseline. 
 
10.2.1 Oxaliplatin [Eloxatin]  
Please refer to the package insert for complete product information. 
 
Availability 
Oxaliplatin is commercially available as an aqueous solution in vials containing 50 mg and 
100 mg at a concentration of 5 mg/mL. The vials do not contain any preservative and 
they are intended for single use. 
 
Storage and Stability 
Intact vials should be stored at room temperature. Solutions diluted in D5W are stable 
for 6 hours at room temperature or 24 hours under refrigeration. 
 
Preparation 
The calculated dose of oxaliplatin should be diluted for infusion with 250 mL to 500 mL 
D5W. Oxaliplatin should not be diluted with a sodium chloride solution. Needles, 
syringes, catheters or IV administration sets containing aluminum should not be used 
with oxaliplatin. As with other platinum compounds, contact with aluminum may result in 
a black precipitate. 
 
Administration 
Oxaliplatin will be administered by intravenous infusion over 120 minutes prior to or 
concurrent with leucovorin. Infusion time may be prolonged (up to 6 hours) in 
subjects experiencing pharyngolaryngeal dysesthesia.  
 
Oxaliplatin is unstable in the presence of chloride or alkaline solutions. Do NOT mix 
or administer oxaliplatin with saline or other chloride-containing solutions. Do NOT 
administer other drugs or solutions in the same infusion line. Flush IV lines/catheters with 
Dextrose 5% in Water both before and after oxaliplatin administration. 
 
Toxicity 
The most commonly observed oxaliplatin toxicities include neurotoxicity, GI toxicity, 
and myelosuppression. Three neurotoxicity syndromes have been seen: acute sensory 
neuropathy develops within hours to 2 days after oxaliplatin administration. Symptoms 
include paresthesias, dysesthesias, and hypoesthesia of the hands, feet, and perioral 
region. Jaw spasm, abnormal tongue sensation, dysarthria, eye pain and a sensation of chest 
pressure have also been noted. Acute sensory neuropathy symptoms may be exacerbated 
by exposure to cold temperature or cold objects. Symptoms are reversible, usually 
resolving within 14 days and commonly recurring with further dosing. This syndrome 
has been observed in about 56% of subjects receiving oxaliplatin with 5-FU and 
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Acute pharyngolaryngeal dysesthesia is reported to occur in 1-2% of subjects. This 
syndrome is characterized by a subjective sensation of difficulty breathing or 
swallowing without laryngospasm or bronchospasm or objective evidence of hypoxia. 
Avoidance of cold drinks, food and air is suggested in order to minimize 
pharyngolaryngeal dysesthesia. Antianxiety agents (e.g., lorazepam) may be used to 
treat pharyngolaryngeal dysesthesias once oxygen saturation has been documented to be 
normal. 
 
Peripheral neuropathy persisting > 14 days is characterized by paresthesias, dysesthesias, 
and hypoesthesia. Abnormalities in proprioception may also be seen. Symptoms of 
persistent neuropathy may improve upon discontinuation of oxaliplatin. 
 
Gastrointestinal toxicities include nausea, vomiting (oxaliplatin is considered to be 
moderately emetogenic) and diarrhea. 
 
Neutropenia is reported in 73% of subjects receiving oxaliplatin with 5-FU and leucovorin 
(44% grade 3 or 4). Grade 3 or 4 thrombocytopenia is reported to occur in 4% of subjects 
receiving the combination. 
 
Allergic reactions, similar to those seen with other platinum compounds, have also 
been observed in subjects treated with oxaliplatin. Reactions range from rash to 
anaphylaxis. 
 
Rarely, oxaliplatin has been associated with pulmonary fibrosis, which may be fatal. 
Oxaliplatin should be discontinued in the presence of unexplained pulmonary symptoms 
(e.g. nonproductive cough, dysphagia) or pulmonary infiltrates until interstitial lung 
disease or pulmonary fibrosis have been ruled out. 
 
Recent reports of oxaliplatin extravasation suggest that tissue necrosis may result and 
that oxaliplatin should be considered a vesicant. No standard treatment exists for 
oxaliplatin extravasation although heat and sodium thiosulfate have both been suggested. 
Veno-occlusive disease (VOD) of the liver is a rare complication associated with oxaliplatin 
and 5-FU. Clinical manifestations of VOD include hepatomegaly, ascites, and jaundice. 
Histologically, VOD is characterized by diffuse damage in the centrilobular zone of the 
liver. Sequelae of VOD include hepatomegaly, splenomegaly, portal hypertension, and 
esophageal varices. A recent analysis of resected liver metastases in 153 subjects 
indicated histological findings consistent with VOD in 6/27 subjects who received 5-FU 
alone, 4/17 subjects who received 5-FU and irinotecan, 20/27 subjects who received 5-FU 
and oxaliplatin, and 14/16 who received 5-FU, oxaliplatin and irinotecan. The remaining 
66 subjects had not received chemotherapy prior to resection. There were no such findings 
in these subjects. 
 
 
 


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10.2.2 5-Fluorouracil (5-FU; fluorouracil) 
Please refer to the package insert for complete product information. 
 
Availability 
5-FU is commercially available as a 50 mg/mL solution for injection in 10 mL, 20 mL, 50 
mL and 100 mL vials. 
 
Preparation 
Inspect for precipitate; if found, agitate or gently heat in water bath. Bolus injections 
are prepared using undiluted drug. 
 
46-48 hour infusion of 5-FU should be prepared for administration via ambulatory 
infusion pump according to the individual institution’s standards. These solutions may be 
prepared in D5W or 0.9% NaCl. 5-FU should not be mixed in the same solution with 
most parenteral antiemetics. 
 
Storage and Stability 
Intact vials should be stored at room temperature and protected from light. Slight yellow 
discolor does not usually indicate decomposition. Stability in ambulatory pumps varies 
according to the pump, manufacturer of drug, concentration and diluent. Please refer to 
appropriate reference sources for additional information. 
 
Administration 
In this study, 5-FU is administered as a 400 mg/m2 IV bolus followed by 2400 mg/m2 by 
IV infusion over 46 to 48 hours. The bolus is administered after leucovorin, and the 46-
48 hour infusion follows immediately after the bolus. 
 
Toxicity 
Nausea, diarrhea, vomiting (mild); stomatitis: 5-8 days after treatment initiation; 
myelosuppression: granulocytopenia (9-14 days); thrombocytopenia (7-14 days); Alopecia; 
loss of nails; hyperpigmentation; photosensitivity; maculopapular rash; palmar–plantar 
erythrodysesthesias: (42-82% receiving continuous infusion); CNS effects: cerebral ataxia 
(rare); cardiotoxicity: MI, angina; asymptomatic S–T changes 68%; ocular effects: 
excessive lacrimation and less commonly, tear duct stenosis. 
 
Drug Interactions 
Leucovorin enhances the cytotoxicity of 5-FU by forming a more stable tertiary complex 
with thymidylate synthase. Concomitant administration of 5-FU with warfarin has been 
reported to result in increased INR/prolonged prothrombin time. Subjects receiving both 
drugs should be followed with weekly INRs. 
 
10.2.3   Leucovorin Calcium (Folinic Acid)  
Please refer to the package insert for complete product information. 
 


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In the case of a leucovorin shortage, levo-leucovorin may be administered (dose to be at site 
investigator’s discretion). Other dosing alternatives may also be used during leucovorin 
shortage such as leucovorin 20mg/m2.  
 
Availability 
Leucovorin calcium is commercially available in: 50 mg, 100 mg, 200 mg, 350 mg and 500 
mg vials for reconstitution, and as a solution for injection in 50 mL vials at a concentration 
of 10 mg/mL. 
 
Storage and Stability 
Intact vials should be stored at room temperature and protected from light. Solutions 
reconstituted with BWI are stable for at least 7 days at room temperature. Solutions diluted 
for infusion are stable for 24 hours at room temperature and 4 days under refrigeration. 
 
Preparation 
Leucovorin may be reconstituted with Bacteriostatic Water for Injection (BWI), Sterile 
Water For Injection, or bacteriostatic NaCl or NaCl. Solutions should be further diluted in 
D5W, 0.9% NaCl or Ringers solution for infusion over two hours. 
 
Administration 
Leucovorin will be administered as a 400 mg/m2 IV infusion over 2 hours after 
oxaliplatin administration and immediately before 5-FU. Leucovorin may also be 
administered concurrently with oxaliplatin as a separate IV infusion. 
 
Toxicity 
The only adverse reactions associated with leucovorin are allergic reactions.  These are 
extremely uncommon. 
 
11. 
ADVERSE EVENTS 
 
11.1 
Definitions of Adverse Events  
 
11.1.1 Adverse Event  
Adverse event (AE) means any untoward medical occurrence in a study subject 
administered an investigational drug that does not necessarily have a causal relationship 
with the treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporarily associated with 
participation in an investigational study, whether or not considered related to the 
investigational product. An AE is any sign, symptom, or diagnosis that appears or changes 
in intensity during the course of the study. An AE may be an intercurrent illness or injury 
that impairs the well-being of the subject. 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce 
clinical signs or symptoms or require treatment or further diagnostic tests.  
 


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11.1.2 Serious Adverse Event 
A serious adverse event is any untoward medical occurrence resulting in one or more of the 
following: 
• Results in death: NOTE: deaths due unequivocally to progression are not SAEs. 
• 
Is life-threatening (defined as an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above). Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions not resulting in hospitalization; or 
the development of drug dependency or drug abuse. 
 
11.2 
Adverse Event Reporting 
 
11.2.1 Site Requirements for Recording and Reporting Adverse Events 
Adverse events (AEs) will be recorded from the time of consent and for at least 30 days after 
last dose of study drug, regardless of whether or not the event(s) are considered related to 
the study drug. The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) v4 will be utilized for AE reporting. A 
copy of the CTCAE v4 can be downloaded from the CTEP website at http://ctep.cancer.gov. 
 
This study must be conducted in compliance with FDA regulations, local safety reporting 
requirements and reporting requirements of the sponsor-investigator. 
 
11.2.2 Site Requirements for Reporting Serious Adverse Events 
Site investigators and other site personnel must report any SAE to HCRN within one 
business day of discovery of the event. This includes events both related and unrelated to 
the study drug.  
 
Site investigators will report a follow up to a SAE, including death due to any cause other 
than progression of the cancer under study, that occurs to any subject from the time the 
consent is signed through 90 days following the last dose of study drug, or the initiation of 
new anti-cancer therapy, whichever is earlier, whether or not related to Merck product.  
 
 
 


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The definition of “related” being that there is a reasonable possibility the drug caused the 
adverse experience. 
Unrelated 
The Adverse Event is clearly not related to the study drug 
Unlikely 
The Adverse Event is doubtfully related to the study drug
Possible 
The Adverse Event may be related to the study drug
Probable 
The Adverse Event is likely related to the study drug
Definite 
The Adverse Event is clearly related to the study drug
 
Additionally, SAEs considered by a site investigator to be related to Merck product that is 
brought to the attention of the site investigator at any time outside of the time period 
specified in the previous paragraph also must be reported immediately to HCRN. HCRN 
will report these events to Merck. 
 
The completed SAE/ECI Submission Form must be faxed to HCRN within one business 
day of discovery of the event. The site investigator is responsible for informing the IRB 
and/or the Regulatory Authority of the SAE as per local requirements. All AEs and SAEs 
will be recorded in the subject’s medical record and on the appropriate study specific eCRF 
form within the EDC system.  In addition, all SAEs will be reported on the SAE/ECI 
Submission Form and submitted to HCRN per guidelines outlined in this section. 
 
The original copy of the SAE/ECI Submission Form and the fax confirmation sheet (or 
equivalent) must be kept within the Trial Master File at the study site. 
 
Follow-up information will be faxed to HCRN, using a new SAE/ECI Submission Form 
stating that this is a follow-up to the previously reported SAE and giving the date of the 
original report. Each re-occurrence, complication, or progression of the original event 
should be reported as a follow-up to that event regardless of when it occurs. The follow-up 
information should describe whether the event has resolved or continues, if and how it was 
treated, whether the blind was broken or not (if applicable), and whether the subject 
continued or withdrew from study participation. 
 
11.2.3 Definition of an Overdose for This Protocol and Reporting of Overdose to 
HCRN 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab by 20% over the prescribed dose. No specific information is 
available on the treatment of overdose of pembrolizumab. In the event of overdose, 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 
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All reports of overdose with and without an adverse event must be reported within one 
business day to HCRN. HCRN will report such events to Merck Global Safety within one 
business day of notification of the event. (Attn: Worldwide Product Safety; FAX 215 993-
1220) 
 
11.2.4 Reporting of Pregnancy and Lactation to HCRN 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of site investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner 
that occurs during the trial or within 120 days after the last dose of study drug.  All subjects 
and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
 
Such events must be reported within one business day to HCRN. HCRN will report such 
events to Merck Global Safety within one business day of receiving notification of the 
event. (Attn: Worldwide Product Safety; FAX 215-993-1220) 
 
11.2.5 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be recorded as such on SAE Submission Form and reported within 
one business day to HCRN. HCRN will report these events within one business day of 
receipt to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220).  
 
ECIs that occur in any subject from the date of first dose through 90 days following the last 
dose of study drug, or the initiation of a new anticancer therapy, whichever is earlier, 
whether or not related to the Merck’s product, must be reported as outlined above. 
Events of clinical interest for this trial include: 
• An overdose of Merck product, as defined above, that is not associated with clinical 
symptoms or abnormal laboratory results.  
• An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value 
that is less than 2X the upper limit of normal, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. 
 
11.2.6 Hoosier Cancer Research Network Requirements for Reporting SAEs to Merck 
HCRN will submit all SAEs received from sites to Merck & Co., Inc. within one business 
day of receipt of the SAE Submission Form and to regulatory authorities (FDA) per federal 
guidelines. 
 


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HCRN will submit SAE reports and any other relevant safety information to the Merck 
Global Safety facsimile number:  +1-215-993-1220.  Follow-up information will be 
provided as reasonably requested. 
11.2.7 
Sponsor-Investigator Responsibilities  
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of 
receipt of SAE Submission Form from a site.  The sponsor-investigator will promptly 
review the SAE summary and assess for expectedness and relatedness.   
 
11.2.8 Reporting to the Food and Drug Administration (FDA) 
The FDA deemed this protocol IND exempt after review of the submission packet 
24FEB2015.   
 
As such, HCRN will assist the sponsor-investigator with compliance with requirements for 
informed consent under 21 CFR 50.20 and initial/continuing Institutional Review Board 
review under 21 CFR Part 56.  In addition to complying with the applicable provisions of 
sections 402(i) and 402(j) of the Public Health Service Act (PHS Act) (42 U.S.C. §§ 282(i) 
and (j)), which was amended by Title VIII of the Food and Drug Administration 
Amendments Act of 2007 (FDAAA) (Public Law No. 110-85, 121 Stat. 904). 
 
12. 
STATISTICAL METHODS 
 
12.1 
General Considerations 
This is a multi-institutional, single arm, open-label, phase II study, including a safety run-in 
cohort, of the combination of pembrolizumab plus mFOFLOX6 in subjects with untreated 
locally advanced or metastatic colorectal cancer. After a safety run-in cohort of 6 subjects at 
the tolerated dose level, 24 additional subjects will be enrolled. These 30 subjects will be 
analyzed as a single cohort for subsequent efficacy and safety analyses. PFS and OS will be 
estimated by Kaplan-Meier method. Median PFS (mPFS) and OS (mOS) will be estimated 
with 80% confidence intervals (CIs). The response rates will be estimated with their Agresti-
Coull 95% CIs. Duration of response will be summarized by descriptive statistics. 
Frequencies and proportions will be used to describe toxicities. Common Terminology 
Criteria for Adverse Events (CTCAE) v4 will be used for assessment of acute and late 
toxicities during the follow-up period. Logistic regressions will be used for the exploratory 
objectives studying potential predictors of responses. 
 
12.2 
Study Design 
This is a multi-institutional, single arm, open-label, phase II study with a safety run-in 
cohort. No randomization or blinding will be involved. 
 
12.3 
Definition of Primary Endpoint 
Median progression free survival (mPFS), measured from the time of registration to the time 
of signs of progression per RECIST 1.1 or subject death depending on whichever occurs 
first. 
 
 
 


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12.4 
Definitions of Secondary Endpoints 
• Objective response rate (ORR), calculated with combining the number of subjects 
who achieve complete response and partial response per irRC criteria 
• Disease control rate (DCR), defined as the sum of subjects with complete response, 
partial response and stable disease.  
• Delayed response, evaluated in subjects who achieve stable disease on first tumor 
assessment but they exhibit an objective response on subsequent tumor evaluations 
per irRC.  
• Overall Survival (OS), calculated from the time of registration till the time of subject 
death  
• Toxicity of therapy will be assessed per CTCAE V4.0 
• Response rate per Immune Related Response Criteria (irRC) 
 
12.5 
Definitions of Exploratory Endpoints 
• Assess the association between TLR4, MyD88, NF-kB expression by IHC and 
response rate. 
• Assess Microsatellite status by IHC 
• Assess the association between HMGB1 blood level and response rate. 
• Assess the association between PD-L1 expression and response rate. 
• Blood samples will be stored at the HCRN for future correlatives.  
• Tissue samples will be stored at the HCRN for future correlatives 
 
12.6 
Analysis Plan for Primary Objectives/Aims 
PFS will be estimated by Kaplan-Meier method. In particular, median PFS will be estimated 
with its two-sided 90% CI. 
 
12.7 
Analysis Plan for Secondary Objectives/Aims 
ORR, DCR, delayed response, irRC and toxicities will be summarized by frequency and 
percentages with Agresti-Coull 95% confidence intervals. OS will be estimated using 
Kaplan-Meier method. 
 
12.8 
Analysis Plan for Exploratory Objectives 
Logistic regressions will be used to evaluate the associations between risk factors and 
responses. For the stored blood samples, appropriate statistical methods will be determined 
according to potential future correlatives 
 
12.9 
Interim analysis 
No interim analysis will be performed. 
 
12.10 Subgroup Analysis 
Subgroup analyses will be performed based on PD-1/PD-L1 expressions. Both efficacy 
endpoints and toxicity endpoints will be evaluated in the subgroup analyses. 
 
12.11 Criteria for Stopping Study 
The trial will be terminated if there is any definite pembrolizumab-related death despite 
maximum supportive therapy. 


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12.12 Analysis Datasets 
Population 
Definition
Enrolled 
This will comprise all subjects who meet the 
eligibility criteria and are registered onto the 
study. This data set will be used for subject 
characteristics summaries.
Evaluable 
This will comprise all patients who receive at 
least one dose of trial drug and either undergo at 
least one post-baseline assessment or die before 
any evaluation. This data set will be used for 
response rates and OS evaluations. 
Intention-to-treat (ITT)
This will comprise all subjects who meet the 
eligibility criteria and are registered onto the 
study irrespective of their compliance to the 
planned course of treatment. This data set will be 
used for the primary objective analysis. 
Safety 
This will comprise all subjects who receive at 
least one dose of trial drug. This data set will be 
used for toxicities evaluations. 
 
 
12.13 Sample Size/Accrual/Study Duration/Replacement Rules  
The primary objective of this early Phase II study is to estimate mPFS. Historically, first line 
FOLFOX achieves a median PFS (mPFS) as 9.0 months [37].  If there are moderate 
evidences that adding Pembrolizumab will increase mPFS from 9- to around 14-months, a 
full scale randomized Phase II study will be considered to formally test whether the 
improvement is meaningful and statistically significant.  
 
The sample size N=30 is determined based on budget/recruitment considerations and 
precision of estimation. We expect that these 30 subjects will be uniformly accrued within 
12-months with an additional 24-months follow up. Kaplan-Meier method will be used to 
estimate PFS. mPFS and its two-sided 80% CI will be calculated. Consequently, the half-
width of the CI from the lower bound to the point estimate of mPFS will be around 4.5-
months, which is smaller than the difference between 14- and 9-months. We consider this 
precision level will allow a decision to be made whether to pursue further studies. 
 
12.14 Subject Characteristics and Significant Protocol Violations 
Subject’s characteristics will be summarized by descriptive statistics. Significant protocol 
violations will be documented and reported. 
 
12.15 Concomitant Medications 
Concomitant medications will be documented and managed accordingly. 
 
 
 


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12.16 Disposition 
The number of enrolled subjects will be summarized in flow chart with frequency of 
completion and discontinuation. The subjects discontinued from study medication and their 
corresponding information will be listed.  
 
13. 
TRIAL MANAGEMENT 
This study will be conducted in accordance with the IU Simon Cancer Center’s (IUSCC) 
Data and Safety Monitoring Plan.  This study will have a Data Safety Monitoring Board as 
described below and a DSMB Charter. 
 
In addition HCRN data and safety monitoring activities include: 
• Conduct review of clinical trial for progress and safety 
• Review of all adverse events requiring expedited reporting as defined in the protocol 
• Provide sponsor-investigator with trial progress and safety information monthly.  
• Notification of participating sites of adverse events requiring expedited reporting and 
subsequent committee recommendations for study modifications 
 
13.1 
Data and Safety Monitoring Board 
This study will have a Data and Safety Monitoring Board (DSMB) that will review and 
monitor study progress, toxicity, safety and other data from this trial. The DSMB is separate 
from the IU Simon Cancer Center (IUSCC) Data and Safety Monitoring Committee 
(DSMC). The board is chaired by an independent medical oncologist external to this trial. 
Questions about subject safety or protocol performance will be addressed with the 
sponsor-investigator, statistician and study team members. Should any major concerns arise; 
the DSMB will offer recommendations regarding whether or not to suspend the trial.  
 
The DSMB will meet after the first 6 subjects are treated with at least one dose of study drug 
and observed for a minimum of 4 weeks after first dose of study drug.  The DSMB will then 
meet twice a year thereafter to review accrual, toxicity, response and reporting information. 
Information to be provided to the DSMB may include: subject accrual, treatment regimen 
information, adverse events and serious adverse events reported by category, summary of 
any deaths on study, audit and/or monitoring results.  During DSMB’s initial review of the 
1st six subjects, accrual to the trial will be halted until completion of review. 
 
The DSMB will provide a recommendation to the team after all information is reviewed. 
This information will also be provided to the site investigator sites for submission to their 
respective IRB according to the local IRB’s policies and procedures. 
 
13.1.1 Early Study Closure 
At any time during the conduct of the trial, if it is the opinion of the sponsor-investigator 
that the risks (or benefits) to the subjects warrant early closure of the study, this 
recommendation should be made in writing to the DSMB Alternatively, the DSMB may 
initiate suspension or early closure of the study based on its regular review of the sponsor-
investigator reports. 
 


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13.2 
On-site Monitoring 
Monitoring visits to the trial sites will be made periodically during the trial, to ensure all 
aspects of the protocol are followed. Source documents will be reviewed for verification of 
agreement with data as submitted via the data collection system. The site 
investigator/institution guarantee access to source documents by HCRN or its designee and 
appropriate regulatory agencies. 
 
The trial site may also be subject to quality assurance audit by Merck & Co., Inc. or its 
designee as well as inspection by appropriate regulatory agencies. 
 
It is important for the site investigator and their relevant personnel to be available during the 
monitoring visits and possible audits and for sufficient time to be devoted to the process. 
 
13.3 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the 
trial is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
 
14. 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Case Report Forms and Submission 
This study will utilize electronic case report form (eCRF) in the Hoosier Cancer Research 
Network (HCRN) electronic data capture (EDC) system. Access to the data through EDC 
system is restricted by user accounts and assigned roles. Once logged into the EDC system 
with a user ID and password, the EDC system defines roles for each user, which limits 
access to appropriate data. User information and passwords can be obtained by contacting 
HCRN at (317) 921-2050.  
 
Generally, clinical data will be electronically captured in the EDC system and correlative 
results will be captured in the EDC system or other secure database. If procedures on the 
study calendar are performed for standard of care, at minimum, that data will be captured in 
the source document. Select standard of care data will also be captured in the EDC system, 
according to study-specific objectives. Please see the Data Management Plan for further 
details.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution. It should 
not be made available in any form to third parties, except for authorized representatives of 
appropriate Health/Regulatory Authorities, without written permission from the sponsor-
investigator and HCRN. 
 


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


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The site investigator is responsible for the distribution of these documents to his or her IRB, 
and to the staff at his or her center. The distribution of these documents to the regulatory 
authority will be handled according to local practice. 
 
Merck & Co., Inc.’s willingness to supply study drug is predicated upon the review of the 
protocol. HCRN agrees to provide written notice to Merck & Co., Inc. of any modifications 
to the protocol or informed consent. 
 
15. 
ETHICS 
 
15.1 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved in writing by an IRB. The site investigator must submit written approval to the 
HCRN office before he or she can enroll any subject into the study.  The site investigator is 
responsible for informing the IRB of any amendment to the protocol in accordance with 
local requirements. In addition, the IRB must approve all advertising used to recruit subjects 
for the study. The protocol must be re-approved by the IRB annually, as local regulations 
require.  
 
Progress reports and notifications of serious unexpected adverse drug reactions will be 
provided to the IRB according to local regulations and guidelines. 
 
The site investigator is also responsible for providing the IRB with reports of any serious 
adverse drug reactions from any other study conducted with the investigational product. 
Merck & Co., Inc. will provide this information to the sponsor-investigator. These reports 
will be forwarded to participating sites for submission to their Institutional Review Boards 
per their guidelines. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki, which are consistent with ICH Good Clinical Practice guidelines, 
and applicable regulatory requirements. 
 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should 
be given the opportunity to ask questions and allowed time to consider the information 
provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
Written Informed Consent Form. A copy of the signed Informed Consent Form must be 
given to the subject. 
 
 


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16. 
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37. Tournigand, C., et al., FOLFIRI followed by FOLFOX6 or the reverse sequence in 
advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol, 2004. 22(2): 
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376(9742) p. 687-697 
 
 


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17. 
APPENDIX 
17.1. ECOG Performance Status 
Grade 
Description
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours.
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair.
5 
Dead. 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair.
 
17.2. Common Terminology Criteria for Adverse Events v4 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) v4 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html)  
 
17.3. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging 
technique in this study. 
* As published in the European Journal of Cancer: 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 
1. Wolchok, J.D., et al., Guidelines for the evaluation of immune therapy activity in solid 
tumors: immune-related response criteria. Clin Cancer Res, 2009. 15(23): p. 7412-20. 
2. Tournigand, C., et al., FOLFIRI followed by FOLFOX6 or the reverse sequence in 
advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol, 2004. 22(2): 
p. 229-37.