Study of Pembrolizumab in Combination With Chemotherapy for Patients With Advanced Colorectal Cancer

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

Inclusion Criteria:

- 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.

- Be ≥ 18 years of age on day of signing informed consent.

- Have a performance status of 0 or 1 on the ECOG Performance Scale within 14 days prior
to registration.

- Have histological or cytological evidence of colorectal adenocarcinoma with
confirmation of metastatic disease either by pathologic or radiologic findings.

- 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.

- 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.

- Have measurable disease according to RECIST v1.1 obtained by imaging within 28 days
prior to registration.

- Female subjects 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 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).

- 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:

- 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.

- 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.

- Is unable to receive a port or peripherally inserted central catheter (PICC).

- Has a diagnosis of immunodeficiency or is receiving chronic steroid therapy of
prednisone ≥ 10 mg daily or any equivalent dose of corticosteroids.

- Has previously undergone organ or bone marrow transplantation and is on
immunosuppressive therapy

- Has had major surgery or significant traumatic injury within 4 weeks of study
registration. Subjects 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

- Has baseline peripheral neuropathy/paresthesia grade ≥ 1.

- 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

- 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.

- 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 patients with Sjögren's syndrome

- Has a history of pneumonitis that required steroids or current pneumonitis.

- Has known history of active tuberculosis.

- Has an active infection requiring systemic therapy (≥ grade 2) for more than 3 days
within 1 week of enrollment.

- 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 (MK-3475).

- Has known hypersensitivity to fluorouracil (5FU), oxaliplatin, or other platinum
agents.

- Known hypersensitivity to pembrolizumab or any of its excipients.

- Has known dihydropyrimidine dehydrogenase deficiency (DPD) deficiency (testing not
required)

- 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).

- Has known active Hepatitis B unless subject has been on antiviral agents for at least
2 months (baseline testing not required)

- Has a known history of Human Immunodeficiency Virus (HIV) or Hepatitis C (baseline
testing is not required).

- Has received a live vaccine within 30 days prior to trial registration.

- 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.

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

- 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.