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

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

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

Eligibility Criteria:
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.