Study of Pembrolizumab, Binimetinib, and Bevacizumab in Patients With Refractory Colorectal Cancer

Inclusion Criteria

• Provision to sign and date the consent form.
• Age ≥ 18 years.
• Able to comply with the study protocol, in the investigator's judgment.
• Patient must state willingness to undergo pre- and post-treatment biopsies. According to the investigator's judgement, the planned biopsies should not expose the patient to substantially increased risk of complications.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or one.
• Histologically confirmed unresectable metastatic colorectal adenocarcinoma.
• Progression on at least two prior lines of therapy for unresectable metastatic colorectal adenocarcinoma.

o Administration of bevacizumab previously does not impact study inclusion.

• Measurable disease, according to RECIST v1.1. Note that lesions intended to be biopsied should not be target lesions.
• Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to first dose of study drug treatment:
• WBC ≥ 2.5 and ≤ 15.0 × 109/L
• ANC ≥ 1.5 × 109/L
• Platelet count ≥ 100 × 109/L
• Hemoglobin ≥ 9 g/dL without transfusion in the previous week
• Albumin ≥ 2.5 g/dL
• Serum bilirubin ≤ 1.5 x the upper limit of normal (ULN); patients with known Gilbert's disease may have a bilirubin ≤ 3.0 ×ULN
• INR and PTT ≤ 1.5 × ULN; amylase and lipase ≤ 1.5 × ULN
• AST, ALT, and alkaline phosphatase (ALP) ≤ 3 × ULN with the following exceptions:
• Patients with documented liver metastases: AST and/or ALT ≤ 5 ×ULN
• Patients with documented liver or bone metastases: ALP ≤ 5×ULN
• Creatinine clearance ≥ 50 mL/min
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use of contraceptive methods that result in a failure rate of 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent).
• Prior radiation therapy within 14 days prior to study Cycle 1 Day 1 and/or persistence of radiation-related adverse effects. However, palliative radiation therapy (as long as it does not involve target lesions) is permitted on the study.
• Prior allogeneic bone marrow transplantation or solid organ transplant for another malignancy in the past.
• Spinal cord compression not definitively treated with surgery and/or radiation.
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures.
• Uncontrolled tumor related pain. Patients who require narcotic pain medication during screening should be on a stable dose regimen prior to Cycle 1 Day 1.
• Exclusion criteria related to study medication:
• Current or recent (within 10 days of study enrollment) use of acetylsalicylic acid (> 325 mg/day), clopidogrel (> 75 mg/day) or current or recent (within 10 days of first dose of bevacizumab) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purpose. Note: The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants for at least 2 weeks at the time of Cycle 1 Day 1. Prophylactic use of anticoagulants is allowed.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
• Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells, any components of Binimetinib, Pembrolizumab, or bevacizumab formulations or any premedications.
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-PD-1, anti-PD L1, anti-PD-L2 or MAPK pathway inhibitors (eg; BRAF, MEK, ERK inhibitors).
• Has a diagnosis of immunodefi