This is an open-label, single-center, single-arm phase II clinical trial evaluating the combination of pembrolizumab, binimetinib, and bevacizumab in patients with metastatic colorectal adenocarcinoma who have not responded to prior therapy.

This study will be done in two stages. In stage 1, ten patients will be treated with standard doses of pembrolizumab, binimetinib, and bevacizumab to ensure that the doses are safe and tolerable. In stage 2, patients will be enrolled into either cohort A, where they will be treated with a 7-day run-in of binimetinib, followed by pembrolizumab, bevacizumab, and binimetinib combination treatment in 21 day cycles, or they will be enrolled to cohort B, which does not include the 7-day run-in of binimetinib. Treatment in cohort B will include combination therapy of pembrolizumab, binimetinib, and bevacizumab from first day of treatment.

Inclusion Criteria:

1. Provision to sign and date the consent form.

2. Age ≥ 18 years.

3. Able to comply with the study protocol, in the investigator's judgment.

4. 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.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or one.

6. Histologically confirmed unresectable metastatic colorectal adenocarcinoma.

7. Progression on at least two prior lines of therapy for unresectable metastatic colorectal adenocarcinoma.

   o Administration of bevacizumab previously does not impact study inclusion.

8. Measurable disease, according to RECIST v1.1. Note that lesions intended to be biopsied should not be target lesions.

9. 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

10. 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 < 1% per year during the treatment period and for at least 180 days after the last study treatment. A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

11. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm, as defined below: With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 180 days after the last dose of study treatment. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

1. Cancer-related exclusion criteria:

• Patients with known MSI-high status or unknown MSI status are not eligible for study entry.

• Patients with BRAF V600E mutations are not eligible for the study.

• Surgical procedure (surgical resection, wound revision or any other major surgery) or significant traumatic injury within 60 days prior to enrollment, or anticipation of need for major surgical procedure during the course of the study. Minor surgical procedure within 7 days (including placement of a vascular access device) of study Cycle 1 Day 1.

  1. Study-related biopsies are NOT considered surgical procedures under the exclusion criteria

• Untreated CNS metastases. Treatment of brain metastases, either by surgical or radiation techniques, must have been completed at least 4 weeks prior to initiation of study treatment.

• Treatment with any investigational agent or approved therapy within 21 days (Cycle 1 Day 1).

• Malignancies other than CRC within 3 years prior to Cycle 1 Day 1 with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year overall survival > 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.

  2. 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 immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization.

  3. Exclusion criteria based on autoimmune conditions:

• History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.

• History of non-infectious pneumonitis that required steroids or has current pneumonitis.

• Has an autoimmune disease that has required systemic treatment in the past 2 years with use of disease modifying agents, corticosteroids, or immunosuppressive drugs. Replacement therapy (eg; thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.

  4. Exclusion criteria based on organ function or medical history:

• History of clinically significant cardiac or pulmonary dysfunction including the following:

  1. Inadequately controlled hypertension (that is defined as systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg that is treated or untreated).
  2. History of myocardial infarction within 6 months prior to first dose of study drug in Cycle.
  3. Prior history of hypertensive crisis or hypertensive encephalopathy.
  4. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, evidence of active pneumonitis on screening chest CT scan or non-infectious pneumonitis requiring steroids.

• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of Cycle 1 Day 1.

• History of stroke or transient ischemic attack within 6 months prior to Cycle 1 Day 1.

• Serious non-healing wound, active ulcer or untreated bone fracture.

• History of abdominal fistula or gastrointestinal perforation within 6 months prior to Cycle 1 Day 1.

• History of hemoptysis (≥one teaspoon of bright red blood per episode), or any other serious hemorrhage or at risk of bleeding (gastrointestinal history of bleeds, gastrointestinal ulcers, etc.). INR> 1.5 and aPTT > 1.5 × ULN within 7 days prior to Cycle 1 Day 1. History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding.

• Life expectancy of < 12 weeks.

• Any previous venous thromboembolism≥ Grade 3.

• Proteinuria at screening as demonstrated by urine dipstick ≥ 2+ or 24-hour. proteinuria > 1.0 g.

• Left ventricular ejection fraction (LVEF) below institutional lower limit of normal.

• Uncontrolled serious medical or psychiatric illness.

• Pregnant or lactating, or intending to become pregnant during the study. Women who are not post-menopausal (≥ 12 continuous months of amenorrhea with no identified cause other than menopause) or surgically sterile must have a negative serum pregnancy test within 14 days prior to Cycle 1 Day 1.

  5. Ocular exclusion criteria:

• History or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy, retinal vein occlusion or neovascular macular degeneration.

• Patients will be excluded if they have the following risk factors for retinal vein occlusion: Uncontrolled glaucoma with intraocular pressure ≥21 mmHg. Serum cholesterol ≥ Grade 2. Hypertriglyceridemia ≥ Grade 2. Hyperglycemia (fasting) ≥ Grade 2

  6. Exclusion criteria based on infectious diseases:

• Active infection requiring IV antibiotics at screening.

• Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening). Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. HBV DNA test must be performed in these patients prior to Cycle 1 Day 1.

• Patients with active hepatitis C. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.

• Known HIV infection.

• Influenza vaccination should be given during influenza season. Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to Cycle 1 Day 1 or at any time during the study and for at least 5 months after the last dose of study drug.

3 years, 4 months