Study of Pembrolizumab, Binimetinib, and Bevacizumab in Patients With Refractory Colorectal Cancer
Condition: Colorectal Cancer; Metastatic Cancer
MeSH terms: Colorectal Neoplasms
Intervention: Pembrolizumab; Bevacizumab; Binimetinib
Intervention description: An intravenous, potent and highly selective humanized monoclonal antibody of the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.; The pharmacokinetics of bevacizumab are characterized by a slow CL, long half-life, and a volume of distribution consistent with limited extravascular distribution.; Binimetinib (MEK162/ARRY-438162) is an orally bioavailable, small molecule selective and potent mitogen-activated protein kinase (MEK) 1 and MEK 2 inhibitor.
Intervention MeSH terms: Bevacizumab; Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 53.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Pembrolizumab; Binimetinib; Bevacizumab; Combination Therapy

Summary:

      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.
    

Eligibility criteria:

        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.