Encorafenib, Binimetinib, and Nivolumab in Treating Patients With Microsatellite Stable BRAF V600E Metastatic Colorectal Cancer
Encorafenib, Binimetinib, and Nivolumab in Treating Patients With Microsatellite Stable BRAF V600E Metastatic Colorectal Cancer
This phase I/II trial studies the side effects and how well encorafenib, binimetinib, and
 nivolumab work in treating patients with microsatellite stable, BRAFV600E gene-mutated
 colorectal cancer that has spread to other places in the body (metastatic). Encorafenib and
 binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for
 cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's
 immune system attack the cancer, and may interfere with the ability of tumor cells to grow
 and spread. Giving encorafenib, binimetinib, and nivolumab may work better in treating
 patients with colorectal cancer compared to standard treatments.
PRIMARY OBJECTIVES:

 I. To describe overall response rate (ORR) upon treatment with encorafenib, binimetinib, and
 nivolumab in patients with BRAFV600E, microsatellite stable (MSS) metastatic colorectal
 cancer (mCRC).

 II. To determine the safety and tolerability of nivolumab, encorafenib, and binimetinib in
 patients with BRAFV600E, MSS mCRC.

 SECONDARY OBJECTIVES:

 I. To estimate median progression-free survival (PFS) upon treatment with encorafenib,
 binimetinib, and nivolumab.

 II. To estimate median overall survival (OS) upon treatment with encorafenib, binimetinib,
 and nivolumab.

 III. To estimate median time to response (TTR) upon treatment with encorafenib, binimetinib,
 and nivolumab.

 IV. To estimate median duration of response (DoR) upon treatment with encorafenib,
 binimetinib, and nivolumab.

 V. To estimate disease control rate (DCR) upon treatment with encorafenib, binimetinib, and
 nivolumab.

 EXPLORATORY (CORRELATIVE) OBJECTIVES:

 I. To assess genomic and immune changes upon treatment with encorafenib, binimetinib, and
 nivolumab in tumor tissue, blood and stool.

 II. To correlate genomic and immune changes upon treatment with encorafenib, binimetinib, and
 nivolumab in tumor tissue, blood and stool with radiographic response.

 III. To evaluate contrast-enhanced computed tomography (CT) imaging for disease burden that
 is not measurable by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)
 and to correlate location and patterns of metastatic disease with clinical outcomes.

 OUTLINE:

 Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, binimetinib PO twice
 daily (BID) on days 1-28, and nivolumab intravenously (IV) on day 1. Cycles repeat every 28
 days for a maximum of 24 cycles of treatment. If disease progression or recurrence occurs,
 treatment may be resumed outside of the context of the clinical trial.

 After completion of study treatment, patients are followed up at 30 and 100 days, then every
 3 months thereafter.
Inclusion Criteria:

 -  Participants must have histologically or cytologically confirmed diagnosis of
 adenocarcinoma of the colon or rectum, with clinical confirmation of unresectable
 and/or metastatic disease that is measurable according to Response Evaluation Criteria
 in Solid Tumors (RECIST 1.1) criteria

 -  Confirmation of BRAFV600E tumor as detected from testing performed in a Clinical
 Laboratory Improvement Act (CLIA)-certified laboratory

 -  Confirmation of MSS status from testing performed in a CLIA-certified laboratory

 -  Prior treatment with at least one systemic chemotherapy regimen for mCRC, or
 recurrence/progression with development of unresectable or metastatic disease within 6
 months of adjuvant chemotherapy for resected CRC

 -  Eastern Cooperative Oncology Group performance status (ECOG PS) =< 1 (Karnofsky >=
 70%)

 -  Absolute neutrophil count (ANC) >= 1.0 x 10^9/L

 -  Hemoglobin (Hgb) >= 9 g/dL with or without transfusions

 -  Platelets (PLT) >= 100 x 10^9/L without transfusions

 -  Total bilirubin =< 1.5 x upper limit of normal (ULN) and < 2 mg/dL

 -  Note: Patients who have a total bilirubin level > 1.5 x ULN and/or have Gilbert's
 disease will be allowed if their direct bilirubin level is =< 0.5 mg/dl or ULN,
 whichever is higher.

 -  Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 3 x ULN

 -  Serum creatinine =< 1.5 x ULN, or calculated creatinine clearance (determined as per
 Cockcroft-Gault) >= 50 mL/min at screening

 -  Corrected QT (QTc) interval =< 480 ms (preferably the mean from triplicate
 electrocardiograms [ECGs])

 -  Ability to understand a written informed consent document, and the willingness to sign
 it

 -  The effects of the study drugs on the developing human fetus are unknown. Female
 patients must either be postmenopausal for at least 1 year, surgically sterile for at
 least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from
 screening through 5 months after discontinuation of study treatment if of childbearing
 potential

 -  Female participants of childbearing potential (WOCBP) must agree to use adequate
 contraception: *see list below this paragraph* for the duration of study
 participation and for 5 months (i.e., 30 days [duration of ovulatory cycle] plus
 the time required for the investigational drug to undergo approximately five
 half-lives) after last administration of study treatment. Only for all females of
 childbearing potential, the pregnancy test result must be negative within 24
 hours of starting treatment. Should a woman become pregnant or suspect she is
 pregnant while she or her partner is participating in this study, she should
 inform her treating physician immediately

 -  Males who are sexually active with WOCBP must agree to follow instructions for
 method(s) of contraception *see list below this paragraph* for the duration of
 study treatment with nivolumab and 7 months after the last dose of study
 treatment (i.e., 90 days [duration of sperm turnover] plus the time required for
 the investigational drug to undergo approximately five half-lives.)

 -  Accepted means of contraception:

 -  Complete abstinence from sexual intercourse when this is in line with the
 preferred and usual lifestyle of the patient

 -  Double barrier methods

 -  Condom with spermicide in conjunction with use of an intrauterine device

 -  Condom with spermicide in conjunction with use of a diaphragm

 -  Birth control patch or vaginal ring

 -  Oral, injectable, or implanted contraceptives

 -  Due to the potential of encorafenib to induce CYP3A4, hormonal agents
 (including but not limited to birth control patch, vaginal ring, oral,
 injectable, or implanted contraceptives) are permissible only when combined
 with other highly effective or acceptable methods

 -  Surgical sterilization (bilateral oophorectomy with or without hysterectomy,
 tubal ligation or vasectomy) at least 6 weeks prior to taking study
 treatment. In the case of oophorectomy alone, only when the reproductive
 status of the woman has been confirmed by follow-up levels of luteinizing
 hormone, follicle-stimulating hormone, and/or estradiol

 -  Men treated or enrolled on this protocol must also agree to use adequate
 contraception prior to the study, for the duration of study participation, and
 100 days after last administration of study treatment

 -  Able to take oral medications

 Exclusion Criteria:

 -  Concurrent corticosteroid therapy or concurrent use of any other immunosuppressive
 medication (corticosteroid use on study as a pre-medication for IV contrast
 allergies/reactions is allowed). Subjects who are receiving daily steroid replacement
 therapy (the equivalent of prednisone =< 10 mg daily) serve as an exception to this
 rule

 -  Prior immune checkpoint therapy including, but not limited to, an anti-PD-1,
 anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated
 antigen-4 (CTLA-4) antibody, or any other prior immunotherapy agent administered with
 antineoplastic intent

 -  Prior B-raf (BRAF)- or mitogen-activated extracellular kinase (MEK)-targeted therapy

 -  Known hypersensitivity or contraindication to any component of binimetinib or
 encorafenib or their excipients

 -  Prior allogeneic tissue/solid organ transplant

 -  Interstitial lung disease (ILD) or history of pneumonitis that has required oral or IV
 steroids

 -  Receipt of a live vaccine within 30 days prior to the first administration of study
 medication. Seasonal flu vaccines that do not contain a live virus are permitted

 -  History of a grade 3 or 4 allergic reaction attributed to humanized or human
 monoclonal antibody therapy

 -  Active infection requiring concurrent antibiotic use

 -  Any symptomatic brain metastasis

 -  Note: Patients previously treated or untreated for this condition who are
 asymptomatic in the absence of corticosteroid and anti-epileptic therapy are
 allowed. Brain metastases must be stable for >= 4 weeks, with imaging (e.g.,
 magnetic resonance imaging [MRI] or computerized tomography [CT]) demonstrating
 no current evidence of progressive brain metastases at screening

 -  Leptomeningeal disease

 -  Previous or concurrent malignancy within 3 years of study entry, with the following
 exceptions: adequately treated basal or squamous cell skin cancer, superficial bladder
 cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other
 noninvasive or indolent malignancy; other solid tumors treated curatively without
 evidence of recurrence for at least 3 years prior to study entry

 -  Impaired cardiovascular function or clinically significant cardiovascular diseases,
 including any of the following:

 -  History of acute coronary syndromes (including myocardial infarction, unstable
 angina, coronary artery bypass grafting, coronary angioplasty, or stenting) < 6
 months prior to screening

 -  Symptomatic chronic heart failure (i.e. grade 2 or higher), history or current
 evidence of clinically significant cardiac arrhythmia and/or conduction
 abnormality < 6 months prior to screening (including resting bradycardia,
 uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular
 tachycardia)

 -  Left ventricular ejection fraction (LVEF) < 50% as determined by multi-gated
 acquisition (MUGA) or echocardiogram (ECHO)

 -  Uncontrolled hypertension defined as persistent elevation of systolic blood pressure
 >= 160 mmHg or diastolic blood pressure >= 100 mm Hg, despite current therapy

 -  Known positive serology for HIV (human immunodeficiency virus), active hepatitis B,
 and/or active hepatitis C infection

 -  Known history of acute or chronic pancreatitis (history of acute pancreatitis with no
 recurrent events in the prior 24 months are permitted)

 -  Patients with a history of inflammatory bowel disease, including ulcerative colitis
 and Crohn?s disease, are excluded from this study, as are patients with a history of
 symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive
 sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g.,
 Wegener?s granulomatosis]); central nervous system (CNS) or motor neuropathy
 considered of autoimmune origin (e.g., Guillain-Barre Syndrome and myasthenia gravis,
 multiple sclerosis). Patients with Graves? disease will be allowed

 -  Impaired gastrointestinal (GI) function or disease that may significantly alter the
 absorption of study drug (e.g., ulcerative diseases, uncontrolled vomiting,
 malabsorption syndrome, small bowel resection with decreased intestinal absorption)

 -  Concurrent neuromuscular disorder that is associated with elevated creatine kinase
 (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral
 sclerosis, spinal muscular atrophy)

 -  History or current evidence of retinal vein occlusion (RVO) or current risk factors
 for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity
 or hypercoagulability syndromes); history of retinal degenerative disease

 -  History of thromboembolic or cerebrovascular events =< 12 weeks prior to the first
 dose of study treatment. Examples include transient ischemic attacks, cerebrovascular
 accidents, hemodynamically significant (i.e. massive or sub-massive) deep vein
 thrombosis or pulmonary emboli

 -  Note: Patients with either deep vein thrombosis or pulmonary emboli that does not
 result in hemodynamic instability are allowed to enroll as long as they are on a
 stable dose of anticoagulants for at least 4 weeks

 -  Note: Patients with thromboembolic events related to indwelling catheters or
 other procedures may be enrolled

 -  Any other condition that would, in the investigator?s judgment, contraindicate the
 patient?s participation in the clinical study due to safety concerns or compliance
 with clinical study procedures

 -  Major surgery =< 6 weeks prior to starting study drug or failure to recover from side
 effects of such procedure at the discretion of the treating investigator

 -  Pregnant or nursing (lactating) females, where pregnancy is defined as the state of a
 female after conception and until the termination of gestation, confirmed by a
 positive human chorionic gonadotropin (hCG) laboratory test

 -  Prisoners or persons who are involuntarily incarcerated

 -  Medical, psychiatric, cognitive or other conditions that may compromise the patient's
 ability to understand the patient information, give informed consent, comply with the
 study protocol or complete the study