Encorafenib, Binimetinib, and Nivolumab in Treating Microsatellite Stable BRAF V600E Metastatic Colorectal Cancer

Stopped early · Phase 1

Conditions studied: Metastatic Colon Adenocarcinoma, Metastatic Colorectal Adenocarcinoma, Metastatic Microsatellite Stable Colorectal Carcinoma, Metastatic Rectal Adenocarcinoma, Stage III Colon Cancer, Stage III Colorectal Cancer, Stage III Rectal Cancer, Stage IIIA Colon Cancer, Stage IIIA Colorectal Cancer, Stage IIIA Rectal Cancer, Stage IIIB Colon Cancer, Stage IIIB Colorectal Cancer, Stage IIIB Rectal Cancer, Stage IIIC Colon Cancer, Stage IIIC Colorectal Cancer, Stage IIIC Rectal Cancer, Stage IV Colon Cancer, Stage IV Colorectal Cancer, Stage IV Rectal Cancer, Stage IVA Colon Cancer, Stage IVA Colorectal Cancer, Stage IVA Rectal Cancer, Stage IVB Colon Cancer, Stage IVB Colorectal Cancer, Stage IVB Rectal Cancer, Stage IVC Colon Cancer, Stage IVC Colorectal Cancer, Stage IVC Rectal Cancer

In brief

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.

Key facts

Study ID

NCT04044430

Run by

University of California, San Francisco

People needed

2

Starts

2020-08-31

Expected to finish

2022-07-31

Last updated by the study team

2023-01-09

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• 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

You may not qualify if…

• 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

Where it is running

• Kaiser Permanente Northern California — San Francisco, California, United States
• Univeristy of California, San Francisco — San Francisco, California, United States

Full record on ClinicalTrials.gov

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