Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRAFV600E Mutated Unresectable or Metastatic Colorectal Cancer
Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRAFV600E Mutated Unresectable or Metastatic Colorectal Cancer
This phase I/II trial studies the best dose and side effects of encorafenib, cetuximab, and
 nivolumab and how well they work together in treating patients with microsatellite stable,
 BRAFV600E gene mutated colorectal cancer that cannot be removed by surgery (unresectable) or
 has spread to other places in the body (metastatic). Encorafenib and cetuximab 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, cetuximab, and nivolumab may work better in treating patients with colorectal
 cancer compared to cetuximab alone.
PRIMARY OBJECTIVES:

 I. To describe overall response rate (ORR) upon treatment with encorafenib, cetuximab, and
 nivolumab.

 II. To determine the safety and tolerability of nivolumab, encorafenib, and cetuximab.

 SECONDARY OBJECTIVES:

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

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

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

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

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

 EXPLORATORY OBJECTIVES:

 I. To assess genomic and immune changes upon treatment with encorafenib, cetuximab, and
 nivolumab.

 II. To demonstrate feasibility of establishing humanized patient-derived xenograft models in
 matched patients with BRAFV600E metastatic colorectal cancer (mCRC).

 OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

 Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab
 intravenously (IV) over 1 hour on days 1 and 15, and nivolumab IV over 30 minutes on day 1.
 Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

 -  Provision of signed informed consent prior to any screening procedures being performed

 -  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 by a Clinical Laboratory Improvement
 Amendments (CLIA)-certified laboratory

 -  Confirmation of microsatellite stable (MSS) status in a CLIA-certified laboratory

 -  Prior treatment with at least one, but no more than two, systemic chemotherapy
 regimen(s) for mCRC, or recurrence/progression with development of unresectable or
 metastatic disease within 6 months of adjuvant chemotherapy for resected colorectal
 cancer

 -  Eastern Cooperative Oncology Group (ECOG) performance status =< to 1

 -  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

 -  Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 2.5 x upper
 limit of normal (ULN)

 -  Total bilirubin =< to 1.5 x ULN and < 2 mg/dL

 -  Note: Patients who have a total bilirubin level > 1.5 x ULN will be allowed if
 their indirect bilirubin level is =< 1.5 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)

 -  Able to take oral medications

 -  Female patients are either postmenopausal for at least 1 year, are surgically sterile
 for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy
 from screening through follow-up if of childbearing potential. Note: Permitted
 contraception methods should be communicated to the patients and their understanding
 confirmed. For all females, the pregnancy test result must be negative within 24 hours
 of starting treatment with nivolumab. Males to avoid fathering a child from screening
 through 100 days following the end of therapy

 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 treatment with a BRAF inhibitor, MEK inhibitor, or ERK inhibitor (of note,
 regorafenib is not considered a BRAF inhibitor for the context of eligibility
 criteria)

 -  Prior treatment with anti-EGFR therapies

 -  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 immune-modulating agent administered
 with antineoplastic intent (monoclonal antibodies used against VEGF are permitted)

 -  Prior allogeneic tissue/solid organ transplant

 -  History of (non-infectious) 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 > or equal to
 4 weeks, with imaging (e.g., magnetic resonance imaging [MRI] or computed 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

 -  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 except atrial fibrillation and paroxysmal
 supraventricular tachycardia

 -  Uncontrolled hypertension defined as persistent elevation of systolic blood pressure
 >= 170 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 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)

 -  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) women, 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

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