Inclusion Criteria:

PRE-REGISTRATION

• Histological confirmation of a pancreatic malignancy as confirmed by the local pathology lab.
• Patients whose disease has progressed on (or who were intolerant of) at least one line of therapy for metastatic disease.
• Patients whose disease has recurred with metastatic disease:
  • ≤ 12 weeks of completion of neoadjuvant or adjuvant systemic chemotherapy; or
  • Patients with locally advanced disease whose disease progressed to metastatic disease on; or
  • ≤ 12 weeks after completion of systemic chemotherapy would also be eligible.
• Provide informed written consent ≤ 28 days prior to pre-registration.
• Central electronic/paper confirmation of the presence of a BRAF V600E mutation. This review is mandatory prior to pre-registration to confirm eligibility. Results from a Clinical Laboratory Improvement Act (CLIA)/College of American Pathologists (CAP) certified testing lab (commercial or institutional) that confirm the presence of a BRAF V600E mutation in the patient's tumor must be submitted for central review

REGISTRATION 

• Registration must occur ≤ 30 days after pre-registration.
• Confirmation of the presence of BRAF V600E mutation in the patient's tumor.
• Measurable disease.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2. (Form is available on the Academic and Community Cancer Research United [ACCRU] web site).
• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (obtained 14 days prior to registration).
• Platelet count ≥ 75,000/mm^3 (obtained ≤ 14 days prior to registration).
• Hemoglobin ≥ 9.0 g/dL (obtained ≤ 14 days prior to registration).
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained ≤ 14 days prior to registration).
• Aspartate transaminase (AST) ≤ 2.5 x ULN; in participants with liver metastases ≤ 5 x ULN (obtained ≤ 14 days prior to registration).
• Aminotransferase (ALT) ≤ 2.5 x ULN; in participants with liver metastases ≤ 5 x ULN (obtained ≤ 14 days prior to registration).
• Calculated creatinine clearance must be ≥ 45 ml/min using the Cockcroft Gault formula (obtained ≤ 14 days prior to registration).
• Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only.
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study).
  • Note: During the active monitoring phase of a study (i.e., active treatment), participants must be willing to return to the consenting institution for follow-up.
• Ability to swallow the investigational product tablets and capsules.
• Willing to provide tissue and blood samples for correlative research purposes.

Exclusion Criteria:

REGISTRATION

• Patients whose tumor harbors a BRAF non-V600E mutation or a BRAF fusion.
• Prior therapy with BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib) and/or a MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib).
• Known hypersensitivity or contraindication to any component of binimetinib or encorafenib or their excipients.
• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception.
    • NOTE: Female participants of childbearing potential must agree to use methods of contraception that are highly effective or acceptable, and to not donate ova from screening until 30 days after the last dose of study drug.
    • NOTE: Male participants must agree to use methods of contraception that are highly effective or acceptable, and to not donate sperm from screening until 90 days after the last dose of study drug.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
  • NOTE: Patients known to be human immunodeficiency virus ( HIV) positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 6 months prior to registration.
• Left ventricular ejection fraction (LVEF) ≤ 50% as determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO).
• Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150/100 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
• Triplicate average baseline corrected QT (QTc) interval ≥ 480 ms.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Patients who have had another active malignancy within the past two years are ineligible EXCEPT FOR patients with cervical cancer in situ, in situ carcinoma of the bladder, non-melanoma carcinoma of the skin, or patients who have had therapy with curative intent for breast or prostate cancer, but remain on adjuvant hormonal therapy.
• Received anticancer therapy including chemotherapy, immunotherapy, or antineoplastic biologic therapy (e.g., erlotinib, cetuximab, bevacizumab etc.), ≤ 14 days (≤ 28 days for an antibody-based therapy) prior to registration.
• Patients who have undergone major surgery (e.g., in-patient procedures) ≤ 6 weeks prior to registration or who have not recovered from side effects of such procedure.
• Patients who have had radiotherapy ≤ 14 days prior to registration or who have not recovered from side effects of such procedure.
  • NOTE: Palliative radiation therapy must be complete 7 days prior to the first dose of study treatment.
• Patient has not recovered to ≤ grade 1 from toxic effects of prior therapy before registration.
  • EXCEPTIONS: Stable chronic conditions (≤ grade 2) that are not expected to resolve (such as neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies).
• Uncontrolled or symptomatic brain metastases or leptomeningeal carcinomatosis that are not stable, require steroids, are potentially life-threatening or have required radiation ≤ 28 days prior to registration.
  • NOTE: Patients with previously treated brain metastases may participate provided they are stable (e.g., without evidence of progression by radiographic imaging for ≤ 28 days prior to registration and neurologic symptoms have returned to baseline), and have no evidence of new or enlarging brain metastases or central nervous system (CNS) edema, and does not require steroids at least 7 days before the first dose of study treatment.
• Impairment of gastrointestinal function or disease which may significantly alter the absorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting or diarrhea, malabsorption syndrome, small bowel resection with decreased intestinal absorption), or recent (≤ 12 weeks) history of a partial or complete bowel obstruction, or other condition that will interfere significantly with the absorption or oral drugs.
• Known history of acute or chronic pancreatitis.
• Concurrent neuromuscular disorder that is associated with elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amytrophic lateral sclerosis, spinal muscular atrophy).
• History or current evidence of RVO or current risk factors for retinal vein occlusion (RVO) (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease.
• Current use of prohibited medication (including herbal medications, supplements, or foods), or use of prohibited medication ≤ 7 days prior to registration.
• History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to registration. 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 emobli that do not result in hemodynamic instability are allowed to enroll as long as they are on a stable dose of anticoagulants for ≤ 4 weeks prior to registration.
  • NOTE: Patients with thromboembolic events related to indwelling catheters or other procedures may register.
• Evidence of hepatitis B Virus (HBV) or hepatitis C Virus (HCV) infection.
  • NOTE: Patients with laboratory evidence of cleared HBV or HCV infection may register.
  • NOTE: Patients with no prior history of HBV infection who have been vaccinated against HBV and who have a positive antibody against hepatitis B surface antigen as the only evidence of prior exposure may register.