Binimetinib and Encorafenib for the Treatment of Pancreatic Cancer in Patients With a Somatic BRAF V600E Mutation
Binimetinib and Encorafenib for the Treatment of Pancreatic Cancer in Patients With a Somatic BRAF V600E Mutation
This phase II trial studies the side effects and how well the combination of binimetinib and
 encorafenib work in treating patients with pancreatic cancer with a somatic BRAF V600E
 mutation. Binimetinib and encorafenib may stop the growth of tumor cells by blocking some of
 the enzymes needed for cell growth. Giving binimetinib and encorafenib may work better
 compared to the usual treatment in treating patients with pancreatic cancer and a somatic
 BRAF V600E mutation.
PRIMARY OBJECTIVE:

 I. To determine the efficacy of the combination of binimetinib and encorafenib as >= 2nd line
 of treatment for patients with metastatic pancreatic cancer with BRAF V600E mutation.

 SECONDARY OBJECTIVES:

 I. To determine in patients treated with the combination of binimetinib and encorafenib as >=
 2nd line of treatment for patients with metastatic pancreatic cancer with BRAF V600E
 mutation:

 Ia. The median progression-free survival. Ib. The median overall survival. Ic. Duration of
 response. Id. Time to response. Ie. The safety and tolerability.

 OUTLINE:

 Patients receive encorafenib orally (PO) once daily (QD) and binimetinib PO twice daily (BID)
 on days 1-25. Treatment repeats every 28 days for up to 36 cycles in the absence of disease
 progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up every 3 months for up to 5
 years.
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: NOTE: 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