Binimetinib And Encorafenib For The Treatment Of Pancreatic Cancer In Patients With A Somatic BRAF V600E Mutation

Study Overview

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.

Locally Advanced Pancreatic Carcinoma
Metastatic Pancreatic Carcinoma
Recurrent Pancreatic Carcinoma
Stage III Pancreatic Cancer AJCC v8
Stage IV Pancreatic Cancer AJCC v8

DRUG: Binimetinib
DRUG: Encorafenib

ACCRU-GI-1907
NCI-2020-02972 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
ACCRU-GI- 1907 (OTHER Identifier) (OTHER: Academic and Community Cancer Research United)
P30CA015083 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2020-05-12	Results First Submitted 2023-12-12	Last Update Submitted that met QC Criteria 2024-05-03
First Submitted that Met QC Criteria 2020-05-12	Results First Submitted that Met QC Criteria 2023-12-29	Last Update Posted (ACTUAL) 2024-05-06
First Posted (ACTUAL) 2020-05-15	Results First Posted 2024-01-23	Last Verified 2023-09

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Treatment (encorafenib, binimetinib) Patients receive encorafenib PO QD and binimetinib PO BID on days 1-25. Treatment repeats every 28 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity.	DRUG: Binimetinib Given PO DRUG: Encorafenib Given PO

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Treatment (encorafenib, binimetinib)

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

DRUG: Binimetinib

Given PO

DRUG: Encorafenib

Given PO

Primary Outcome Measures	Measure Description	Time Frame
Objective Response Rate (ORR) at 24 Weeks	An objective response is defined as a complete or partial response with a confirmation scan not less than 4 weeks after the initial scan. Disease status will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria. The final ORR point estimate and corresponding 95% confidence interval will be reported.	24 weeks

Secondary Outcome Measures	Measure Description	Time Frame
Progression-free Survival (PFS)	Progression-free survival is defined as the time from registration to clinical or radiographic disease progression or death, whichever occurs first, as defined by RECIST 1.1 criteria. PFS will be estimated using the Kaplan-Meier method. The median PFS and corresponding 95% confidence interval will be reported.	25 months
Overall Survival	Overall survival (OS) is defined as the time from registration to death from any cause. OS will be estimated using the Kaplan-Meier method. The median overall survival and corresponding 95% confidence interval will be reported.	25 months
Duration of Response	Duration of response is defined as the duration of time from first documentation of an objective response to the earliest date disease progression is documented or death from any cause. Duration of response will be estimated using the Kaplan-Meier method. The median duration of response and corresponding 95% confidence interval will be reported.	12 months
Time to Response	Time to response is defined as the duration of time from registration to the first documentation of an objective response. Time to response will be estimated using the Kaplan-Meier method. The median time to response and corresponding 95% confidence interval will be reported.	25 months
Number of Patients With Grade 3+ Adverse Events	Adverse Events as defined by National Institute of Health (NIH) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. All patients who have initiated treatment will be considered evaluable for adverse event analyses. The rate of patients experiencing a grade 3+ adverse event will be reported.	25 months

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

National Cancer Institute (NCI)

Investigators

PRINCIPAL_INVESTIGATOR: Andrew E Hendifar, Academic and Community Cancer Research United

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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