Binimetinib and Encorafenib for the Treatment of Advanced Solid Tumors With Non-V600E BRAF Mutations

NCT03839342 | Active Not Recruiting Phase 2 FDA Drug

• 1 other identifier: BEAVER-001 / IST-818-207X
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single-centre, open-label Phase II study of the investigational drugs binimetinib and encorafenib that will be taken my mouth (orally) daily in adult patient with advanced and/or metastatic solid tumors for which no other standard therapy is available. The main purpose is to evaluate the objective response rate (ORR) of the study drugs in the growth of the cancer in patients with class 2 and 3 BRAF mutations.

Conditions

Solid Tumor

Keywords

Advanced Cancer; Advanced Solid Tumors; Non-V600 BRAF Mutations

Outcome Measures

Primary Outcomes (1)

• Objective response rate defined as per RECIST v1.1.

  2.5 years

Secondary Outcomes (7)

• Number of participants with toxicities as per NCI CTCAE v5.0.

  2.5 years

• Disease progression defined as per RECIST v1.1 and monitored throughout the study period. Progression Free Survival defined as time from study registration to disease progression or death from any cause.

  2.5 years

• Disease Control Rate defined in accordance with RECIST v1.1, as the percentage of patients who achieve a complete response, partial response or stable disease after 24 weeks of treatment.

  2.5 years

• Overall survival measured as the length of time from the first day of treatment to the day of death. Median OS will be reported.

  2.5 years

• Change in circulating tumor DNA (ctDNA) profiles measured by serial analysis of ctDNA profiles at baseline, mid-cycle 1, with each subsequent cycle, and at progression, validated by comparison to molecular profiles of corresponding fresh tumor biopsies

  2.5 years

Study Arms (1)

Binimetinib + Encorafenib

EXPERIMENTAL

Binimetinib and encorafenib are administered orally on a twice daily or once daily schedule, respectively in 28-day cycles. Treatment will continue until it is discontinued due to unacceptable toxicity, clinical or radiological disease progression as per RECIST 1.1, investigator decision, and/or withdrawal of consent.

Drug: Binimetinib; Drug: Encorafenib

Interventions

Binimetinib DRUG

MEK inhibitor, 45mg oral tablet

Binimetinib + Encorafenib

Encorafenib DRUG

BRAF inhibitor, 450mg oral capsule

Binimetinib + Encorafenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Informed consent
• Signed written and voluntary informed consent.
• Patient must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
• Age \> 18 years, male or female.
• Disease characteristics
• Patient must be diagnosed with a histologically or cytologically-documented, locally-advanced, or metastatic solid malignancy that is incurable and has either (a) failed prior standard therapy, (b) for which no standard therapy exists, or (c) standard therapy is not considered appropriate by the patient and treating physician.
• Measurable disease by RECIST v1.1 criteria.
• Malignancy must express one of the following BRAF alterations: BRAF mutation affecting codon: 241, 257, 367, 462, 463, 464, 466, 467, 469, 485, 581, 586, 594, 595, 596, 597 598, 599, 601; V600 BRAF mutations: V600K (for any malignancy except melanoma), V600D, V600M, V600R; BRAF deletions ie. V600\_K601delinsE or 1799\_1801 del TGA; BRAF insertions ie. T599dup; BRAF fusions ie. KIAA1549:BRAF
• All patients enrolled must be willing and able to provide at least 1 archival and/or fresh tumor biopsy at baseline for histopathological and molecular evaluation during the screening period with binimetinib and encorafenib. Additional matched pre-treatment and on-treatment fresh tumor biopsies are mandatory for 10 patients enrolled in stage 2. Any patient with insufficient or inadequate archival tissue samples will be required to provide a fresh tumor biopsy. For all other patients, a fresh baseline biopsy is optional, but highly recommended. If a patient only has a single measurable lesion by RECIST v1.1, this lesion can be used for baseline biopsy if it is 2cm or greater.
• Patient must be able to swallow pills
• Patient must be willing to provide serial blood samples for molecular profiling of ctDNA evolution
• Patient characteristics
• ECOG performance status 0-1.
• Patient must have adequate organ function as determined by the following:
• Renal function: i. Serum creatinine \< 1.5 ULN (upper limit of normal range) or a calculated creatinine clearance of \> 50mL/min using the following Cockcroft-Gault formula:

You may not qualify if:

• Patients meeting any of the following criteria are excluded from the study:
• Any patient with a tumor expressing a BRAF V600E mutation
• Any patient with melanoma whose tumor expresses a BRAF V600K mutation
• Prior therapy with any BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib) and/or any MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib).
• Patients receiving any systemic chemotherapy, immunotherapy, or targeted therapy, within 4 weeks from the last dose prior to study treatment. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment. Local treatment (e.g. by local surgery or radiotherapy) of isolated lesions for palliative intent is acceptable within 2 weeks, with prior consultation and in agreement with the principal investigator.
• 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 computed tomography \[CT\]) demonstrating no current evidence of progressive brain metastases at screening.
• History or current evidence of retinal vein occlusion (RVO) or current risk factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease
• 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 (note: based on mechanism of action, BRAF inhibitors may cause progression of cancers associated with RAS mutations)
• 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. New York Heart Association Class ≥ 2), 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 ≥ 150 mmHg or diastolic blood pressure ≥ 100mmHg, despite current therapy;
• Known positive serology for HIV (Human immunodeficiency virus) that is not currently controlled with anti-retroviral therapy,
• Has a known history of or is positive for active hepatitis B (defined as hepatitis B surface antigen \[HBsAg\] reactive) or hepatitis C (defined as HCV RNA \[qualitative\] is detected). HBV DNA must be undetectable and HBsAg negative at Screening Visit. Participants who have had definitive treatment for HCV are permitted if HCV RNA is undetectable at Screening Visit.

Sponsors & Collaborators

• University Health Network, Toronto: lead

Study Sites (1)

Princess Margaret Cancer Centre

Toronto, Ontario, M5G2M9, Canada

Location

Related Publications (1)

• Rajkumar S, Berry D, Heney KA, Strong C, Ramsay L, Lajoie M, Alkallas R, Nguyen TT, Thomson C, Ahanfeshar-Adams M, Dankner M, Petrella T, Rose AAN, Siegel PM, Watson IR. Melanomas with concurrent BRAF non-p.V600 and NF1 loss-of-function mutations are targetable by BRAF/MEK inhibitor combination therapy. Cell Rep. 2022 Apr 5;39(1):110634. doi: 10.1016/j.celrep.2022.110634.

  PMID: 35385748 DERIVED

MeSH Terms

Interventions

binimetinib; encorafenib

Study Officials

• Anna Spreafico, MD

  Princess Margaret Cancer Centre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 8, 2019
• First Posted: February 15, 2019
• Study Start: June 7, 2019
• Primary Completion: December 1, 2025
• Study Completion: December 1, 2025
• Last Updated: February 3, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will share

Locations

CA (1)