Clinical Trials /

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

NCT03839342

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Binimetinib and Encorafenib for the Treatment of Advanced Solid Tumors With Non-V600E BRAF Mutations
  • Official Title: Binimetinib and Encorafenib for the Treatment of Advanced Solid Tumors With Non-V600E BRAF Mutations

Clinical Trial IDs

  • ORG STUDY ID: BEAVER-001 / IST-818-207X
  • NCT ID: NCT03839342

Conditions

  • Solid Tumor

Interventions

DrugSynonymsArms
BinimetinibBinimetinib + Encorafenib
EncorafenibBinimetinib + Encorafenib

Purpose

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.

Detailed Description

      BRAF is a gene in humans that is commonly altered in cancer, resulting in a change to the
      proteins created from this mutation. These altered proteins interact with a process in the
      body known as the MAPK (mitogen-activated protein kinase) pathway and promote the growth of
      cancer. Three classes of BRAF mutations have been identified to understand why some patients
      respond to treatment and others do not. Class 2 and 3 BRAF mutations have worse overall
      survival. This study will look at participants in these classes (non-V600E BRAF mutations).

      Binimetinib is an oral drug (tablet) that stops the function of MEK (mitogen-activated
      protein kinase kinase). MEK is a part of the MAPK pathway, so blocking this step helps in
      stopping the pathway from confinuing to grow the cancer.

      Encorafenib is an oral drug (capsule) that stops the function of BRAF V600-mutant kinase, the
      protein that is produced from a type of BRAF gene mutation. This protein promotes the MAPK
      pathway so blocking this protein stops the MAPK pathway from growing the cancer.

      Patients will visit the clinic up to 2 times every 4 weeks (1 cycle) for tests and procedures
      while taking the study drugs daily. Procedures will involve review of medication and history,
      imaging scans, blood sample collection for safety and research purposes, urine collection,
      ECGs, eye exam, MUGA scans and mandatory and optional tumor biopsies.
    

Trial Arms

NameTypeDescriptionInterventions
Binimetinib + EncorafenibExperimentalBinimetinib 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.
  • Binimetinib
  • Encorafenib

Eligibility Criteria

        Inclusion Criteria:

        Informed consent

          1. Signed written and voluntary informed consent.

          2. Patient must be willing and able to comply with scheduled visits, treatment plan,
             laboratory tests and other study procedures.

          3. Age > 18 years, male or female.

             Disease characteristics

          4. 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.

          5. Measurable disease by RECIST v1.1 criteria.

          6. 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

          7. 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.

          8. Patient must be able to swallow pills

          9. Patient must be willing to provide serial blood samples for molecular profiling of
             ctDNA evolution

             Patient characteristics

         10. ECOG performance status 0-1.

         11. 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:

             Creatinine clearance = [(140-age) x wt (kg) x Constant*] / creatinine (umol/L)

             *Constant = 1.23 for men, and 1.04 for women

             • Bone marrow function (without hematopoietic growth factors or transfusion): i.
             Absolute neutrophil count (ANC) > 1.0 x 109/L ii. Leukocytes > 2.0 x 109/L iii.
             Hemoglobin > 90 g/L or > 9g/dL iv. Platelets > 75 x 109/L v. Previous blood
             transfusions are acceptable, however patients must have achieved the above hemoglobin
             and platelet targets without requiring a blood transfusion within 14 days prior to
             study entry.

             • Liver function: i. Total bilirubin ≤ 1.5 × ULN and < 35 uMol/L; OR total bilirubin
             >1.5 × ULN with indirect bilirubin < 1.5 × ULN. Total bilirubin < 1.5 x ULN or ≤ 3 x
             ULN for patients with Gilbert Syndrome.

             ii. Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) < 2
             x ULN, unless patients are known to have liver metastases. For patients with known
             liver metastases, Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase
             (ALT/SGPT) < 5 x ULN

             • Cardiac function: i. A normal left ventricular ejection fraction (LVEF) of ≥ 50% by
             a MUGA scan or echocardiogram performed within 4 weeks of the study commencement.

             ii. QTc interval ≤ 480 ms (triplicate ECGs)

         12. Female participants of childbearing potential as described in Section 5.5.4, must have
             a negative serum β HCG test result.

         13. Female participants of childbearing potential must agree to use methods of
             contraception that are highly effective or acceptable, as described in Section 5.5.4,
             and to not donate ova from Screening until 30 days after the last dose of study drug

         14. Male participants must agree to use methods of contraception that are highly effective
             or acceptable, as described in Section 5.5.4, and to not donate sperm from Screening
             until 90 days after the last dose of study drug.

         15. Subject is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including follow
             up.

        Exclusion Criteria:

        Patients meeting any of the following criteria are excluded from the study:

          1. Any patient with a tumor expressing a BRAF V600E mutation

          2. Any patient with melanoma whose tumor expresses a BRAF V600K mutation

          3. Prior therapy with any BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib)
             and/or any MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib).

          4. 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.

          5. 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.

          6. 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

          7. Leptomeningeal disease

          8. 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)

          9. Impaired cardiovascular function or clinically significant cardiovascular diseases,
             including any of the following:

         10. History of acute coronary syndromes (including myocardial infarction, unstable angina,
             coronary artery bypass grafting, coronary angioplasty, or stenting) <6 months prior to
             screening,

         11. 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;

         12. Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥
             150 mmHg or diastolic blood pressure ≥ 100mmHg, despite current therapy;

         13. Known positive serology for HIV (Human immunodeficiency virus) that is not currently
             controlled with anti-retroviral therapy,

         14. 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.

         15. Known history of acute or chronic pancreatitis. Patients with previous history of
             pancreatitis caused by immunotherapy are not excluded if pancreatitis is resolved.

         16. History of chronic inflammatory bowel disease or Crohn's disease requiring medical
             intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12
             months prior to starting study treatment

         17. Impaired gastrointestinal function or disease that may significantly alter the
             absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled
             vomiting, malabsorption syndrome, small bowel resection with decreased intestinal
             absorption)

         18. History of known hypercoaguability risk factors (other than cancer) ie. Factor V
             Leiden. Patients with a history of previous DVT or PE who are currently asymptomatic
             and treated with anticoagulation therapy are allowed.

         19. Concurrent neuromuscular disorder that is associated with the potential of elevated CK
             (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis,
             spinal muscular atrophy)

         20. Patients who are planning on embarking on a new strenuous exercise regimen after first
             dose of study treatment. Note: Muscular activities, such as strenuous exercise, that
             can result in significant increases in plasma CK levels should be avoided while on
             binimetinib treatment

         21. 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, e.g., active infection/inflammation requiring systemic
             therapy, intestinal obstruction, unable to swallow medication, social/ psychological
             issues, etc. Previous bacterial infections are acceptable if patients completed
             antibiotic course 3 days prior to initiating study treatment.

         22. Patients who have undergone major surgery ≤ 3 weeks prior to starting study drug or
             who have not recovered from side effects of such procedure;

         23. 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 hCG laboratory test;

         24. Medical, psychiatric, cognitive or other conditions that may compromise the patient's
             ability to understand the patient information, give informed consent, comply with the
             study protocol or complete the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate defined as per RECIST v1.1.
Time Frame:2.5 years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Number of participants with toxicities as per NCI CTCAE v5.0.
Time Frame:2.5 years
Safety Issue:
Description:
Measure: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.
Time Frame:2.5 years
Safety Issue:
Description:
Measure: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.
Time Frame:2.5 years
Safety Issue:
Description:
Measure:Overall survival measured as the length of time from the first day of treatment to the day of death. Median OS will be reported.
Time Frame:2.5 years
Safety Issue:
Description:
Measure: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
Time Frame:2.5 years
Safety Issue:
Description:
Measure:Number of fresh tumor biopsies collected, frozen, and stored for subsequent development of patient derived xenografts.
Time Frame:2.5 years
Safety Issue:
Description:
Measure:Number of identified molecular mechanisms of acquired resistance to binimetinib and encorafenib in tumors with non-V600E BRAF mutations, measured by analysis of molecular profiles and validated with PDX models in vitro and in vivo.
Time Frame:2.5 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University Health Network, Toronto

Trial Keywords

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

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