Clinical Trial 19441

• Overview

  Study Title:

  Pilot Study of Adaptive BRAF-MEK Inhibitor Therapy for Advanced BRAF Mutant Melanoma

  Summary:

  This pilot early phase I trial studies how well encorafenib, binimetinib, and nivolumab work in treating patients with BRAF mutant stageIIIC-IV melanoma. Encorafenib and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cellgrowth. Immunotherapy with nivolumab, may induce changes in body's immune system and may interfere with the ability of tumor cells togrow and spread. Giving encorafenib, binimetinib, and nivolumab may kill more tumor cells.

  Objective:

  Primary Objective: Determine feasibility of an adaptive intermittent treatment design, as defined by how many patients successfully reach 16 weeks with the prescribed on/off schedule without progression of disease. Secondary Objectives: Estimate time to treatment failure, defined as the time from the day of first dose of study drugs to the first day of treatment with another regimen or with the same regimen in a non-adaptive fashion. Estimate objective tumor response rate. Assess toxicity and dose delivery, both over the entire course of therapy and on a per day basis. Perform single cell analyses in tumor biopsies and measure BRAF cfDNA in serial plasma samples.

• Treatments

  Therapies:

  Chemotherapy (NOS); Immunotherapy; Therapy (NOS)

  Medications:

  BMS-936558 (Nivolumab); Binimetinib (); Cobimetinib (); Encorafenib (); Nivolumab (Opdivo); Not Applicable (); RO5185426 (Vemurafenib); Vemurafenib (Zelboraf)

• Inclusion Criteria

  • Must have cytologically or histologically-confirmed unresectable melanoma that harbors a BRAF V600 mutation determined by pyrosequencing assay or equivalent genotyping assay in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory, meeting one of the following American Joint Committee on Cancer (AJCC) 8th edition staging criteria: a.) AJCC stage IV (Tany, Nany, M1a(1), M1b(1), M1c(1) or M1d(1)); b.) AJCC stage IIIC (at least N2b) or IIID with unresectable nodal/locoregional involvement.
  • Age 18 years or older
  • Must have serum LDH > institutional upper limit of normal (ULN) at time of study enrollment.
  • Must have adequate hepatic, renal, and bone marrow function. There are no specific minimum criteria for enrollment; this will at the discretion of the treating physician, as any patient who would be considered for standard of care treatment with these drugs may be considered for this trial.
  • Must have an Eastern Cooperative Oncology Group (ECOG) performance status of > Willing to give written informed consent per institutional guidelines and must be able and willing to adhere to dose and visit schedules.
  • Negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women.
  • Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician.
  • Treatment-naïve and previously treated patients will be included; however, patients may not have received a BRAF or MEK inhibitor in the past 24 weeks.
  • May have received prior systemic and/or radiation therapy. All adverse events associated with prior systemic therapy or radiation therapy must have resolved to ≤ Grade 1 prior to start of study.
  • Must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

• Exclusion Criteria

  • Females who are pregnant, intend to become pregnant or are nursing.
  • Have been previously treated with BRAF/MEK inhibitor therapy in the past 24 weeks.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements. Patients with a baseline left ventricular ejection fraction of less than 40% will be ineligible.
  • HIV-positive patients on combination antiretroviral therapy.
  • Untreated or uncontrolled brain metastases. Patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e., not requiring corticosteroids) at the time of study start will be eligible.
  • Previous malignancy is not an exclusion provided that the other malignancy is considered under control, patient is not on concomitant anti-cancer drug therapy, and target lesions from melanoma are clearly defined for response assessment.
  • Unwillingness or inability to comply with study and follow-up procedures.
  • The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment: St. John's wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer); Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor).
  • Ocular:History of or evidence of retinal pathology on baseline ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, RVO, or neovascular macular degeneration.

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