Clinical Trials /

Adaptive BRAF-MEK Inhibitor Therapy for Advanced BRAF Mutant Melanoma

NCT03543969

Description:

This is a pilot study evaluating the feasibility of using adaptive intermittent dosing of vemurafenib and cobimetinib in BRAF mutant patients with elevated baseline lactate dehydrogenase (LDH). The purpose of this study is to determine whether an intermittent adaptive dosing of vemurafenib and cobimetinib may be superior to standard, continuous dosing with these study drugs.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Adaptive BRAF-MEK Inhibitor Therapy for Advanced BRAF Mutant Melanoma
  • Official Title: Pilot Study of Adaptive BRAF-MEK Inhibitor Therapy for Advanced BRAF Mutant Melanoma

Clinical Trial IDs

  • ORG STUDY ID: MCC-19441
  • NCT ID: NCT03543969

Conditions

  • Melanoma (Skin)
  • Skin Cancer
  • Skin Melanoma
  • Skin Carcinoma

Interventions

DrugSynonymsArms
VemurafenibZelboraf®, BRAF/MEK-inhibitorBRAF-MEK Inhibitor Therapy
CobimetinibCOTELLIC®, BRAF/MEK-inhibitorBRAF-MEK Inhibitor Therapy

Purpose

This is a pilot study evaluating the feasibility of using adaptive intermittent dosing of vemurafenib and cobimetinib in BRAF mutant patients with elevated baseline lactate dehydrogenase (LDH). The purpose of this study is to determine whether an intermittent adaptive dosing of vemurafenib and cobimetinib may be superior to standard, continuous dosing with these study drugs.

Detailed Description

      Vemurafenib and cobimetinib are already U.S. Food and Drug Administration (FDA)-approved for
      the treatment of BRAF-mutant metastatic melanoma; however, melanoma often develops resistance
      to these drugs over time, and the tumors start to re-grow. Investigators will use the
      participant's LDH (lactate dehydrogenase) levels obtained from routine blood work, along with
      CT scans to decide when to hold or resume their study treatment. Investigators hypothesize
      that this type of dosing schedule with vemurafenib and cobimetinib may potentially delay the
      time to progression and re-growth of their melanoma.
    

Trial Arms

NameTypeDescriptionInterventions
BRAF-MEK Inhibitor TherapyExperimentalVemurafenib twice a day and cobimetinib daily, 3 weeks on / 2 weeks off / 3 weeks on, for an 8-week cycle. After 8 week cycle, response to these study drugs will be analyzed based on several parameters to determine if participants will proceed in the study. Participants will be invited for post-treatment follow-up visits for up to 5 years.
  • Vemurafenib
  • Cobimetinib

Eligibility Criteria

        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.

          -  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 ≤2.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:8 Week Completion Rate
Time Frame:At the end of the first 8 week treatment period
Safety Issue:
Description:Number of participants who reach 8 weeks with the prescribed on/off schedule without progression of disease. Progression as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Secondary Outcome Measures

Measure:Time to Treatment Failure
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Objective Tumor Response Rate
Time Frame:Up to 5 years
Safety Issue:
Description:Number of participants with tumor response. Response according to RECIST 1.1.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:H. Lee Moffitt Cancer Center and Research Institute

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