Vemurafenib and Cobimetinib in Treating Participants with BRAF Mutant Stage IIIC-IV Melanoma
- All races and ethnicities are eligible and no upper limit of age is specified
- Subjects 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 Act (CLIA) certified laboratory, meeting one of the following American Joint Committee on Cancer (AJCC) (8th edition) staging criteria: * AJCC stage IV (Tany, Nany, M1a(1), M1b(1), M1c(1) or M1d(1)) * AJCC stage IIIC (at least N2b) or IIID with unresectable nodal/locoregional involvement
- Subjects must have serum lactate dehydrogenase (LDH) > institutional upper limit of normal (ULN) at time of study enrollment
- Subjects 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
- Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
- Subjects must be 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. Women of non-childbearing potential may be included without serum pregnancy test if they are either surgically sterile or have been postmenopausal for >= 1 year
- 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. Effective methods of contraception are defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (e.g., implants, injectables, combined oral contraception or intra-uterine devices). At the discretion of the Investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
- Treatment-naive and previously treated patients will be included; however, patients may not have received a BRAF or MEK inhibitor in the past 24 weeks
- Patients 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
- Subjects must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- Female subjects who are pregnant, intend to become pregnant or are nursing
- Subjects 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 < 40% will be ineligible
- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions vemurafenib and cobimetinib
- Subjects with 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)
- History of or evidence of retinal pathology on baseline ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration
I. Determine feasibility of an adaptive intermittent treatment design, as defined by how many patients successfully reach 8 weeks with the prescribed on/off schedule without progression of disease.
I. 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.
II. Estimate objective tumor response rate.
III. Assess toxicity and dose delivery, both over the entire course of therapy and on a per day basis.
IV. Perform single cell analyses in tumor biopsies and measure BRAF cell-free deoxyribonucleic acid (cfDNA) in serial plasma samples.
Participants receive vemurafenib orally (PO) twice daily (BID) and cobimetinib PO once daily (QD) on weeks 1-3 and 6-8. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity for participants whose disease show improvement or remain stable on computed tomography scan.
After completion of study treatment, participants are followed up every 3 months for 1 year, then every 6 months for up to 5 years.
Trial Phase Phase O
Trial Type Treatment
Moffitt Cancer Center
- Primary ID MCC-19441
- Secondary IDs NCI-2018-01245
- Clinicaltrials.gov ID NCT03543969