Phenformin Hydrochloride in Combination with BRAF Inhibitor and MEK Inhibitor in Treating Patients with Stage III-IV BRAF V600E/K-Mutated Melanoma

Inclusion Criteria

• American Joint Committee on Cancer (AJCC) (2009) stage IV melanoma, or stage III melanoma not curable by surgery and which is progressing or in patients whom neo-adjuvant treatment is deemed acceptable; patients must have at least 1 target lesion measurable by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
• The melanoma must harbor an activating BRAF V600 mutation. Prior therapy with a BRAF and/or MEK inhibitor is allowed in the dose-escalation phase only. However, patients who discontinued previous RAF inhibitor due to intolerance of the drug rather than due to progression will not be eligible
• Histologic proof of melanoma reviewed and confirmed by the treating institution; the melanoma must have a documented BRAF V600E or BRAF V600K mutation by genotyping or immunohistochemistry (IHC) performed by a Clinical Laboratory Improvement Act (CLIA) certified laboratory. * At Memorial Sloan-Kettering (MSK), the Diagnostic Molecular Pathology laboratory has developed and implemented a targeted capture-based next-generation deoxyribonucleic acid (DNA) sequencing assay, MSK-integrated mutation profiling of actionable cancer targets (IMPACT), to profile all protein-coding exons and selected introns from 410 oncogenes and tumor suppressor genes in formalin-fixed paraffin embedded tissues; MSK-IMPACT has been approved by the New York (NY) State Department of Health to be run as a clinical assay in the CLIA-compliant diagnostic molecular pathology laboratory; MSK-IMPACT is capable of detecting mutations, copy number alterations, and structural variations; BRAF exon15 was captured by the MSK-IMPACT panel and the c.1799T>A (p.V600E) mutation was fully validated as per New York State (NYS) requirements; detailed results of the validation of this mutation were included in the validation package submitted to NY State Department of Health
• * At Massachusetts General Hospital (MGH), samples will be tested using a multiplex polymerase chain reaction (PCR) technology called anchored multiplex PCR (AMP) for single nucleotide variant (SNV) and insertion/deletion (indel) detection in genomic DNA using next generation sequencing (NGS); briefly, genomic DNA was isolated from a formalin-fixed paraffin embedded tumor specimen is sheared with the Covaris M220 instrument, followed by end-repair, adenylation, and ligation with an adapter; a sequencing library targeting hotspots and exons in 39 genes (including BRAF, exons 11 and 15) is generated using two hemi-nested PCR reactions; Illumina MiSeq 2 x 147 base paired-end sequencing results are aligned to the hg19 human genome reference using BWA-MEM; MuTect and a laboratory-developed insertion/deletion analysis algorithm are used for SNV and indel variant detection, respectively; this assay has been validated to detect SNV and indel variants at 5% allelic frequency or higher in target regions with sufficient read coverage; this test was developed, and its performance characteristics were determined by the MGH Center for Integrated Diagnostics
• Patients must be adequately recovered from surgery, radiation therapy, or any surgical complications prior to enrollment
• Age >= 18 years old
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• The ability to swallow pills and otherwise follow the protocol
• Patients with treated central nervous system (CNS) metastases will be eligible if not symptomatic, the CNS disease has been stable for a minimum of 6 weeks and the patient requires less than or equal to the equivalent of 2 mg/day of dexamethasone
• Absolute neutrophil count >= 1.5 K/mcL
• Platelets >= 100 K/mcL
• Hemoglobin >= 9.0 g/dL
• Total bilirubin =< 1.2 X institutional upper limit of normal (ULN) OR =< 3.0 X institutional ULN if the patient has Gilbert's syndrome
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.2 X institutional upper limit of normal (ULN)
• Creatinine =< 1.4 mg/dl

Exclusion Criteria

• Type I or type II diabetes
• A history of renal failure (unless recovered for at least 6 months), lactic acidosis, recurrent or severe hypoglycemia, or significant chronic obstructive lung disease; patients will not be excluded for reversible episodes of elevated creatinine due to hypovolemia
• Acute or chronic liver or renal disease
• Concurrent use of hypoglycemic agents or any systemic therapy for melanoma; palliative limited-field radiation therapy will be allowed
• Current use of a prohibited medication: * Vemurafenib ** Avoid inducers and inhibitors of CYP3A4 ** Careful with drugs metabolized by CTP1A2 (clozapam, olanzapine, fluvoxamine, haloperidol, theophylline, caffeine) * Encorafenib ** Avoid inducers and inhibitors of CYP3A4 ** Avoid drugs that increase QTc interval * Dabrafenib ** Avoid inducers and inhibitors of CYP3A4 or CYP2CA8
• Presence of conditions that will interfere significantly with the absorption of drugs
• A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Pregnant and/or lactating women
• A prior or concurrent metastatic second malignancy within 3 years, even if it does not require active therapy; for example, patients with concomitant indolent B-cell malignancies will not be eligible; patients with a prior resected in-situ or stage I malignancy felt to be cured will be eligible
• Other uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; New York Heart Association class >= 2 will be an exclusion criterion
• Corrected QT (QTc) interval > 500 msec unless a bundle branch block is also present
• Patients with brain metastases unless they meet the criteria
• Patients currently receiving other anti-melanoma treatment; toxicities attributable to any prior therapy must have resolved to grade 1 or better prior to enrollment; grade 2 endocrinopathies, except diabetes, that are ongoing from prior immunotherapy will not exclude the patient as long as the patient is on appropriate replacement doses of hormone
• Patients receiving steroid treatment exceeding replacement dosing
• In the dose expansion phase of the trial, prior treatment with a BRAF inhibitor will be an exclusion criterion; this includes prior adjuvant dabrafenib/trametinib.