The purpose of this study is to test whether it is safe to give phenformin with the standard drug combination of one of 3 FDA-approved combinations of BRAF inhibitor + MEK inhibitor which are standard treatments for patients with metastatic melanoma whose melanoma has a mutation in a gene called BRAF.

Inclusion Criteria:

• 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 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 BRAFV600E or BRAFV600K mutation by genotyping or IHC12 performed by a CLIA certified laboratory. At MSK, the Diagnostic Molecular Pathology laboratory has developed and implemented a targeted capture-based next-generation DNA sequencing assay, MSK-IMPACTTM, to profile all protein-coding exons and selected introns from 410 oncogenes and tumor suppressor genes in formalin-fixed paraffin embedded tissues (Cheng, D.T., et al., J Mol Diagn, 2015. 17(3): p. 251-64). MSK-IMPACTTM has been approved by the NY State Department of Health to be run as a clinical assay in the CLIA-compliant Diagnostic Molecular Pathology laboratory. MSK-IMPACTTM is capable of detecting mutations, copy number alterations, and structural variations. BRAF Exon15 was captured by the MSK-IMPACTTM panel and the c.1799T>A (p.V600E) mutation was fully validated as per NYS requirements. Detailed results of the validation of this mutation were included in the validation package submitted to NY State Department of Health.

• At 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 (Li H and Durbin R. Bioinformatics 2009;25(14):1754-60). MuTect (Cibulskis K, et al. Nat Biotechnol 2013;31(3):213-9) 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.

• ECOG performance status of 0-2.

• The ability to swallow pills and otherwise follow the protocol.

• Patients with treated CNS metastases will be eligible if not symptomatic the CNS disease has been stable for a minium of 6 weeks and the patient requires less than or equal to the equivalent of 2 mg/day of dexamethasone.

• Patients must have adequate organ and marrow function as defined below:

  • 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
  • AST (SGOT) and ALT (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 (Refer to Appendix C for specific drugs).

• 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.

• QTc interval > 500 msec unless a bundle branch block is also present.

• Patients with brain metastases unless they meet the criteria of section 6.1.8.

• 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.

Inclusion of Women and Minorities:

• Both men and women, and members of all races and ethnic groups are eligible for this trial.