Clinical Trial of Phenformin in Combination With Dabrafenib and Trametinib for Patients With BRAF-mutated Melanoma

Inclusion Criteria:

- AJCC (2009) stage IV melanoma, or stage III melanoma not curable by surgery and which
is progressing. 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

- Hb- A1c ≤ 5.7%, or 5.8-6.5% with a normal fasting glucose

Exclusion Criteria:

- Type I or Type II diabetes, or Hgb A1c >6.5%.

- 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 while on Dabrafenib/Trametinib

- 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.)

- 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.

Inclusion of Women and Minorities:

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