LCCC 1128: Open Label Phase II Trial of the BRAF Inhibitor (Dabrafenib) and the MEK Inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; Correlation of Resistance With the Kinome and Functional Mutations

Main Study Inclusion Criteria: Subject must meet all of the inclusion criteria to participate in this study: Age ≥18 years Signed written informed consent Histologically confirmed V600E or V600K BRAF mutant melanoma Unresectable Stage III/IV melanoma ECOG PS 0-2 Normal organ function as defined by the following: * Absolute neutrophil count \>1.2 × 109/L * Hemoglobin \>9 g/dL, platelets \>75 × 109/L * PT/INR and PTT ≤1.5 x ULN (Note: subjects receiving anticoagulation treatment may enroll with INR established within the therapeutic range prior to D1 of treatment) * Albumin \>2.5 g/dL * Total bilirubin \<1.5 x ULN (patients with elevated bilirubin due to Gilbert's disease will not be excluded) * AST and ALT \< 2.5× ULN * CrCl ≥50mL/min per Cockcroft-Gault Prior anti-cancer treatment related toxicities except alopecia and lab values as outlined in the criterion above must be less than or equal to Grade 1 as per CTCAEv4 Willing to undergo biopsy for research purposes only Females of child-bearing potential: willing to use two forms of effective contraception, and to continue use for 16 weeks post last dose of study medication. Effective contraception is defined as any medically recommended method (or combination of methods) as per standard of care, including abstinence. Females of non-childbearing potential are those who are postmenopausal (defined as greater than 1 year without menses with appropriate clinical profile, e.g., age appropriate: \>45 years in the absence of hormone replacement therapy (HRT). In questionable cases, the subject must have a follicle stimulating hormone (FSH) value \>40 mIU/mL and an estradiol value \<40pg/mL (\<140 pmol/L); or who have had a bilateral tubal ligation or tubal occlusion, bilateral oophorectomy, or hysterectomy. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described from D1 of treatment, throughout the treatment period, and for 16 weeks after the last dose of study treatment. If a subject becomes pregnant during the treatment period of the study, the study treatments should be stopped immediately. In women of child-bearing potential, negative serum pregnancy test within 48 hours prior to day 1 of study treatment and agree to use effective contraception. Effective contraception is defined as: (a) an intrauterine device with a documented failure rate of less than 1% per year. (b) male partner sterilization prior to the female subject's entry, and this male is the sole sexual partner for that female. (c) complete abstinence from sexual intercourse for 14 days prior to enrollment throughout study treatment, and for at least 4 months after the last dose of study treatment. Abstinence is only acceptable when in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar ovulation, symptothermal, post-ovulation methods, etc) and withdrawal are not acceptable methods of contraception. (d) double- barrier contraception: condom and occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/cream/suppository). Note: hormonal based methods (e.g. oral contraceptives) are not permitted. Female subjects who are lactating must discontinue nursing prior to the first dose of study treatment and must refrain from nursing throughout the treatment period and for 4 months following the last dose of study treatment Measurable disease as defined by RECIST v1.1 Able to swallow and retain oral medication Left ventricular ejection fraction by ECHO ≥ institutional lower limit of normal Main Study Exclusion Criteria: Any subject meeting any of the following exclusion criteria at baseline will be ineligible for study participation: Patients with a history of a prior malignancy are excluded unless they have been disease free for 3 or more years or unless they have a completely resected non-melanoma skin cancer, and/or subjects with indolent second malignancies. History of malignancy with confirmed activating RAS mutation at any time. Note: Prospective RAS testing is not required. However, if the results of previous RAS testing are known, they must be used in assessing eligibility. Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib (GSK2118436), vemurafenib, and LX281/BMS-908662) or a MEK inhibitor (including but not limited to trametinib (GSK1120212), AZD6244, and RDEA119); NOTE: There is no limit to the number of other prior therapies, and patients may be previously untreated. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO). Active GI or intracranial hemorrhage History or evidence of cardiovascular risk including any of the following: * QTc ≥ 480 msec; * History or evidence of current clinically significant uncontrolled arrhythmias; o Exception: Subjects with controlled atrial fibrillation for \>30 days prior to D1 of study treatment are eligible. * History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to study entry; * Patients with history of hypertension should have hypertension adequately controlled (BP\<140/90) with appropriate anti-hypertensive therapy or diet prior to study entry; * Patients with intra-cardiac defibrillators or permanent pacemakers; * Known cardiac metastases; * Abnormal cardiac valve morphology (≥grade 2) documented by echocardiogram (subjects with grade 1 abnormalities \[i.e., mild regurgitation/stenosis\] can be entered on study). Subjects with moderate valvular thickening should not be entered on study. History of known glucose-6-phosphate dehydrogenase (G6PD) deficiency Brain metastases are excluded unless: * All known lesions were previously treated with surgery or stereotactic surgery (whole-brain radiation is not allowed unless given after definitive treatment with surgery or stereotactic surgery), AND * Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in lesion size) for ≥ 12 weeks prior to D1 of study treatment (stability must be confirmed with two consecutive magnetic resonance image (MRI) or computed tomography (CT) scans with contrast, AND * Asymptomatic with no corticosteroid requirements for ≥ 4 weeks prior to D1 of study treatment, AND * Treatment with any CYP enzyme inducing anticonvulsants occurred \< 4 weeks prior to D1 of study treatment NOTE: if study subject has history of brain metastasis, but currently has no evidence of disease in brain (NED), confirmation by two consecutive scans separated by ≥6 weeks prior to D1 of treatment is required. Pulmonary embolism on active therapy History of interstitial lung disease or pneumonitis Known HIV, Hepatitis B or C infection (with the exception of chronic or cleared HBV and HCV infection which will be allowed provided the following tests are done at screening: viral hepatitis serology, Hepatitis B surface antigen and Hepatitis B core antibody (IgM) and/or Hepatitis C RNA) Currently active GI disease, or prior surgery that may affect ability to absorb oral medications History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED): * Predisposing factors to RVO or RPED (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) * Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR such as: * Evidence of new optic disc cupping * Evidence of new visual field defects * Intraocular pressure \> 21 mm Hg Currently receiving cancer therapy (chemotherapy, radiotherapy, immunotherapy, or biologic therapy) NOTE: palliative radiation therapy is permitted for non-target lesions that are either new or present at baseline provided total dose does not exceed 30 Gy. However, radiation skin injury has been reported with concurrent use of dabrafenib and radiation. To reduce this risk, it is recommended that dabrafenib be held for seven days before and two days after radiation in subjects receiving dabrafenib in combination with trametinib when palliative radiation is prescribed. Use of other prohibited medications within 5 half-lives or 14 days prior to the first dose of study drugs or requires any of these medications while receiving medication on this study Pregnant or lactating female Inclusion Criteria for Off-Study Subjects to Receive Progression Biopsy Currently progressing on Trametinib/Deabrafenib Combination Therapy Willing to undergo biopsy for research purposes only. Tumor amenable to research biopsy. Signed written informed consent to have a progression biopsy performed on the LCCC 1128 protocol. Previously enrolled on the LCCC 1128 study and did not have a progression biopsy previously performed while on study.