MCS110, Dabrafenib Mesylate, and Trametinib in Treating Patients with BRAF V600E or V600K Mutated Melanoma

Inclusion Criteria

• For enrollment to the phase I portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via Next Generation [NextGen] sequencing using the Dana Farber Cancer Institute [DFCI]/Brigham and Women's Hospital [BWH] OncoPanel or any Clinical Laboratory Improvement Amendments [CLIA]-certified method) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective
• For enrollment to the phase II portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) and have had progression of disease on prior BRAF and MEK inhibitor therapy
• Participants enrolling to the phase I portion of the trial must have evaluable or measurable disease
• Participants enrolling to the phase II portion of the trial must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2
• Life expectancy of greater than 8 weeks
• Absolute neutrophil count >= 1.5 K/uL
• Platelets >= 100 K/uL
• Hemoglobin >= 9 g/dL
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN
• Serum creatinine =< 1.5 x institutional ULN
• Prothrombin time (PT)-international normalized ratio (INR) =< 1.5 x institutional ULN (for participants on anticoagulation therapy, =< 1.5 x their baseline value)
• Activated partial thromboplastin time (aPTT) =< 1.5 x institutional ULN (for participants on anticoagulation therapy, =< 1.5 x their baseline value)
• Participants must have a left ventricular ejection fraction (LVEF) >= 50%
• Participants must have a corrected QT (QTc) of =< 480 msec for both females and males on the screening electrocardiogram (EKG)
• The effects of MCS110, trametinib and dabrafenib on the developing human fetus are unknown. For this reason and because anti-cancer agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months after the last dose of MCS110. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of MCS110 administration. Highly effective contraception methods include: * Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment * Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject * Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment * Double-barrier contraception: condom and occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/cream/suppository)
• Ability to understand and the willingness to sign a written informed consent document
• Participants must have archival tumor tissue available. Participants without archival tissue may be enrolled at the discretion of the principal investigator
• All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values) must be =< grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0; National Cancer Institute [NCI], 2009) at the time of randomization

Exclusion Criteria

• Participants who have had chemotherapy, radiotherapy, biologic therapy, major surgery, or another investigational agent within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study. Previous BRAF/MEK inhibitor use is allowed with no washout period for the phase I and II portions
• Participants who have not recovered to =< CTCAE grade 1 or baseline from toxicity as a result of previous cancer treatment prior to entering the study (with the exception of alopecia and peripheral neuropathy which can be =< grade 2)
• For enrollment to the phase II portion: participants who have not received prior BRAF or MEK inhibitor therapy
• Participants with known untreated brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Participants with a history of brain metastases that have been treated, are no longer taking corticosteroids, and have been stable on imaging for >= 4 weeks following the last date of treatment are permitted
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MCS110, dabrafenib, or trametinib
• 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
• Pregnant women are excluded from this study because MCS110, dabrafenib and trametinib are anti-cancer agents with the potential for teratogenic or abortifacient effects. Pregnancy status will be verified at various points in the trial and a serum pregnancy test will be required. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MCS110, dabrafenib or trametinib, breastfeeding should be discontinued if the mother is treated with MCS110, dabrafenib or trametinib
• Participants with a known history of human immunodeficiency virus (HIV) are ineligible because of the potential for pharmacokinetic interactions with MCS110, dabrafenib, and trametinib with antiretroviral agents. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy
• Participants with a personal or family history of long QT syndrome
• Participants with a history of a second primary malignancy. Exceptions include: patients with a history of malignancies that were treated curatively and have not recurred within 3 years prior to study entry; resected basal and squamous cell carcinomas of the skin, and completely resected carcinoma in situ of any type
• Participants with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of dabrafenib and trametinib in the opinion of the treating investigator (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)
• Participants who are unable to swallow or retain oral medication
• Participants that require co-administration of strong or moderate CYP3A inhibitors, as these medications may alter dabrafenib and trametinib concentrations
• Participants who require treatment with medications that are strong or moderate CYP3A inducers, as these medications may alter the concentration of trametinib
• Participants with evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration. This includes participants with a history of or current evidence of retinal vein occlusion or retinal pigment epithelial detachment
• Participants taking corticosteroids (>= 10 mg of prednisone or equivalent). Exceptions may be discussed with the overall principal investigator (PI) on a case by case basis