MCS110 With BRAF/MEK Inhibition in Patients With 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 NextGen sequencing using the DFCI/BWH OncoPanel or any 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 CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease.
• •Age ≥ 18 years. As no dosing or adverse event data are currently available in participants \< 18 years of age, children are excluded from this study but will be eligible for future pediatric trials.
• •ECOG performance status 0 - 2 (see Appendix A).
• •Life expectancy of greater than 8 weeks.
• •Participants must have normal organ and marrow function as defined below:
• •* Absolute neutrophil count ≥ 1.5 K/uL
• •* Platelets ≥ 100 K/uL
• •* Hemoglobin ≥ 9 g/dL
• •* Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)
• •* AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN
• •* Serum creatinine ≤ 1.5 × institutional ULN
• •* PT-INR ≤ 1.5 × institutional ULN (for participants on anticoagulation therapy, ≤ 1.5 × their baseline value)
• •* aPTT ≤ 1.5 × institutional ULN (for participants on anticoagulation therapy, ≤ 1.5 × their baseline value)
• •Participants must have a left ventricular ejection fraction (LVEF) ≥ 50%.
• •Participants must have a QTc of ≤ 470 msec for females and ≤ 450 for males on the screening 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 as listed on Table 1) must be ≤ Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0; NCI, 2009) at the time of randomization