LY3022855 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 cannot have received prior BRAF or MEK inhibitor therapy.
• Participants enrolling to the phase I portion of the trial must have evaluable or measurable disease (see Section 11 for definitions).
• 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 - 1 (see APPENDIX A).
• 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 on the screening EKG.
• The effects of LY3022855 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 and for the duration of study participation. 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 LY3022855 administration.
• 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.

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.
• 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 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 metas