Hsp90 Inhibitor XL888, Vemurafenib, and Cobimetinib in Treating Patients with BRAF Mutated Stage IIIB-IV Melanoma That Cannot Be Removed by Surgery

Inclusion Criteria

• Subjects must have cytologically or histologically-confirmed unresectable melanoma that harbors a BRAF V600 mutation determined by pyrosequencing assay or equivalent genotyping assay in a Clinical Laboratory Improvement Act (CLIA) certified laboratory, meeting one of the following American Joint Committee on Cancer (AJCC) staging criteria: * AJCC stage IV (T any, N any, M1a, b, or c) * AJCC stage IIIB or IIIC with unresectable nodal/locoregional involvement
• Hemoglobin >= 9 g/dL (obtained within 4 weeks prior to initiation of study treatment)
• Absolute neutrophil count >= 1,500/mcL (obtained within 4 weeks prior to initiation of study treatment)
• Platelets >= 100,000/mcL (obtained within 4 weeks prior to initiation of study treatment)
• Adequate renal function, as indicated by creatinine =< 1.5 x the upper limit of normal (ULN) (obtained within 4 weeks prior to initiation of study treatment)
• Bilirubin =< 1.5 x ULN (obtained within 4 weeks prior to initiation of study treatment)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 3 x institutional upper limit of normal (obtained within 4 weeks prior to initiation of study treatment)
• If liver metastasis present, then AST/ALT =< 5 x ULN (obtained within 4 weeks prior to initiation of study treatment)
• Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
• Subjects must be willing to give written informed consent per institutional guidelines and must be able and willing to adhere to dose and visit schedules
• Negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women; women of non-childbearing potential may be included without serum pregnancy test if they are either surgically sterile or have been postmenopausal for >=1 year
• Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician
• Treatment-naive and previously treated patients will be included; however, patients may not have received a BRAF, MEK or HSP90 inhibitor in the past
• Patients may have received prior systemic and/or radiation therapy; all adverse events associated with prior systemic therapy or radiation therapy must have resolved to =< grade 1 prior to start of study
• Subjects must have measurable disease as defined by RECIST 1.1

Exclusion Criteria

• Female subjects who are pregnant, intend to become pregnant or are nursing
• Subjects previously treated with BRAF, MEK or HSP90 inhibitor therapy
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with XL888 and vemurafenib/cobimetinib
• Subjects with untreated or uncontrolled brain metastases or evidence of leptomeningeal disease; patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e. not requiring corticosteroids) at the time of study start will be eligible
• Previous malignancy is not an exclusion provided that the other malignancy is considered under control, patient is not on concomitant anti-cancer drug therapy, and target lesions from melanoma are clearly defined for response assessment
• History of malabsorption or other condition that would interfere with absorption of vemurafenib
• Unwillingness or inability to comply with study and follow-up procedures
• The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment: * St. John’s wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer) * Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor)
• Ocular: * History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusions (RVO), or neovascular macular degeneration
• Cardiac: * History of clinically significant cardiac dysfunction, including the following: ** Current unstable angina ** Current symptomatic congestive heart failure of New York Heart Association (NYHA) class 2 or higher ** History of congenital long QT syndrome or mean corrected QT (QTc) or corrected QT interval by Fredericia (QTcF) > 450 msec at baseline or uncorrectable electrolyte abnormalities ** Uncontrolled hypertension >= grade 3 (patients with a history of hypertension controlled with anti-hypertensives to =< grade 1 and patients with hypertension grade 2 that have treating physician approval of safety, are eligible) ** Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 40%, whichever is lower ** Uncontrolled arrhythmias ** Myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack within the previous 6 months