XL888 + Vemurafenib + Cobimetinib for Unresectable BRAF Mutated Stage III/IV Melanoma

Inclusion Criteria:

- Must be 18 years of age or above. All races and ethnicities are eligible and no upper
limit of age is specified.

- 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 Amendments (CLIA) certified laboratory, meeting
one of the following AJCC staging criteria: 1.) American Joint Committee on Cancer
(AJCC) stage IV (Tany, Nany, M1a, b, or c); 2.) AJCC stage IIIB or IIIC with
unresectable nodal/locoregional involvement.

- Adequate hepatic, renal, and bone marrow function with parameters obtained within 4
weeks prior to initiation of study treatment.

- Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.

- Willing to give written informed consent per institutional guidelines and must be able
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-naïve and previously treated patients will be included; however, patients
may not have received a BRAF, Mitogen Activated Kinase (MEK) or HSP90 inhibitor in the
past.

- 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.

- Must have measurable disease as defined by Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1.

Exclusion Criteria:

- Women who are pregnant, intend to become pregnant or are nursing.

- 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.

- HIV-positive patients on combination antiretroviral therapy.

- Potential participants 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
study drugs.

- 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
occlusion (RVO), or neovascular macular degeneration.

- Cardiac: History of clinically significant cardiac dysfunction.