Background: BRAF inhibitors are clinically active in advanced BRAFV600 mutant melanoma patients, but resistance is common. Multiple resistance mechanisms involve HSP90 clients and preclinical data have shown abrogation of resistance using concurrent treatment with the HSP90 inhibitor XL888. Methods: The combination of vemurafenib (960 mg PO BID) with dose cohorts of XL888 (30, 45, 90 or 135 mg PO twice weekly [BIW]) was investigated in patients with advanced BRAFV600 mutant melanoma. A modified Ji dose escalation design was used. Primary endpoints were safety and determination of a recommended phase 2 dose (RP2D). Dose-limiting toxicity (DLT) was defined as treatment-related grade ≥ 3 adverse event or inability to deliver 75% of planned XL888 dose in the first 8 weeks. Results: Nineteen patients (14 with M1C disease) were enrolled: cohorts 1 and 2 (n = 3 each), cohort 3 (n = 7), cohort 4 (n = 6). Two DLTs (diarrhea and pancreatitis) occurred in cohort 4, while a third patient received < 75% of planned XL888. Therefore cohort 3 dose was determined to be RP2D: vemurafenib 960 mg BID + XL888 90 mg BIW. Most common grade 3 toxicities (in > 1 patient) were hyperproliferative skin events (n = 5, 26%), diarrhea (n = 2, 11%), rash (n = 2) and headaches (n = 2) and one grade 4 lipase elevation. Skin toxicities were lower in cohorts 3/4. Objective responses were observed in 13 of 18 evaluable patients (72%; 95% CI: 47 - 90%) with 2 complete responses (CRs) and 11 partial responses (PR). Two patients with a PR who underwent surgical resection had a pathologic CR. Median PFS was 7.4 months (95% CI: 3.7 – 16.2); median overall survival was 33.1 months (5.75 – not reached). Targeted proteomics of patients’ baseline and day 8 PBMCs showed significant increases in HSP71 expression (a marker of HSP90 inhibition) (p < 0.05) in cohorts 2 through 4. Analysis of baseline and on-therapy tumor biopsies is ongoing. Conclusions: Promising clinical activity with an acceptable toxicity profile and evidence of HSP90 inhibition was observed with vemurafenib and XL888 in BRAF mutant melanoma patients. As HSP90 inhibitors also abrogate resistance to the combination of BRAF and MEK inhibitors in melanoma, clinical investigation of this approach is also planned. Clinical trial information: NCT01657591