BAMM (BRAF Autophagy and MEK inhibition in Melanoma): A phase I/II trial of dabrafenib, trametinib and hydroxychloroquine in advanced BRAFV600-mutant melanoma

Purpose: Autophagy is a resistance mechanism to BRAF/MEK inhibition in BRAFV600-mutant melanoma. Here we used hydroxychloroquine (HCQ) to inhibit autophagy in combination with dabrafenib 150 mg bid and trametenib 2 mg qd (D+T). Patients and Methods: We conducted a phase I/II clinical trial in 4 centers of HCQ+D+T in advanced BRAFV600-mutant melanoma patients. The primary objectives were the recommended phase II dose (RP2D) and the one-year progression-free survival (PFS) rate of >53%. Results: 34 were evaluable for one-year PFS rate. Patient demographics: elevated LDH: 47%; Stage IV M1c/M1d: 52%; prior immunotherapy: 50%. In phase I, there was no dose limiting toxicity. HCQ 600 mg po bid with D+T was the RP2D. The one-year PFS rate was 48.2% (95% CI = 31.0-65.5%), median PFS was 11.2 months (95% CI = 5.4-16.9 months), and response rate (RR) was 85% (95% CI=64-95%). The complete response rate was 41% and median overall survival (OS) was 26.5 months. In patient with elevated LDH (n=16), the RR was 88% and median PFS and OS were 7.3 and 22 months, respectively. Conclusion: HCQ+D+T was well tolerated and produced a high RR but did not meet criteria for success for the one-year PFS rate. There was a high proportion of pre-treated and elevated LDH patients, an increasingly common demographic in patients receiving targeted therapy. In this difficult to treat population, the the RR and PFS were encouraging. A randomized trial of D+T+HCQ or placebo in BRAFV600-mutant melanoma patients with elevated LDH and previous immunotherapy is being conducted.