GSE193157
The BAMM Trial: BRAF, Autophagy and MEK inhibition in Metastatic Melanoma: A phase I/II trial of dabrafenib, trametinib and hydroxychloroquine in patients with advanced BRAF mutant melanoma
Importance: Autophagy has been identified as a resistance mechanism to BRAF and MEK inhibition in BRAF mutant melanoma. In the BAMM trial, hydroxychloroquine (HCQ) was used to inhibit autophagy in combination with dabrafenib and trametenib in BRAF mutant melanoma patients.   Objective: To a) determine safety and maximal tolerated dose (MTD) of hydroxychloroquine when combined with dabrafenib and trametinib and b) determine antitumor activity of the combination.    Design: Open label non-randomized phase I/II clinical trial   Setting: Prospective  therapeutic clinical trial conducted in 4 centers   Participants: Unresectable Stage III or Stage IV BRAF mutant melanoma patients  Intrevention: HCQ twice daily,  dabrafenib 150 mg twice daily  and trametinib 2 mg daily (D+T)  Main Outcome: Primary outcomes were safety and 1-year progression-free survival (PFS) rate   Results: Between December 2014 and January 2020, 50 patients were screened, 38 patients were enrolled and evaluable for toxicity and 34 patients were evaluable for 1-year PFS rate. Patient demographics were: 29% were ECOG PS 1, 47% had elevated LDH,  52%  were Stage IV M1c or M1d and 53% had previously received therapy for advanced melanoma. In the phase I trial there was no dose limiting toxicity of  HCQ at either 400 (n=3)  or 600 (MTD) mg po bid combined with D+T. For the entire study population, the 1-year PFS rate was 41%   (95% CI =  ), median PFS was 11.9 months (95% CI =  ), overall response rate (ORR) was 85% (95% exact CI=64-95%)and complete response rate of 41% (95% exact CI=25-59%). In a prespecificed subgroup analysis in 18 patients with elevated LDH, the ORR was 88% and median PFS was 8 months   Conlusion and Relevance: The combination of HCQ, dabrafenib and trametinib was well tolerated and produced a high response rate but did not meet the prespecified criteria for success with respect to the 1-year PFS rate. In patients with elevated LDH , the response rate and PFS were encouraging. A randomized placebo controlled trial of dabrafenib and trametinib with/without HCQ in advanced BRAF mutant melanoma patients with elevated LDH and previously treated with immunotherapy is being conducted through the National Clinical Trial Network. Overall design: RNA-seq of high and low progression free survival patients