BAMM (BRAF Autophagy and MEK Inhibition in Melanoma): A Phase I/II Trial of Dabrafenib, Trametinib, and Hydroxychloroquine in Advanced BRAFV600-mutant Melanoma

Janice M. Mehnert, Tara C. Mitchell, Alexander C. Huang, Tomas S. Aleman, Benjamin J. Kim, Lynn M. Schuchter, Gerald P. Linette, Giorgos C. Karakousis, Sheryl Mitnick, Lydia Giles, Mary Carberry, Noelle Frey, Andrew Kossenkov, Roman Groisberg, Leonel F. Hernandez-Aya, George Ansstas, Ann W. Silk, Sunandana Chandra, Jeffrey A. Sosman, Phyllis A. GimottyRosemarie Mick, Ravi K. Amaravadi

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Purpose: Autophagy is a resistance mechanism to BRAF/MEK was 48.2% [95% confidence interval (CI), 31.0%–65.5%], median inhibition in BRAFV600-mutant melanoma. Here we used PFS was 11.2 months (95% CI, 5.4–16.9 months), and response rate hydroxychloroquine (HCQ) to inhibit autophagy in combination (RR) was 85% (95% CI, 64%–95%). The complete RR was 41% and with dabrafenib 150 mg twice daily and trametinib 2 mg every median overall survival (OS) was 26.5 months. In a patient with day (DþT). elevated LDH (n = 16), the RR was 88% and median PFS and OS Patients and Methods: We conducted a phase I/II clinical trial in were 7.3 and 22 months, respectively. four centers of HCQ þ DþT in patients with advanced BRAFV600-Conclusions: HCQ þ DþT was well tolerated and produced mutant melanoma. The primary objectives were the recommended a high RR but did not meet criteria for success for the one-year phase II dose (RP2D) and the one-year progression-free survival PFS rate. There was a high proportion of patients with pretreated (PFS) rate of >53%. and elevated LDH, an increasingly common demographic in Results: Thirty-four patients were evaluable for one-year PFS patients receiving targeted therapy. In this difficult-to-treat rate. Patient demographics were as follows: elevated lactate dehypopulation, the RR and PFS were encouraging. A randomized drogenase: 47%; stage IV M1c/M1d: 52%; prior immunotherapy: trial of DþT þ HCQ or placebo in patients with BRAFV600-50%. In phase I, there was no dose-limiting toxicity. HCQ 600 mg mutant melanoma with elevated LDH and previous immunoorally twice daily with DþT was the RP2D. The one-year PFS rate therapy is being conducted.

Original languageEnglish
Pages (from-to)1098-1106
Number of pages9
JournalClinical Cancer Research
Volume28
Issue number6
DOIs
StatePublished - Mar 15 2022

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