A lead-in safety study followed by a phase 2 clinical trial of dabrafenib, trametinib and hydroxychloroquine in advanced BRAFV600 mutant melanoma patients previously treated with BRAF-/MEK-inhibitors and immune checkpoint inhibitors

Research output: Contribution to journalArticle

Abstract

Patients with advanced v-Raf murine sarcoma viral oncogene homolog B V600 (BRAFV600) mutant melanoma who progressed on prior treatment with v-Raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen-activated protein kinase kinase (MEK) inhibitors and programmed cell death 1 or cytotoxic T-lymphocyte-associated antigen 4 immune checkpoint inhibitors can benefit from retreatment with the combination of a BRAF- and a MEK-inhibitor ('rechallenge'). Hydroxychloroquine can prevent autophagy-driven resistance and improve the efficacy of BRAF-/MEK-inhibitors in preclinical melanoma models. This clinical trial investigated the use of combined BRAF-/MEK-inhibition with dabrafenib and trametinib plus hydroxychloroquine in patients with advanced BRAFV600 mutant melanoma who previously progressed on prior treatment with BRAF-/MEK-inhibitors and immune checkpoint inhibitors. Following a safety lead-in phase, patients were randomized in the phase 2 part of the trial between upfront treatment with dabrafenib, trametinib and hydroxychloroquine (experimental arm), or dabrafenib and trametinib, with the possibility to add-on hydroxychloroquine at the time of documented tumor progression (contemporary control arm). Ten and four patients were recruited to the experimental and contemporary control arm, respectively. The objective response rate was 20.0% and the disease control rate was 50.0% in the experimental arm, whereas no responses were observed before or after adding hydroxychloroquine in the contemporary control arm. No new safety signals were observed for dabrafenib and trametinib. Hydroxychloroquine was suspected of causing an anxiety/psychotic disorder in one patient. Based on an early negative evaluation of the risk/benefit ratio for adding hydroxychloroquine to dabrafenib and trametinib when 'rechallenging' BRAFV600mutant melanoma patients, recruitment to the trial was closed prematurely.

Original languageEnglish
Pages (from-to)183-191
Number of pages9
JournalMelanoma Research
Volume32
Issue number3
Early online date2022
DOIs
Publication statusPublished - 1 Jun 2022

Bibliographical note

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Keywords

  • lead-in safety study
  • phase 2 clinical trial
  • dabrafenib
  • trametinib
  • hydroxychloroquine
  • advanced BRAFV600 mutant melanoma patients
  • BRAF-/MEK-inhibitors
  • immune checkpoint inhibitors

Fingerprint

Dive into the research topics of 'A lead-in safety study followed by a phase 2 clinical trial of dabrafenib, trametinib and hydroxychloroquine in advanced BRAFV600 mutant melanoma patients previously treated with BRAF-/MEK-inhibitors and immune checkpoint inhibitors'. Together they form a unique fingerprint.

Cite this