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Status |
Public on Jan 07, 2022 |
Title |
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 |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
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.
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Overall design |
RNA-seq of high and low progression free survival patients
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Contributor(s) |
Amaravadi R, Mehnert J |
Citation(s) |
35022320 |
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Submission date |
Jan 06, 2022 |
Last update date |
Mar 31, 2022 |
Contact name |
Priyankara J Wickramasinghe |
E-mail(s) |
priyaw@wistar.org
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Phone |
2154956837
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Organization name |
The Wistar Institute
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Department |
Bioinformatics
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Lab |
Genomics
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Street address |
3601 Spruce Street
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City |
Philadelphia |
State/province |
PA |
ZIP/Postal code |
19104 |
Country |
USA |
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Platforms (1) |
GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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Samples (18)
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GSM5775614 |
high progression free survival group, patient 1 |
GSM5775615 |
high progression free survival group, patient 2 |
GSM5775616 |
high progression free survival group, patient 3 |
GSM5775617 |
high progression free survival group, patient 4 |
GSM5775618 |
high progression free survival group, patient 5 |
GSM5775619 |
high progression free survival group, patient 6 |
GSM5775620 |
high progression free survival group, patient 7 |
GSM5775621 |
low progression free survival group, patient 1 |
GSM5775622 |
low progression free survival group, patient 2 |
GSM5775623 |
low progression free survival group, patient 3 |
GSM5775624 |
low progression free survival group, patient 4 |
GSM5775625 |
low progression free survival group, patient 5 |
GSM5775626 |
low progression free survival group, patient 6 |
GSM5775627 |
low progression free survival group, patient 7 |
GSM5775628 |
low progression free survival group, patient 8 |
GSM5775629 |
low progression free survival group, patient 9 |
GSM5775630 |
low progression free survival group, patient 10 |
GSM5775631 |
low progression free survival group, patient 11 |
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Relations |
BioProject |
PRJNA795153 |
Supplementary file |
Size |
Download |
File type/resource |
GSE193157_BAMM_RNAseq.txt.gz |
656.0 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
Raw data are available in SRA |
Processed data are available on Series record |
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