Abstract 3632
Background
Activation of the MAPK pathway via the BRAF V600 mutation has been observed in several tumors. This mutation is observed in a subset of pediatric brain tumors, including HGG and LGG for which limited therapeutic options are currently available. In a phase I/II clinical trial of pediatric patients (pts) with recurrent or refractory BRAF V600–mutant relapsed tumors, the BRAF inhibitor dabrafenib demonstrated its efficacy, including complete responses, in pediatric pts with HGG and LGG. As the combination of dabrafenib plus the MEK inhibitor trametinib has resulted in improved efficacy in multiple adult BRAF V600–mutant tumors, including melanoma and non-small cell lung cancer, this combination warrants further investigation in pediatric pts with gliomas bearing the same mutation.
Trial design
This global, open-label, phase II study (NCT02684058) will evaluate the anti-tumor activity of the combination of dabrafenib plus trametinib in 2 pediatric glioma cohorts recruiting from up to 70 sites across 17 countries. The single-arm BRAF V600–mutated HGG cohort of approximately 40 pts (aged ≥ 6 and < 18 y) with relapsed or refractory disease will be treated with dabrafenib twice daily (BID) plus trametinib once daily (QD) based on age and weight. The primary endpoint for this cohort is overall response rate (ORR) per investigator’s assessment according to Response Assessment in Neuro-Oncology (RANO) criteria. The BRAF V600–mutated LGG cohort of approximately 102 chemotherapy-naive pts (aged ≥ 6 and < 18 y) with unresectable disease will be randomized 2:1 to receive either dabrafenib (BID) plus trametinib (QD) or carboplatin plus vincristine. The primary endpoint for the LGG cohort is ORR per independent assessment according to RANO criteria. Pt crossover from the chemotherapy arm to the experimental arm will be allowed after independent confirmation of radiologic disease progression. Key secondary endpoints for both cohorts include duration of response, progression-free survival, time to response, clinical benefit rate, overall survival, and safety/tolerability.
Clinical trial identification
NCT02684058.
Legal entity responsible for the study
Novartis Pharmaceuticals Corporation.
Funding
Novartis Pharmaceuticals Corporation.
Editorial Acknowledgement
Medical writing assistance was provided by William Fazzone, PhD (ArticulateScience LLC), funded by Novartis Pharmaceuticals Corporation.
Disclosure
D. Hargrave: Consultancy: Novartis. O. Witt: Membership on board of directors or advisory committees: Novartis; Study committee on selumetinib trial: AzstraZeneca. K. Cohen: Research Funding: Novartis; Membership on board of directors or advisory committees: Novartis. T.W. Laetsch: Consultancy: Novartis, Loxo Oncology, Bayer; Research funding: Pfizer. A. Lassaletta: Consultancy: Shire, Clinigen. C. Kramm: Research funding: Novartis, Eisai, Boehringer Ingelheim, Merck. C. Reitmann, M.W. Russo: Employment: Novartis; E. Bouffet: Research funding to institution: Roche, Bristol-Myers Squibb.