Phase I/II trial of Dabrafenib, Trametinib, and Hydroxychloroquine (HCQ)
Award: $350,000 over 2 years (2019 – 2021)
Principal Investigators: Dr. Arzu Onar-Thomas, St. Jude Children’s Research Hospital
The development of MAP kinase-specific targeted inhibitors is the shifting therapeutic strategy for pediatric LGGs and offers many of these children new treatment options. Early phase investigations of RAF and MEK inhibitors in pediatric gliomas have demonstrated reasonable tolerability and superior responses in some patients compared to conventional chemotherapy. However, a significant subset of patients maintains either stable disease or progresses on targeted therapy, suggesting potential benefit from combining RAF or MEK inhibitors with agents targeting other active pathways.
Autophagy is a process by which components of a cell are recycled to promote cell survival, particularly in times of stress. Dr. Mulcahy Levy’s laboratory has generated preclinical data demonstrating specific upregulation of autophagy in BRAF-mutant compared to wild-type glioma cells and has shown that autophagy inhibition can effectively overcome intrinsic and acquired resistance to RAF inhibition. Based on these data and early clinical experience at the University of Colorado, we have proposed a phase I/II trial with dabrafenib (BRAF inhibitor) + trametinib (MEK inhibitor) + hydroxychloroquine (autophagy inhibitor; HCQ) in BRAF V600E-mutant gliomas and a combination of trametinib + HCQ in BRAF fusion or NF1-driven gliomas in children.
The primary aims of this trial are to demonstrate safety and early efficacy of the proposed combinations. Only children whose tumors have failed MEK and/or RAF inhibitors previously will be eligible; thus, we are selecting a specific group of children for whom other therapeutic options are limited and who are most likely to benefit.
This trial will aid understanding of tumor biology that drives response or resistance to targeted therapies through evaluation of the genetics and expression profiles of pre- and post-therapy tumor samples. Knowledge gained will be broadly relevant to other patients with LGG, particularly as more are being treated with targeted agents earlier in their treatment course. We will also use ddPCR to very sensitively track BRAFV600E transcript levels (in patients with known mutation) while on protocol therapy. If as a proof-of-principle, there is a correlation between BRAFV600E transcripts and tumor burden on MRI and/or outcome, this study would strongly support greater utilization of ddPCR to define and track minimal residual disease in pediatric CNS tumors.
