This phase II trial studies how well de-escalating the drugs dabrafenib and trametinib works in treating patients with low-grade gliomas that have a BRAF V600 gene mutation. Dabrafenib and trametinib are in a class of medications called kinase inhibitors. They work by blocking the action of abnormal proteins that signals tumor cells to multiply. This helps stop the spread of tumor cells. This trial may help doctors determine the best dosing strategy for patients who have received dabrafenib and trametinib for 12-24 months: Either stopping dabrafenib and trametinib completely or slowly reducing the dose for an additional 6 months.
PRIMARY OBJECTIVE: I. To determine if there is a difference in rate of rebound and/or clinical progression necessitating the reinstitution of treatment at 4 months after stopping or weaning therapy with dabrafenib mesylate (dabrafenib) and trametinib dimethyl sulfoxide (trametinib) in participants with newly diagnosed or recurrent/progressive LGGs with BRAF V600 mutation. EXPLORATORY OBJECTIVES: I. To describe the toxicity in participants in different phases of drug administration: Ia. Standard dosing schedule of dabrafenib and trametinib. Ib. Abruptly stopping dabrafenib and trametinib. Ic. Weaning dabrafenib and trametinib. II. To assess the time to rebound and/or radiologic or clinical progression for participants who abruptly stop dabrafenib and trametinib versus participants who wean dabrafenib and trametinib. III. To determine the durability of response, defined as time to progression, for patients treated until confirmed best response or for a maximum of 24 months. IV. To monitor response/toxicity by profiling cell-free deoxyribonucleic acid (DNA) (cfDNA) whole genomes in longitudinal blood and cerebrospinal fluid (CSF) specimens. V. To correlate response/toxicity based on pharmacogenomics. VI. To explore response-predictive features in tumor cellular composition and tissue architecture through multi-dimensional data integration (single nucleus multiomics, spatial tumor tissue profiling, digital pathology). VII. To assess radiogenomic prediction models. VIII. To assess machine learning imaging models accuracy in evaluating response and compare to standard Response Assessment in Neuro-Oncology Low Grade Glioma (RANO-LGG) and Response Assessment in Pediatric Neuro-Oncology (RAPNO)-LGG criteria. IX. To describe the microbiome profile in participants receiving dabrafenib and trametinib. X. To characterize cutaneous toxicities across participants with different skin colors taking a weaning regimen of dabrafenib and trametinib compared to participants taking standard dose dabrafenib and trametinib. OUTLINE: Participants receive dabrafenib and trametinib each cycle for a minimum of 12 cycles and up to a maximum of 24 cycles in the absence of disease progression or unacceptable toxicity. Participants are then randomized to 1 of 2 arms. ARM A: Participants stop treatment with dabrafenib and trametinib. ARM B: Participants receive dabrafenib PO BID and trametinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then up to 5 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
96
Given orally (PO)
Given PO
Undergo imaging by MRI
Under collection of blood and optional CSF samples
Undergo optional lumbar puncture
University of Alabama at Birmingham
Birmingham, Alabama, United States
RECRUITINGUniversity of California, San Francisco
San Francisco, California, United States
RECRUITINGJohn Hopkins Medical Center
Baltimore, Maryland, United States
RECRUITINGSt. Louis Children's Hospital Washington University in St. Louis
St Louis, Missouri, United States
RECRUITINGRebound rate (RR)
The Rebound rate is defined as increase in tumor size by 25% or more by Response Assessment in Pediatric Neuro-Oncology-Low Grade Glioma (RAPNO-LGG) criteria and/or clinical progression necessitating the re-institution of therapy occurring within 4 months off therapy for participants with BRAF V600 mutant LGG after abruptly stopping or weaning off dabrafenib and trametinib. RR will be reported by cohort and arm.
Time frame: Up to a maximum of 34 months
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