Efficacy and safety results from a phase I/IIa study of dabrafenib in pediatric patients with <i>BRAF</i> V600–mutant relapsed refractory low-grade glioma.

Abstract

10506 Background: The primary treatment for many pediatric patients (pts) with low-grade glioma (LGG) remains surgical resection with curative intent. However, pts whose tumors cannot be completely resected or recur may require additional treatment, eg, radiotherapy or chemotherapy. Pediatric pts with BRAF V600–mutant LGG may benefit from treatment with the BRAF inhibitor dabrafenib. We report 2-y follow-up data from a 2-part phase I/IIa study investigating dabrafenib in pediatric BRAF V600–mutant LGG (NCT01677741). Methods: Part 1 determined the recommended phase 2 dose (RP2D); the Part 2 disease expansion evaluated efficacy and safety of dabrafenib in 4 pediatric tumor–specific cohorts, including LGG. Efficacy for LGG was determined by investigator and independent (IND) review per Response Assessment in Neuro-Oncology [RANO] criteria. Adverse events (AEs) were assessed per NCI-CTCAE version 4.0 criteria. Results: Thirty-two pediatric pts with relapsed, refractory, or progressive BRAF V600–mutant LGG were enrolled (Dec 2013 to Jul 2015). Fifteen pts were treated in Part 1 (n = 7 at RP2D) and 17 in Part 2. RP2D is 4.5 mg/kg/d for pts ≥ 12 y of age and 5.25 mg/kg/d for pts < 12 y of age, each divided into 2 equal doses per day. Common histologies included pilocytic astrocytoma (n = 13; 41%), ganglioglioma (n = 7; 22%), and pleomorphic xanthoastrocytoma (n = 3; 9%). At interim analysis (Sep 2017), median duration of exposure was 25 mo (range, 0.1-42.6 mo), with 15 ongoing. Most frequent reason for discontinuation was elective, following ≥ 1 yr of treatment. Across all dose levels, the confirmed overall response rate (ORR, complete response [CR] + partial response [PR]) per IND review was 44% (95% CI, 26.4%-62.3%), including 1 CR and 13 PR. Eleven pts had stable disease, and 2 had progressive disease as best response. Median PFS by IND review was 35 mo (95% CI, 12.9 mo-NE). Common AEs of all grades, regardless of causality, included pyrexia (72%), vomiting (53%), and headache (47%). Conclusions: Dabrafenib demonstrated clinical activity with tolerability in pediatric pts with relapsed, refractory, or progressive BRAF V600E mutation–positive LGG and supports its further clinical evaluation. Clinical trial information: NCT01677741.