PNOC014: Phase I Study of Tovorafenib for Children With Relapsed/Recurrent Low-Grade Gliomas and Other Mitogen Activated Protein Kinase Pathway–Activated Tumors

PURPOSE More than a decade ago, researchers identified tovorafenib as a potential therapeutic option for the most common pediatric benign brain tumor, the KIAA1549:BRAF -fused low-grade glioma. Our study aimed to establish the safety, tolerability, dosing, and preliminary efficacy of this drug. PATIENTS AND METHODS We conducted a phase I investigator-initiated trial of tovorafenib. Eligible patients were age 1 to 25 years with radiographically recurrent/progressive mitogen-activated protein kinase pathway–altered tumors. The first phase (IA) followed a 3 + 3 design. Based on initial observed responses and pharmacokinetic data, the trial was modified to include phase IB using a subgroup-specific time to event (Sub-TITE) design to better determine dosing within two subgroups defined by body surface area (BSA ≤1.5 m 2 and >1.5 m 2 ). Toxicities were graded according to Common Terminology Criteria for Adverse Events version 5. Response was classified as complete response (CR), partial response (PR), or stable disease (SD). RESULTS We treated 44 eligible patients (phase IA: 9; phase IB: 35) with high-(n = 6) or low-grade (n = 38) tumors. Pilocytic astrocytoma (n = 19) was the most common diagnosis; KIAA1549:BRAF fusion was the most common molecular alteration (n = 27). No dose-limiting toxicities (DLTs) occurred in phase IA. Phase IB included 6 DLTs: three in each BSA subgroup, all at 530 mg/m 2 /dose, all grade 3. The most common adverse reactions were skin-related. The most common grade 3 adverse event was growth suppression while on treatment. Preliminary response data for 36 evaluable patients in the combined cohorts included 32 patients with CR/PR/SD. Four patients had progressive disease. CONCLUSION This study established the initial tolerability and preliminary efficacy of oral tovorafenib once every week. The recommended phase II dose was 420 mg/m 2 administered orally, once every week. Growth suppression while on drug was an unexpected side effect.