PNOC014: Phase I Study of Tovorafenib for Children With Relapsed/Recurrent Low-Grade Gliomas and Other Mitogen Activated Protein Kinase Pathway–Activated Tumors
Karen D. Wright, Cassie Kline, Susan N. Chi, Mohamed Shebl Abdelbaki, Elias Sayour, David H. Ebb, Matthew B. Miller, Erin E. Crotty, Ashley S. Margol, Lindsay B. Kilburn, Eric H. Raabe, Anne E. Bendel, Jennifer Elster, Lianne Greenspan, Emily S. Krzykwa, Jacquelyn Jones, Keith L. Ligon, Pei-Chi Kao, Clement Ma, Wendy B. London, Michael Prados, Daphne A. Haas-Kogan, Sabine MuellerPURPOSE
More than a decade ago, researchers identified tovorafenib as a potential therapeutic option for the most common pediatric benign brain tumor, the
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;
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.