CTNI-53. PNOC014: PHASE IB STUDY RESULTS OF DAY101(TOVORAFENIB) FOR CHILDREN WITH LOW-GRADE GLIOMAS (LGGS) AND OTHER RAS/RAF/MEK/ERK PATHWAY-ACTIVATED TUMORS. (14th November 2022)

• Record Type: Journal Article
• Authors: Wright, Karen; Kline, Cassie; Abdelbaki, Mohamed; Ebb, David; Sayour, Elias; Elster, Jennifer; Leary, Sarah; Miller, Matthew; Margol, Ashley; Cohen, Kenneth; Kilburn, Lindsay; Bendel, Anne; Kao, Pei-Chi; Ma, Clement; London, Wendy; Mueller, Sabine; Prados, Michael; Haas-Kogan, Daphne
• Is Part Of: Neuro-oncology. Volume 24(2022)Supplement 7
• Page Start: vii84
• Page End: vii84
• Publication Date: 2022-11-14
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac209.318
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: BACKGROUND: Pharmacokinetic modeling for previously reported phase 1A data of pan-RAF inhibitor DAY101 in RAS/RAF/MEK/ERK pathway-altered tumors suggested a correlation between higher doses and improved efficacy without clear safety data. The protocol was amended to explore differential dosing across different body surface areas (BSA). METHODS: Eligible patients were < 25 years old with radiographically recurrent/progressive RAS/RAF/MEK/ERK pathway-altered tumors. We applied a novel modification of a TITE-BOIN design to determine recommended phase 2 dosing of oral, weekly DAY101 in evaluable patients within two BSA subgroups: ≤ 1.5 m 2 or > 1.5 m 2 . Target toxicity probability was closest to 20%. We tested 420 and 530 mg/m 2 . Dose limiting toxicities (DLTs) were determined within Cycle 1. Evaluable patients had either ' complete ' or ' partial ' information. Complete information meant patient had a DLT or received 3 of 4 planned doses with no DLT. Partial information meant patient received only 1 or 2 doses or did not complete the DLT observation period. Three patients with complete information at a given dose level were required before dose escalation. The primary endpoint driving dose escalation was time from start of Cycle 1 to first DLT or, if no DLT, time from start of Cycle 1 to minimum of date of last contact or end of Cycle 1. RESULTS: We treated 35 eligible patients: 21 KIAA1549:BRAF-, 9 BRAFV600E-, 4 novel RAF- and one FGFR1-altered tumors. Histologically, cohort included 30 LGGs, 4 high grade gliomas and 1 soft tissue sarcoma. There were 6 DLTs: 3 in each BSA subgroup, all at 530 mg/m 2 /dose, all grade 3, and 5 known side effects ( 2 fatigue, 3 rash, 1 menorrhagia). CONCLUSIONS: Oral weekly DAY101 is well tolerated. The TITE model recommends 530 mg/m 2 /dose PO weekly for patients with BSA < 1.5m 2 and 420 mg/m 2 /dose PO weekly for patients with BSA >1.5m 2 .