CTP-02. A Phase 1 trial of Deflexifol™ in pediatric patients with relapsed or refractory brain tumors

Abstract BACKGROUND Deflexifol is a novel combination of 5-fluorouracil (5-FU) and leucovorin, allowing for co-delivery in one infusion. 5-FU has documented activity in pediatric ependymoma. It is hypothesized that this novel formulation will enhance efficacy and reduce toxicity, enabling higher active doses within the brain. We report results of a first-in-child Phase 1 trial of Deflexifol in children with relapsed or refractory brain tumors including ependymoma. METHODS Children (aged 1-21 years) with relapsed or refractory brain tumors were eligible for Phase 1 enrolment, using a rolling 6 design. Intravenous Deflexifol was administered on Days 1-3 and Days 15-17 of a 28-day cycle, as a bolus followed by a 46-hour infusion. The starting dose (Dose level 0) was a 525mg/m2 bolus (of delivered 5-FU) and 3400mg/m2 infusion, with pre-defined levels for dose escalation/de-escalation. The maximum tolerated dose (MTD) was determined based on cycle 1 dose-limiting toxicity (DLT) (Common Terminology Criteria for Adverse Events, v5.0). Pharmacokinetic samples were collected. RESULTS Nine participants (aged 4-14 years), with ependymoma (n=6), DMG (n=2), ETMR (n=1) were enrolled. At the starting dose, two of three participants experienced DLTs of Grade 3 oral mucositis and Grade 4 neutropenia. Six participants were enrolled at Dose level -1 (525mg/m2 bolus and 3000mg/m2 infusion), with one DLT of Grade 4 neutropenia. Grade 3 and 4 non-DLTs included: neutropenia (14 occurrences), leucopenia (4), febrile neutropenia (3), oral mucositis (2) and palmar-plantar erythrodysesthesia syndrome (2). No participants discontinued treatment due to toxicity. Pharmacokinetic analysis is ongoing and will be presented. CONCLUSIONS The pediatric MTD and Recommended Phase 2 Dose for Deflexifol are 525mg/m2 bolus and 3000mg/m2 infusion, equivalent to 88% of the adult MTD. This study has demonstrated that Deflexifol is well tolerated in children. A Phase 2 expansion cohort is planned to evaluate the activity of Deflexifol in children with ependymoma.