CTNI-04. A PHASE 1, FIRST-IN-HUMAN STUDY OF REGORAFENIB PLUS TEMOZOLOMIDE WITH OR WITHOUT RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED MGMT METHYLATED, IDH WILDTYPE GLIOBLASTOMA: THE REGOMA-2 TRIAL

Abstract BACKGROUND Regorafenib (REG) is an oral multikinase inhibitor that has shown synergistic antitumor effects with radiotherapy and temozolomide (TMZ) in glioblastoma. This phase 1 study evaluated the safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary activity of REG in combination with standard GBM treatment. METHODS Using a 3 + 3 design, this multicenter study assessed REG at doses of 80mg, 120mg, and 160mg in patients with MGMT-methylated, IDH wild-type GBM (WHO2021) and ECOG PS 0-1. -Cohort A: REG+maintenance TMZ after standard chemoradiotherapy (CT-RT) -Cohort B: REG concurrently with CT-RT, continued with TMZ. REG was given 3 weeks on/1 off. DLTs were monitored during the first two maintenance cycles (cohort A) and during CT-RT (cohort B). Toxicity was assessed using CTCAEv5.0, and tumor response by RANO criteria. PK was also evaluated. RESULTS In cohort A (n=9), no DLTs occurred. One patient each at Levels 1 and 2 had grade 3 (G3) hematologic toxicity; at Level 3, one had G3 gastrointestinal toxicity. In cohort B (n=12), two DLTs occurred at Level 3: G3 hypertransaminasemia and G4 thrombocytopenia. Additional G3 toxicities included hypertension, hyperbilirubinemia, and hypertransaminasemia. No grade≥3 AEs occurred at Level 1. PK analysis of REG showed a significant reduction (p=0.038) in the AUC, with a geometric mean ratio of 80% (CI9064–98%) when given with TMZ. PK analysis of TMZ showed a slight but significant reduction in the Cmax and AUC (p=0.003 and 0.015, respectively) when given with REG. This suggest a weak PK interaction. CONCLUSION The MTD of REG for cohort A was 160mg, and for cohort B 120mg with a weak PK interaction between the two drugs. The MTD of 120mg can be considered the recommended dose of REG in combination with standard Stupp therapy for the phase 2 study. Preliminary activity analyses are ongoing.