A phase 1, first-in-human study of regorafenib plus temozolomide with or without radiotherapy in patients with newly diagnosed MGMT methylated, IDHwt glioblastoma: The REGOMA-2 trial.

2068 Background: Regorafenib (REG) is an oral multikinase inhibitor and in vivo studies demonstrated a synergistic antitumor effect when combined with radiotherapy (RT) and temozolomide (TMZ) against glioblastoma (GBM). We conducted a phase 1 study to evaluate the safety, dose limiting toxicity (DLT), maximum tolerated dose (MTD) of REG, pharmacokinetics (PK), preliminary activity of this combination. Methods: This phase 1 multicenter academic study used a "3 + 3" design to evaluate REG doses of 80mg (Level 1), 120mg (Level 2), 160mg (Level 3) in 2 different cohorts of pts with histologic diagnosis of MGMT-methylated, IDHwt GBM (WHO 2021) and ECOG PS 0-1. In cohort A, pts who completed the concurrent chemoradiotherapy (CT-RT) regimen received REG in combination with standard maintenance TMZ; cohort B received REG concurrently with standard CT-RT and continued REG with maintenance TMZ. REG was administered according to the standard schedule of 3 weeks on/1 week off. The DLT evaluation period for cohort A was during the first two maintenance cycles and for cohort B during the concurrent CT-RT phase. During the DLT period, blood and clinical assessments were performed weekly. Toxicity was assessed by CTCAE v 5.0. RANO criteria were used for neuroradiologic assessment. Pharmacokinetics (PK) was also evaluated. Results: In cohort A, none of the 9 pts enrolled (median age 52ys) had a DLT at any dose; 1 pt in Level 2 had REG delayed and TMZ dose reduced due to grade (G) 2 thrombocytopenia. At Level 1 and 2, 1 G3 haematological toxicity, respectively. At Level 3, 1 pt had a G3 gastrointestinal toxicity. In cohort B, 12 pts were enrolled (median age 53ys); at Level 3, 2 of 6 pts reported a DLT (n=1 G3 hypertransaminasemia with a dose reduction of REG (51%) and TMZ (50%) and n=1 G4 thrombocytopenia at the last day of RT). One case of G3 hypertension and 1 case of G3 hypertransaminasemia were also reported. REG was reduced in another pt due to G2 pain (no DLT); at Level 2 there was 1 case of G3 hyperbilirubinemia. There were no G3-4 AEs at Level 1. PK analysis of REG alone or in combination with TMZ showed a significant reduction (P=0.038) in the AUC, with a geometric mean ratio (GMR) of 80% (CI 90 64 – 98%) when given together 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, with GMR of 72% (CI 90 57 – 91%) and 86% (CI 90 79 – 92%), respectively. These results suggest a weak PK interaction between the two drugs. Conclusions: The MTD of REG for cohort A was 160mg, 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. Clinical trial information: NCT06095375 .