Abstract BACKGROUND Regorafenib (REG) is an oral multikinase inhibitor. 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), and preliminary activity of this combination. MATERIAL AND METHODS This phase 1 multicenter academic study used a “3 + 3” design to evaluate REG doses of 80 mg (Level 1), 120 mg (Level 2), 160 mg (Level 3) in 2 different cohorts of pts with histological diagnosis of MGMT-methylated, IDH wt 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 52 ys) had a DLT at any dose. One pt in Level 2 had REG delayed and TMZ dose reduced due to grade (G) 2 thrombocytopenia; at Level 1 and 2, one G3 haematological toxicity, respectively; at Level 3, one pt had a G3 gastrointestinal toxicity. In cohort B, 12 pts were enrolled (median age 53 ys); 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 one case of G3 hypertransaminasemia were also reported. REG was reduced in another pt due to G2 pain (no DLT); at Level 2 there was one 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% (CI90 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%(CI90 57 - 91%) and 86% (CI90 79 - 92%), respectively. These results suggest a weak PK interaction between the two drugs. CONCLUSION The MTD of REG for cohort A was 160 mg, for cohort B 120mg with a weak PK interaction between the two drugs. The MTD of 120 mg can be considered the recommended dose of REG in combination with standard Stupp therapy for the phase 2 study. Preliminary activity analyses are ongoing.
Padovan et al. (Wed,) studied this question.
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