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.
Year: 2025
Type: conference-abstract
Abstract: 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 .
Source: Journal of Clinical Oncology
Authors: Marta Padovan, Matteo Simonelli, Amedeo De Nicolò, Paola Del Bianco, Giulia Cerretti, Mario Caccese, Pasquale Persico, Giorgia Menegatti, Alberto Bosio, Angelo Dipasquale, Marta Maccari, Agnese Losurdo, Marina Coppola, Marco Krengli, Sara Lonardi, Antonio D'Avolio, Gian Luca De Salvo, Giuseppe Lombardi
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4410816729