CTNI-15. REGORAFENIB IN COMBINATION WITH TEMOZOLOMIDE WITH OR WITHOUT RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED MGMT-METHYLATED, IDH WILDTYPE GLIOBLASTOMA: A PHASE I DOSE-FINDING STUDY (REGOMA-2)

Glioblastoma (GBM) has activation of multiple signaling pathways in the tumor microenvironment, including the receptor tyrosine kinases, VEGFR, FGFR and PDGFR. The potential response to anti-angiogenic agents makes GBM an attractive target for regorafenib (REG). Antitumor activity of REG in recurrent GBM patients was shown in the REGOMA trial. Interestingly, in “in vivo” studies, beneficial effects were observed with the combination of REG and temozolomide (TMZ) in subcutaneously xenografts. This phase I open-label multicentric study will evaluate the addition of REG to standard of care treatment with TMZ as adjuvant therapy (cohort A), and in combination with TMZ+RT as concomitant therapy (cohort B), in newly diagnosed MGMT-methylated, IDH wildtype GBM patients. Primary objectives are: to determine the safety and tolerability of REG and to establish the maximum tolerated dose (MTD) of REG in those two cohorts. Secondary objectives are: assessment of pharmacokinetics of REG, TMZ and possible pharmacokinetic interactions between TMZ and REG (cohort A); assessment of preliminary antitumor activity; evaluation of quality of life during the treatment. The dose escalation will be explored according to a “3 + 3” design, starting from cohort A and following 3 dose levels of REG [80 mg, 120 mg and 160 mg; level -1 40 mg will be evaluated in case of Dose-Limiting Toxicity (DLT) during REG 80 mg]. After finding the MTD in cohort A, the cohort B dose escalation will start, exploring escalating oral doses of REG in combination with concomitant TMZ+RT (60 Gy/30 fractions); in the adjuvant phase of cohort B, REG will be given (in association to TMZ) at MTD shown in the prior adjuvant phase dose escalation.The DLT evaluation period will be two cycles from the start of cycle 1 of adjuvant or from day 1 to last day of the concomitant phase. Approximately 36 subjects will be enrolled.