REGOMA: A Randomized, Multicenter, Controlled Open-Label Phase II Clinical Trial of Regorafenib Compared to Lomustine in Relapsed Glioblastoma Patients

Background: Glioblastoma is a highly vascularized tumor and currently there are limited treatment options at recurrence. Regorafenib is an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases. We report the results of the first randomized, phase 2 study of regorafenib in recurrent glioblastoma. Methods: REGOMA was a randomized, multicenter, open-label phase 2 trial undertaken in 10 hospitals in Italy. Eligible patients with histologically confirmed glioblastoma, Eastern Cooperative Oncology Group performance status 0 or 1, and documented disease progression after temozolomide chemoradiotherapy were randomly assigned 1:1 by a web-based system and stratified by center and surgery at recurrence to receive regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle or lomustine 110 mg/m2 once every 6 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall survival in the intention-to-treat population. Findings: Between November 27, 2015 and February 23, 2017, 124 patients were screened and 119 patients were randomized to receive regorafenib (n=59) or lomustine (n=60﴿. Median follow up was 15∙4 months (IQR 13∙818∙1). Regorafenib improved overall survival with a hazard ratio of 0∙50 (95%CI 0∙33-0∙75; log-rank test p=0∙0007); median overall survival was 7∙4 months (95%CI 5∙8-12∙0) in the regorafenib group and 5∙6 months (95%CI 4∙7-7∙3) in the lomustine group. Grade 3-4 treatment-related adverse events occurred in 33 (56%) of 59 patients treated with regorafenib and 24 (40%) of 60 with lomustine. The most frequent grade 3 or 4 adverse events related to regorafenib were hand-foot skin reaction (10%), lipase increased (10%), and blood bilirubin increased (10%). No death was considered drug-related. Clinical Trial Number: The trial was not overseen by a data monitoring committee and was registered in the Clinical Trials Register data base with the number 2014003722-41 and in ClinicalTrials.gov with number NCT02926222. Funding Statement: Istituto Oncologico Veneto was the sponsor of this academic study. Bayer S.p.A. Italy provided partial financial support and provided regorafenib free of charge for all patients randomized to the regorafenib arm. Bayer S.p.A. Italy had no role in the design of the study, data collection, or analysis. Bayer provided editorial assistance and had the right to review the report before publication. The corresponding author had the final responsibility for the decision to submit for publication on behalf of all the authors. Declaration of Interests: Veneto Institute of Oncology received a grant from Bayer SpA to partially support the study conduction; GL received personal fees from Bayer SpA, outside the submitted work; GL, GLDS, SI are co-inventors in a pending patent application broadly relevant to this work; BD reports personal fees and non-financial support from Bayer, personal fees and non-financial support from BMS, personal fees from IPSEN, personal fees from EISAI, personal fees from Lilly, personal fees from MSD, personal fees from Merck Kga, non-financial support from Sanofi, outside the submitted work; VZ reported personal fees and other from Bristol-Mayers Squibb, other from Celgene, non-financial support and other from Merck, personal fees and non-financial support from Bayer, personal fees and non-financial support from Roche, personal fees from Pfizer, personal fees from Janssen, personal fees from Novartis, personal fees from Astellas, personal fees from Servier, outside the submitted work. All other authors declare no competing interests. Ethics Approval Statement: (Missing clear governing body approval statement - clinic/committee names?) All participating centers were required to obtain written approval of the study from their local authorities and ethics committees. All patients had to sign an informed consent form approved by the Ethical Committee of the enrolling institution according to national regulations. The study was conducted according to the Declaration of Helsinki and the Good Clinical Practice guidelines. Central data management, data base development, statistical analysis, site monitoring, safety management and trial management were performed by the Clinical Trial Unit of the Veneto Institute of Oncology (Padua, Italy). The REGOMA trial was registered in the EU Clinical Trials Register (EU-CTR), one of the Primary Registries meeting the ICMJE requirements. This registration was performed before patient enrolment and specifically was a pre-requisite to obtain approval from our Competent Authority (AIFA) and Ethics Committee.