Abstract CT167: Phase II study of dianhydrogalactitol (VAL-083) in patients with bevacizumab-naive recurrent glioblastoma, MGMT-unmethylated
Authors: O'Brien Barbara J. , Groot John De , Kamiya-Matsuoka Carlos , Weathers Shiao-Pei , Bacha Jeffrey A. , Brown Dennis M. , Steino Anne , Langlands John , Schwartz Richard , Kanekal Sarath , Lopez Lorena , Penas-Prado Marta 
Published: August 2018

Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard of care includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) and maintenance TMZ. The vast majority of GBM patients experience recurrent/progressive disease within a year from initial diagnosis, and median survival after recurrence is 3-9 months. Effective therapies for recurrent GBM (rGBM) are lacking and these patients have a dismal prognosis, representing a significant unmet medical need. Unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT), a validated biomarker for TMZ-resistance, is strongly correlated with TMZ-resistance. Second-line treatment with the anti-angiogenic agent bevacizumab has not improved survival and 5-year survival is less than 3%. VAL-083 is a bi-functional DNA-targeting agent rapidly inducing interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell-death. VAL-083's cytotoxicity is independent of MGMT status in vitro and VAL-083 overcomes TMZ-resistance in GBM cell lines, GBM cancer stem cells and in vivo GBM models. We completed a 3:3 dose-escalation trial of VAL-083 in TMZ- and bevacizumab-refractory rGBM. 40mg/m2/day given on days 1, 2, and 3 of a 21-day cycle was well-tolerated with 6% grade 3 or 4 thrombocytopenia. This dose was selected for further clinical development in a pivotal Phase 3 study in TMZ- and bevacizumab-refractory rGBM. The trial described here is an ongoing single-arm, biomarker-driven Phase 2 clinical trial in MGMT-unmethylated bevacizumab-naïve adult rGBM. 48 patients will receive VAL-083 40mg/m2/day on days 1, 2, and 3 of a 21-day cycle. Tumor response will be assessed by MRI approximately every 42 days, according to RANO criteria. The primary objective of this study is to determine if VAL-083 improves overall survival (OS) for MGMT-unmethylated rGBM patients compared to a historical median survival control of 7.2 months for MGMT-unmethylated rGBM patients treated with lomustine (Wick et al, EORTC26101). Secondary efficacy endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and to evaluate the occurrence of symptoms and to evaluate quality of life (QOL) measures during the progression-free period using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) self-reporting tool. Enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT02717962.
Citation Format: Barbara J. O'Brien, John De Groot, Carlos Kamiya-Matsuoka, Shiao-Pei Weathers, Jeffrey A. Bacha, Dennis M. Brown, Anne Steino, John Langlands, Richard Schwartz, Sarath Kanekal, Lorena Lopez, Marta Penas-Prado. Phase II study of dianhydrogalactitol (VAL-083) in patients with bevacizumab-naive recurrent glioblastoma, MGMT-unmethylated [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT167.