Abstract CT273: Phase 2 trial of dianhydrogalactitol (VAL-083) in patients with newly diagnosed MGMT-unmethylated glioblastoma
Authors: Chen Zhong-ping , Guo Cheng-cheng , Yang Qun-ying , Lei Jia-Wei , Wu Shao-xiong , Johnson Gregory , Langlands John , Kwan Claire , Kanekal Sarath , Schwartz Richard , Bacha Jeffrey A. , Steino Anne , Brown Dennis M. 
Published: September 2020

Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery followed by chemoirradiation and temozolomide (TMZ). An unmethylated promoter for O6-methylguanine DNA methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is strongly correlated with poor outcomes. The majority of glioblastoma multiforme (GBM) patients have an unmethylated MGMT promoter status, leading to limited response to TMZ and decreased survival. Dianhydrogalactitol (VAL-083) is a novel bi-functional DNA targeting agent that induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated drug-resistance and has demonstrated cytotoxicity in MGMT-unmethylated GBM cell lines, cancer stem cells (CSCs) and in vivo models. Furthermore, VAL-083 acts as a radiosensitizer in GBM CSCs and non-CSCs. A Phase 2, open-label, biomarker-driven, study has been initiated to evaluate the tolerability and efficacy of VAL-083 in combination with radiation therapy (RT) in newly diagnosed MGMT-unmethylated GBM patients. A treatment regimen, consisting of a 6-week induction period of VAL-083 given IV at 20, 30, or 40 mg/m2/day x 3 days every 21 days and concurrent radiation (2 Gy daily, 5 days/week) followed by up to 24 weeks of maintenance therapy with single-agent VAL-083, is being evaluated. The study has 2 stages: Stage 1 is a dose-escalation and induction format to establish a recommended dose of VAL-083 when administered concurrently with RT based on safety and tolerability. The dose escalation stage has been completed and we identified a recommended dose of 30 mg/m2/day of VAL-083 in combination with RT as generally safe and well-tolerated. Stage 2 comprises an expansion stage to enroll up to 20 additional patients at 30 mg/m2/day IV infusion on days 1, 2, and 3 of 21-day cycles and is currently ongoing. Tumor response will be assessed by MRI, according to RANO criteria. Efficacy endpoints include progression-free survival (PFS) and overall survival (OS). Additional endpoints include safety evaluations and pharmacokinetic assessments of plasma and CSF samples. As of 21st January 2020, 19 subjects have initiated treatment in stage 2. The enrollment, safety data and primary results update will be provided at the meeting. Clinicaltrials.gov identifier: NCT03050736.
Citation Format: Zhong-ping Chen, Cheng-cheng Guo, Qun-ying Yang, Jia-Wei Lei, Shao-xiong Wu, Gregory Johnson, John Langlands, Claire Kwan, Sarath Kanekal, Richard Schwartz, Jeffrey A. Bacha, Anne Steino, Dennis M. Brown. Phase 2 trial of dianhydrogalactitol (VAL-083) in patients with newly diagnosed MGMT-unmethylated glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT273.