Abstract CT168: Phase I/II study of dianhydrogalactitol (VAL-083) with radiation therapy in patients with newly diagnosed glioblastoma, MGMT-unmethylated
Authors: Chen Zhong-ping , Guo Chengcheng , Bacha Jeffrey , Steino Anne , Langlands John , Kwan Claire , Kanekal Sarath , Schwartz Richard , Lopez Lorena , Brown Dennis M. 
Published: August 2018

Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery followed by concomitant chemo-radiation and adjuvant temozolomide (TMZ). Unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT), a validated biomarker for TMZ-resistance, is strongly correlated with TMZ-resistance. In addition, defective DNA mismatch repair (MMR) has been identified as a secondary mechanism of TMZ resistance. MGMT-unmethylated tumors represent a majority of newly diagnosed GBM patients demonstrating significantly inferior progression free and overall survival compared to MGMT-methylated GBM patients. VAL-083 is a first-in-class bi-functional DNA-targeting agent that has shown activity against GBM in NCI-sponsored clinical trials both as a single agent and in combination with radiotherapy. VAL-083 rapidly induces interstrand DNA cross-links at N7-guanine, leading to persistent DNA double-strand breaks and cell death in GBM cell lines and GBM cancer stem cells (CSCs). VAL-083's unique cytotoxic mechanism circumvents MGMT-mediated chemoresistance and maintains cytotoxic activity in cancer cells deficient in MMR. Furthermore, VAL-083 acts as a radiosensitizer in GBM CSCs and non-CSCs, in vitro. We completed a 3:3 dose-escalation trial of VAL-083 in temozolomide- 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 bevacizumab refractory rGBM. The present trial is an ongoing open-label, biomarker-driven, Phase 1/2 study to evaluate the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients. A treatment regimen, consisting of a 6-week induction period of VAL-083 and concurrent radiation (2 Gy given daily, 5 days/week) followed by up to 24 weeks of adjuvant maintenance therapy with single-agent VAL-083, is being evaluated as an alternative to standard-of-care in MGMT-unmethylated GBM. The study is being conducted in two parts: 1) a dose-escalation part (20, 30, and 40 mg/m2/day IV infusion on days 1, 2, and 3 of a 21-day cycle) in up to 10 patients, to assess safety and activity of VAL-083 when administered concurrently with radiation therapy; 2) an expansion phase, in which VAL-083 will be studied in up to 20 additional patients at the determined well-tolerated dose. 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 (when available). Enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT03050736.
Citation Format: Zhong-ping Chen, Chengcheng Guo, Jeffrey Bacha, Anne Steino, John Langlands, Claire Kwan, Sarath Kanekal, Richard Schwartz, Lorena Lopez, Dennis M. Brown. Phase I/II study of dianhydrogalactitol (VAL-083) with radiation therapy in patients with newly diagnosed 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 CT168.