Abstract CT168: Phase I/II study of dianhydrogalactitol (VAL-083) with radiation therapy in patients with newly diagnosed glioblastoma, MGMT-unmethylated

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.