Actr-06. Clinical Trial of Val-083 in Newly Diagnosed MGMT-Unmethylated Gbm: Half-Way Report

Abstract

Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated methylguanine DNA-methyltransferase (MGMT gene, which confers a limited response to standard of care treatment with temozolomide (TMZ) resulting in a lower survival. 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 repair of the O6 guanine alkylator TMZ. A Phase 2 study has been initiated for VAL-083 in newly diagnosed MGMT unmethylated GBM. The study has 2 stages: Stage 1 is a dose-escalation and induction format to confirm the recommended dose of VAL-083 when administered concurrently with radiation therapy (RT) based on safety and tolerability. The subjects received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days along with standard radiation treatment. Stage 2 comprises an expansion phase to enroll up to 30 patients. The dose escalation stage is complete and 30 mg/m2/day of VAL-083 in combination with RT was generally safe and well-tolerated. As of 17 May, 2019, 18 patients have been enrolled. Fifteen patients have completed their prospectively planned MRI scans and had their initial assessment for tumor progression. Of these 15 patients, seven were assessed as a complete response (CR), and eight patients as having stable disease (SD). Of the remaining three patients, one died prior to their post-cycle 3 MRI and two have not been on study long enough to reach their planned post-cycle 3 MRI. As of the data cutoff, 14 of the 18 patients were still alive. Consistent with our prior experience, myelosuppression was the most common adverse event. Three dose-limiting toxicities have been reported - one at the 40 mg/m2/day and two at the 30 mg/m2/day dose. Further enrollment, safety & study updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT03050736.

Updates in IDH-Wildtype Glioblastoma

“…It is a bifunctional alkylating agent that introduces interstrand-crosslinks at the N 7 -guanine sites that are resistant to MGMT and induces cytotoxicity independent of the MMR pathway [ 181 – 184 ]. Dose-escalation data from a phase I/II clinical trial [ 185 , 186 ] have shown that doses in the range of 30–40 mg/m 2 /day (IV for 3 days in a 21-day cycle) are well tolerated and active in both methylated and unmethylated disease. Currently, it is being evaluated in the GBM AGILE trial (see later) in newly diagnosed methylated and unmethylated patients as well as in recurrent disease.…”