P11.41.B PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM: CASE STUDY REPORTS

Abstract

Abstract BACKGROUND VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. In vitro and in vivo studies have demonstrated VAL-083 circumvents MGMT-mediated chemoresistance and differentiates it from other therapies used in the treatment of GBM, including temozolomide (TMZ). VAL-083 also acts as a radiosensitizer against GBM cancer stem cells in vitro. MATERIAL AND METHODS A Phase 2 study was conducted to evaluate the safety and tolerability of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM following surgical resection. Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days in combination with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 with RT. RESULTS A total of 29 patients were enrolled in the study and completed treatment, with 25 patients receiving 30 mg/m2/day VAL-083. The median number of cycles completed by all patients was 9 (range 2-13). Consistent with our prior experience, myelosuppression was the most common adverse event. In a sub-group of patients, levels of VAL-083 in CSF were found to be at least as high as those in plasma. At study completion, the median progression free survival (PFS) for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. Here we report on two patient cases. The first, a 32-yo woman, WHO Gr. 4 GBM (MGMT unmethylated), who received conventional radiotherapy with concurrent chemotherapy with VAL-083 followed by adjuvant VAL-083, for a total of 13 cycles of VAL-083. This patient is tumor free suvival more than 4 years till last follow-up (Mar 2023 ). The second, a 49-yo man, WHO Gr. 4 GBM (MGMT unmethylated), who received radiotherapy with concurrent chemotherapy with VAL-083 followed by adjuvant VAL-083, for a total of 12 cycles of VAL-083. Two years after initial treatment with VAL-083 was discontinued, a new lesion was found, and the patient had a second resection, which revealed WHO Gr. 3 astrocytoma. The patient was re-treated with VAL-083,and was stable till last follow-up(Mar 2023). CONCLUSION The results from the study and these patient cases, support the potential benefit of VAL-083 as a treatment alternative against GBM tumors with MGMT-mediated resistance to TMZ. Clinicaltrials.gov: NCT03050736.