Study of VAL-083 in Patients With MGMT Unmethylated, Bevacizumab-naive Glioblastoma in the Adjuvant or Recurrent Setting

Recurrent GBM is characterized by a dismal prognosis, with a median overall survival of 6.9 months. While a standard of care is established for the initial treatment of GBM - radiation with concurrent and adjuvant temozolomide chemotherapy - management of recurrent disease (NCCN, 2014) remains suboptimal. Treatment options include repeat surgery, re-irradiation, or chemotherapy (including experimental targeted therapies, biologic agents, and immunotherapies). Only a minority of patients has response to these treatments, and the resultant benefits in progression-free and overall survival are in the order of weeks to months. Prognosis and response to therapy are known to be better in patients with a methylated MGMT promoter gene. Epigenetic silencing of MGMT by promoter methylation is an important factor in predicting outcome for patients with GBM treated with temozolomide. Approximately 66% of GBM tumors are MGMT unmethylated (high expression of MGMT), which through a MGMT repair mechanism, confers resistance to temozolomide, the standard chemotherapy treatment of GBM. VAL-083, Dianhydrogalactitol (DAG), unlike temozolomide, is demonstrated to be active independent of MGMT resistance mechanisms, in vitro. Thus, it may provide a treatment option for those patients that are considered likely to be poor responders to temozolomide. This is a non-comparative, two arm, biomarker-driven study with VAL-083 in GBM patients with either recurrent disease (Group 1) or newly diagnosed GBM patients requiring maintenance therapy after chemoradiation with temozolomide (Group 2). Group 1: A total of up to 83 patients with recurrent/progressive GBM will be enrolled. This will include 35 patients treated at 40 mg/m2 and up to 48 patients treated at 30 mg/m2. Group 2: Up to an additional 36 newly diagnosed GBM patients who have completed chemoradiation treatment with temozolomide and received no subsequent maintenance temozolomide will be enrolled. Eligible patients will receive VAL-083 IV on days 1, 2, and 3, for up to 12, 21-day treatment cycles or until they fulfill one of the criteria for study discontinuation (disease progression, death, intolerable toxicities, investigator's judgment, or withdrawal of consent). Disease status will be evaluated with clinical and MRI evaluation every other 21-day cycle, while the patient is receiving VAL-083 treatment, and then approximately every 42 ± 7 days while remaining on study. Symptom burden will be evaluated using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) completed by patients at baseline and at the time of each imaging evaluation. Interval medical histories, targeted physical exams, neurologic evaluations, complete blood counts, and other laboratory and safety assessments will be performed approximately every 21-days. Blood samples will be taken at Cycle 1 Day 1 pre-dose, 15 ± 5 min, 30 ± 5 min, 60 ± 10 min, 120 ± 10 min, 240 ± 15 min, and 360 ± 15 min after the end of the of iv infusion with VAL-083 to determine the PK profile and dose-exposure relationship of VAL-083. Toxicity will be evaluated and documented using the NCI CTCAE version 4. This study will take approximately 36 months to enroll.