Safety Study of VAL-083 and Radiotherapy in Patients With Newly Diagnosed GBM Having Unmethylated MGMT Expression

Malignant gliomas are the most common primary central nervous system tumors found in adults, with WHO Grade IV malignant glioma (GBM) representing the most aggressive and prevalent sub-type of these tumors having one of the worst 5-year survival rates among all human cancers.

Standard therapy for patients with malignant gliomas has traditionally involved maximal surgical resection/debulking of the primary tumor (if feasible), followed by adjuvant radiotherapy over 6-8 weeks, with or without chemotherapy. The oral alkylating agent temozolomide was found to increase median survival when used in combination with radiotherapy, compared to radiotherapy alone, in patients with newly diagnosed GBM. However, expression of O6-methylguanine methyltransferase (MGMT) in GBM has been linked to poor patient outcome in patients treated with temozolomide.

The study drug, dianhydrogalactitol (VAL 083) is a bi-functional N7 DNA alkylating agent which has demonstrated cytotoxic activity that is independent of chemo-resistance due to expression of MGMT. This makes VAL-083 an ideal candidate to treat patients who are unlikely to respond to temozolomide due to MGMT expression in their GBM. Furthermore, VAL-083 acted as a radio-sensitizer at low (1 - 2.5μM) concentrations in all GBM cultures tested.

VAL-083 has been studied extensively in the United States by the National Cancer Institute. The NCI studies suggested that VAL-083 appeared to have activity in some types of cancer (lung and brain), including GBM; however, further VAL-083 research was not pursued in the US due to an increased focus on targeted biologic therapies during that era. VAL-083 has also been studied in the People's Republic of China, where it is currently approved and marketed for treatment of chronic myeloid leukemia and lung cancer. At present, VAL-083 is being studied in clinical trials in the United States as a third-line treatment option for patients with recurrent GBM following failure of surgery, radiation therapy, temozolomide and bevacizumab. Interim results support safety of VAL-083 in this population; to date, a regimen of 40mg/m2/d x 3 days IV in a 21 day cycle has been confirmed to be safe and well tolerated.

This phase 2, open-label, single arm study will be conducted in a dose-escalation cohort scheme to confirm the optimal dose of VAL-083, when administered concurrently with radiation therapy. Dose escalation will proceed in three sequential cohorts, consisting of patients receiving VAL-083 at 20, 30 and 40 mg/m2/d x 3 every 21 days.

This trial will be conducted in 2 parts. Part 1 will consist of 1) a 42-day induction period, during which patients will receive VAL-083 while undergoing radiation treatment at a dose of 2 Gy per fraction given once daily five days per week (Monday through Friday) over a period of six weeks (for a total dose of 60 Gy), followed by 2) adjuvant maintenance therapy with VAL-083 alone, administered daily x 3 IV every 3 weeks at the same assigned dose, for a maximum of 8 maintenance cycles. Part 2 will comprise an expansion phase, in which VAL-083 will be studied in up to 20 additional subjects. The dose of VAL-083 that will be studied in Part 2 will be determined from Part 1.