About the Trial
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.
Patients will undergo safety assessments including physical examinations, vital signs, hematology, serum chemistry, and urinalysis.
In both parts of the study, a pharmacokinetic study may be conducted at treatment Cycle 1 Day 1, in consenting patients. For patients consenting to CSF collection by lumbar puncture, a CSF sample will be obtained after completion of the Cycle 1, Day 3 VAL-083 infusion. These patients will also have a blood sample taken for VAL-083 plasma level after completion of drug infusion.
Response parameters will be evaluated according to the Response Assessment in NeuroOncology (RANO).