Abstract CT217: Phase I/II study of dianhydrogalactitol in patients with recurrent malignant glioblastoma multiforme
Authors: Shih Kent C. , Patel Manish R. , Butowski Nicholas , Bacha Jeffrey A. , Brown Dennis M. , Steino Anne , Schwartz Richard , Kanekal Sarath , Lopez Lorena M. , Burris Howard A. 
Published: August 2015

Abstract
Glioblastoma multiforme (GBM) is the most common and deadly form of human brain cancer. Median survival for patients with recurrent GBM is &lt;6 months. Front-line systemic therapy is temozolomide, but resistance due to O6-methylguanine-DNA-methyltransferase (MGMT) activity is implicated in poor prognoses. Dianhydrogalactitol (VAL-083) is a structurally unique bi-functional DNA alkylating agent that crosses the blood-brain barrier and accumulates in brain tumor tissue. In recent in vitro studies, VAL-083 overcame resistance to MGMT and demonstrated cytotoxic activity against GBM cell lines, as well as GBM cancer stem cells, and was shown to act as a radiosensitizer. Previous clinical trials suggest that VAL-083 has activity against a range of tumors, including GBM. In light of extensive safety data and promising efficacy in CNS tumors, we initiated a new phase I/II clinical study to establish the maximum tolerated dose (MTD) using an optimized dosing scheme. The goal of the current clinical trial is to determine an appropriate dose for advancement into registration trials as a potential new therapy for the treatment of refractory GBM.
Historical NCI-sponsored studies in GBM achieved promising results with limited toxicity using a dosing regimen of 25mg/m2/day for five days every five weeks. The present dosing regimen utilizes a daily dose for three days every three weeks. Seven cohorts have completed the current trial with no drug-related serious adverse events: MTD was not yet reached at 40mg/m2/day; 50mg/m2/day is being studied and higher doses may be explored. Compared to historical trials, the present regimen delivers substantively more drug as measured by Cmax and dose density. A dose density of 25 mg/m2/week in combination with radiation was previously shown superior to radiation alone against GBM; a dose density of 50 mg/m2/week is being enrolled in the current trial. Pharmacokinetic analyses show dose-dependent linear systemic exposure with a short plasma 1-2h terminal half-life; Cmax at 40mg/m2 in the current trial ranged from 1130-739ng/mL (7.7-5.1μM). Calculated CNS tissue concentrations, based on the plasma concentrations, exceed concentrations known to be effective against glioma cell lines in vitro. Methods: Open-label, single-arm phase I/II dose-escalation study in patients with histologically-confirmed initial diagnosis of primary WHO Grade IV malignant glioma (glioblastoma). Patients enrolled have previously been treated with surgery and/or radiation, if appropriate, and must have failed both bevacizumab and temozolomide, unless contraindicated. The study utilizes a 3+3 dose-escalation design. Patients receive VAL-083 IV on days 1, 2, and 3 of a 21-day cycle. Tumor response is assessed according to RANO criteria prior to every other 21-day treatment cycle, and patients exhibiting stable disease or tumor regression are allowed to remain on study drug. ClinicalTrials.gov Identifier NCT01478178.
Citation Format: Kent C. Shih, Manish R. Patel, Nicholas Butowski, Jeffrey A. Bacha, Dennis M. Brown, Anne Steino, Richard Schwartz, Sarath Kanekal, Lorena M. Lopez, Howard A. Burris. Phase I/II study of dianhydrogalactitol in patients with recurrent malignant glioblastoma multiforme. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT217. doi:10.1158/1538-7445.AM2015-CT217