Abstract 4672: Phase I/II study of val-083 in patients with recurrent malignant glioma or secondary brain tumor.
Authors: Brown Dennis M. , Bacha Jeffrey A. , Garner William J. , Shih Kent C. , Burris Howard A. , Schwartz Richard 
Published: August 2014

Abstract
Background: Recurrent glial tumors of the brain remain one of the most challenging malignancies to treat. Median survival for patients with recurrent disease is approximately 6 months for glioblastoma multiforme (GBM), as front-line therapy temozolomide (TMZ) is subject to resistance by DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). VAL-083 represents a first-in-class bi-functional N7 DNA alkylating agent that readily crosses the blood-brain barrier and accumulates in brain tissue. Previously published pre-clinical and clinical studies suggest that VAL-083 has activity against a range of tumor types, including GBM. Furthermore, research shows that VAL-083 overcomes MGMT-driven drug resistance in vitro and has activity against cancer stem cells. Hence, the purpose of this Phase I/II study is to determine the safety and the maximal tolerated dose (MTD) of VAL-083 in patients with recurrent GBM or progressive secondary brain tumor, and to explore the pharmacokinetic properties and tumor responses to treatment.
Objectives Part 1:
1) Establish the dose-limiting toxicities (DLT) of VAL-083 and identify appropriate dose and dosing regimen of VAL-083
2) Assess the safety and characterize the toxicities associated with VAL-083
3) Collect information about anti-tumor activity of VAL-083
Objectives Part 2:
4) Confirm the safety and tolerability of the chosen dose/dosing regimen in a larger number of patients
5) Obtain preliminary evidence of anti-tumor activity in GBM, as measured by response rate and progression free survival
Methods: An open-label, single arm Phase I/II dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity of VAL-083 in patients with i) histologically confirmed initial diagnosis of primary WHO Grade IV malignant GBM, now recurrent, or ii) progressive secondary brain tumor, having failed standard brain radiotherapy, and with brain tumor progression after at least one line of systemic therapy. The study utilizes a 3 + 3 dose escalation design, until the MTD or the maximum specified dose is reached. Patients receive VAL-083 intravenously at the assigned dose on days 1, 2, and 3 of each 21-day treatment cycle. In Phase II, additional patients will be treated at the MTD (or other selected optimum Phase II dose) to measure tumor responses. All patients enrolled have previously been treated with surgery and/or radiation, if appropriate, and must have failed both bevacizumab and TMZ, unless contraindicated. Results (study ongoing): Cohort 1 (3 patients) and cohort 2 (4 patients) were completed without reaching DLT and no drug-related adverse effects (AEs) were detected. 28.5% (2/7 patients) show stable disease or tumor regression in response to VAL-083 treatment as assessed by regular MRI scans and check-ups. Cohort 3 currently has 1 patient enrolled without reaching DLT. ClinicalTrials.gov Identifier: NCT01478178
Citation Format: Dennis M. Brown, Jeffrey A. Bacha, William J. Garner, Kent C. Shih, Howard A. Burris, Richard Schwartz. Phase I/II study of val-083 in patients with recurrent malignant glioma or secondary brain tumor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4672. doi:10.1158/1538-7445.AM2013-4672