Phase I/II study of VAL-083 in patients with recurrent malignant glioma or progressive-secondary brain tumor

Kent Shih 1, Jeffrey A. Bacha2, Dennis Brown2, William J. Garner2, Anne Steino2, Richard Schwart2, Sarath Kanekal2, Mike Li2, Lorena Lopez2, Howard A. Burris, III3
1Tenesse Oncology, Nashville,TN, USA, 2DelMar Pharmaceuticals, Vancouver, BC, Canada, 3Sarah Cannon Research Institue, Nashville, TN, USA

BACKGROUND: Median survival for patients with recurrent glioblastoma multiforme (GBM) is approximately 6-months. O6-methylguanine-DNA-methyltransferase (MGMT) chemo-resistance has been implicated in poor outcomes for GBM patients following front-line temozolomide therapy.VAL-083 is a bi-functional DNA alkylator that crosses the blood-brain barrier with preferential accumulation in brain tumor tissue. VAL-083 demonstrated activity against a range of tumor-types, including GBM, in historical studies. Moreover, VAL-083 overcomes chemo-resistance by MGMT in vitro. OBJECTIVE: To determine the safety, tolerability, pharmacokinetics, anti-tumor activity, and characterize appropriate dosing regimen in patients with recurrent GBM or progressive-secondary brain tumor. METHOD: Open-label, single-arm Phase I/II dose-escalation study in patients with histologically-confirmed initial diagnosis of malignant GBM or progressive-secondary brain tumor. The study utilizes a 3+3 dose-escalation design. Patients receive VAL-083 i.v. on days 1, 2, and 3 of a 21 day cycle. GBM patients have previously been treated with surgery and/or radiation, if appropriate, and must have failed both bevacizumab and temozolomide, unless contraindicated. Secondary brain tumor patients have failed standard brain radiotherapy with tumor progression after at least one line of systemic therapy. RESULTS (ONGOING):  Cohorts 1 through 3 were completed, with an expansion of cohort 3 ongoing. No drug-related serious adverse events (SAEs) were detected, and maximum tolerated dose (MTD) not reached. 25% (2/8) of evaluable GBM and 16.7% (1/6) of evaluable progressive-secondary brain tumor patients show stable disease or tumor-regression at doses investigated to date. Pharmacokinetic analyses show dose-dependent increase in exposure. NOTES: Due to prior chemotherapy and radiation therapy, patients with secondary brain tumors are likely more prone to myelosuppression and may have a different MTD. Therefore, the trial will be split i) GBM and ii) progressive-secondary brain tumors, so that the MTD and impact of MGMT-driven chemoresistance can be assessed in GBM, while separately exploring the potential for treating solid-tumor brain metastases. Identifier: NCT01478178