Clinical trials of VAL-083 in patients with chemo-resistant glioblastoma.

Abstract

TPS2082 Background: Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard of care includes surgery, radiation and treatment with temozolomide (TMZ), however nearly all tumors recur and the prognosis for recurrent GBM is dismal. Most GBM tumors have unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT); a validated biomarker for TMZ-resistance. Second-line treatment with anti-angiogenic agent bevacizumab has not improved overall survival (OS) and 5-year survival is less than 3%. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent targeting N7-Guanine and inducing interstrand DNA cross-links, double-strand breaks and cell death in GBM cell lines and GBM cancer stem cells, independent of MGMT status in vitro. VAL-083 readily crosses the blood-brain barrier and accumulates in brain tumor tissue. Our recent phase I/II clinical trial in recurrent GBM patients failing both TMZ and bevacizumab, suggested that VAL-083 offers clinically meaningful survival benefits for patients with recurrent GBM and pinpointed a new dosing regimen (40 mg/m2/d on days 1,2,3 of a 21-day cycle) which was well-tolerated and was selected for study in subsequent GBM trials. Methods: These trials include i) an ongoing single-arm, biomarker driven, Phase 2 study to determine if VAL-083 treatment of MGMT-unmethylated adult GBM patients at first recurrence/progression, prior to bevacizumab improves overall survival at 9 months, compared to historical control with lomustine (clinicaltrials.gov identifier: NCT02717962). ii) A pivotal Phase 3 study in recurrent GBM after failing both TMZ and bevacizumab. The control arm will consist of a limited number of salvage chemotherapies currently used in bevacizumab-failed GBM. If successful, this study will serve as the basis for a New Drug Application (NDA) submission for VAL-083. iii) A single arm, biomarker driven, Phase 2 study to confirm the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high MGMT levels. The results of these studies may support a new treatment paradigm in chemotherapeutic regimens for the treatment of GBM. Clinical trial information: NCT02717962.