ATNT-13A PHASE I DOSE ESCALATION AND CENTRAL NERVOUS SYSTEM (CNS) PHARMACOKINETIC STUDY OF DEXANABINOL IN PATIENTS WITH BRAIN CANCER

Abstract

BACKGROUND: Dexanabinol is a synthetic analogue of tetrahydrocannabinol previously developed as a neuroprotector and subsequently identified through a network pharmacology platform as a potential anti-cancer therapeutic by e-Therapeutics PLC. Dexanabinol was selected for further investigation based on its tumoricidal activity observed in vitro and in vivo, presumably due to inhibitory activity against NFkB, COX-2, and TNFα. This phase I dose-escalation trial examines the safety of multiple dosing of dexanabinol and drug penetration into the central nervous system in patients with brain cancer. METHODS: Patients having failed prior therapy or having no further available standard therapies and Karnofsky Performance Score of ≥ 60% were included. Dose escalation was performed using a'3 + 3' design. Patients received weekly dexanabinol via an intravenous infusion. The objectives were to determine the safety, tolerability, recommended phase 2 dose, pharmacokinetics, and anti-tumor activity. RESULTS: 26 patients have been enrolled at escalating doses of dexanabinol (range 2 to 36 mg/kg). Two patients at the highest dose level were non-evaluable for dose tolerability and no dose limiting toxicities occurred in this study. Dose escalation was stopped due to emerging data in another clinical study (ETS2101-001). To date, adverse events attributed to dexanabinol were grades 1 or 2 and consisted of a depressed level of consciousness and light headedness in 3/26 pts; diarrhea and itching in 2/26 pts; fatigue, chest discomfort and tingling in mouth in 1/26 pts. From 2 to 36 mg/kg, systemic exposure to dexanabinol (AUC0-1 and Cmax) increased greater than dose proportionately; dexanabinol was present in appreciable levels in the CSF, which implies the possibility of exposure of intracranial tumors to drug. Four of 24 efficacy-evaluable patients (17%) experienced stable disease with median duration of two cycles (28-day cycle) as best response. CONCLUSIONS: Dexanabinol was safe and well-tolerated warranting continued investigation. A Phase 1b program with dexanabinol is planned.