Phase I dose-escalation, safety, and CNS pharmacokinetic study of dexanabinol in patients with brain cancer. Issue 1 (15th February 2021)

• Record Type: Journal Article
• Authors: Juarez, Tiffany M; Piccioni, David; Rose, Lara; Nguyen, Angel; Brown, Bradley; Kesari, Santosh
• Is Part Of: Neuro-oncology advances. Volume 3:Issue 1(2021)
• Publication Date: 2021-02-15
• Subjects: brain cancer -- cerebrospinal fluid drug exposure -- dexanabinol -- NFκB -- tetrahydrocannabinol; 616.99481
• DOI: 10.1093/noajnl/vdab006
• Languages: English
• ISSNs: 2632-2498

Abstract

Abstract: Background: Dexanabinol is a synthetic analogue of tetrahydrocannabinol identified as a potential anti-cancer therapeutic by e-Therapeutics PLC. Dexanabinol was selected for further investigation based on its preclinical tumoricidal activity. This phase I dose-escalation trial examined the safety, drug penetration into the central nervous system (CNS), preliminary antitumor activity, and recommended phase II dose. Methods: Dexanabinol formulated in cremophor/ethanol was administered once weekly via 3-hour intravenous infusion to patients with brain cancer. Results: A total of 26 patients were dosed once weekly at 2, 4, 8, 16, 24, 28, and 36 mg/kg. Two patients at 36 mg/kg were nonevaluable for dose level confirmation, having withdrawn early for reasons unrelated to study treatment. A recommended phase II dose of dexanabinol was established at 28 mg/kg due to related, reversible adverse events at higher dose levels that required medications for symptomatic relief. The most common drug-related toxicities were the depressed level of consciousness and lightheadedness, diarrhea, itching, fatigue, chest discomfort, and tingling in the mouth. Systemic exposure to dexanabinol (AUC0- t and C max ) increased from 2 to 36 mg/kg, with dose nonproportionality apparent at the highest dose; dexanabinol was present in appreciable levels in the cerebrospinal fluid (CSF), which implies the possibility of exposure of intracranial tumors to drug. Five of 24 efficacy-evaluable patients (21%) experienced stable disease with a median duration of 2 cycles (28-day cycle) as the best response. Conclusions: Dexanabinol administered weekly by intravenous infusion was safe and well-tolerated up to 28 mg/kg in brain cancer patients, but has limited antitumor activity in patients with brain cancer.