ATNT-13A PHASE I DOSE ESCALATION AND CENTRAL NERVOUS SYSTEM (CNS) PHARMACOKINETIC STUDY OF DEXANABINOL IN PATIENTS WITH BRAIN CANCER
| Autor: | Minya Pu, Tiffany Juarez, Lara Rose, Santosh Kesari, Bradley D. Brown, Angel Nguyen, David Piccioni, Karen Messer |
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| Rok vydání: | 2015 |
| Předmět: |
Drug
Cancer Research Lightheadedness business.industry media_common.quotation_subject Cmax Pharmacology chemistry.chemical_compound Oncology Pharmacokinetics chemistry Tolerability Anesthesia medicine Itching Neurology (clinical) medicine.symptom Dexanabinol Adverse effect business Abstracts from the 20th Annual Scientific Meeting of the Society for Neuro-Oncology media_common |
| Zdroj: | Neuro-Oncology. 17:v13.1-v13 |
| ISSN: | 1523-5866 1522-8517 |
| DOI: | 10.1093/neuonc/nov205.13 |
| Popis: | 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 NFκB, 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 antitumor 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 lightheadedness 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-∞ 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. |
| Databáze: | OpenAIRE |
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