Phase I dose-escalation, safety, and CNS pharmacokinetic study of dexanabinol in patients with brain cancer
| Autor: | Tiffany Juarez, Angel Nguyen, David Piccioni, Lara Rose, Santosh Kesari, Bradley D. Brown |
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| Rok vydání: | 2021 |
| Předmět: |
Lightheadedness
Clinical Trials and Supportive Activities Clinical Investigations Cmax dexanabinol 01 natural sciences 03 medical and health sciences chemistry.chemical_compound tetrahydrocannabinol 0302 clinical medicine Pharmacokinetics Clinical Research medicine AcademicSubjects/MED00300 NF kappa B 030212 general & internal medicine 0101 mathematics Adverse effect Dexanabinol Tetrahydrocannabinol Cancer brain cancer business.industry 010102 general mathematics Neurosciences Evaluation of treatments and therapeutic interventions Symptomatic relief cerebrospinal fluid drug exposure chemistry Anesthesia 6.1 Pharmaceuticals Itching AcademicSubjects/MED00310 medicine.symptom business medicine.drug NFκB |
| Zdroj: | Neuro-oncology advances, vol 3, iss 1 Neuro-oncology Advances |
| Popis: | 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 Two patients at 36 mg/kg were nonevaluable for dose level confirmation, having withdrawn early for reasons unrelated to study treatment.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 Cmax) 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. |
| Databáze: | OpenAIRE |
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