Sorafenib administered using a high-dose, pulsatile regimen in patients with advanced solid malignancies
| Autor: | Lemonitsa H. Mammatas, Henk M.W. Verheul, Richard Honeywell, Godefridus J. Peters, C W Menke-van der Houven van Oordt, E L Swart, M Rovithi, A S Zandvliet |
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| Přispěvatelé: | Medical oncology, Clinical pharmacology and pharmacy, CCA - Cancer Treatment and quality of life, Medical oncology laboratory |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Sorafenib Male Cancer Research medicine.medical_specialty Drug-Related Side Effects and Adverse Reactions Perforation (oil well) Cmax Phases of clinical research High dose Toxicology Gastroenterology Drug Administration Schedule 03 medical and health sciences Pulsatile Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2] 0302 clinical medicine All institutes and research themes of the Radboud University Medical Center Internal medicine Neoplasms medicine Humans Pharmacology (medical) Protein Kinase Inhibitors Pharmacology Dose-Response Relationship Drug business.industry Standard treatment Area under the curve Middle Aged Drug monitoring digestive system diseases Regimen 030104 developmental biology Treatment Outcome Oncology Pulse Therapy Drug 030220 oncology & carcinogenesis Area Under Curve Toxicity Phase I clinical trial Cola Original Article Female business medicine.drug |
| Zdroj: | Cancer Chemotherapy and Pharmacology, 85, 5, pp. 931-940 Cancer Chemotherapy and Pharmacology Cancer Chemotherapy and Pharmacology, 85(5), 931-940. Springer Verlag Cancer Chemotherapy and Pharmacology, 85, 931-940 Mammatas, L H, Zandvliet, A S, Rovithi, M, Honeywell, R J, Swart, E L, Peters, G J, Menke-van der Houven van Oordt, C W & Verheul, H M W 2020, ' Sorafenib administered using a high-dose, pulsatile regimen in patients with advanced solid malignancies : a phase I exposure escalation study ', Cancer Chemotherapy and Pharmacology, vol. 85, no. 5, pp. 931-940 . https://doi.org/10.1007/s00280-020-04065-5 |
| ISSN: | 0344-5704 |
| DOI: | 10.1007/s00280-020-04065-5 |
| Popis: | Background (Pre)clinical evidence is accumulating that intermittent exposure to increased doses of protein kinase inhibitors may improve their treatment benefit. In this phase I trial, the safety of high-dose, pulsatile sorafenib was studied. Patients and methods High-dose sorafenib was administered once weekly in exposure escalation cohorts according to a 3 + 3 design. Drug monitoring was performed in weeks 1–3 and doses were adjusted to achieve a predefined target plasma area under the curve (AUC)(0–12 h). The effect of low gastric pH on improving sorafenib exposure was investigated by intake of the acidic beverage cola. Results Seventeen patients with advanced malignancies without standard treatment options were included. Once weekly, high-dose sorafenib exposure was escalated up to a target AUC(0–12 h) of 125–150 mg/L/h, achieving a twofold higher Cmax compared to standard continuous dosing. Dose-limiting toxicity was observed in three patients: grade 3 duodenal perforation (2800 mg sorafenib), grade 5 multiorgan failure (2800 mg sorafenib) and grade 5 biliary tract perforation (3600 mg sorafenib). The mean difference between observed and target AUC(0–12 h) was 45% (SD ± 56%) in week 1 using a fixed starting dose of sorafenib compared to 2% (SD ± 32%) in week 3 as a result of drug monitoring (P = 0.06). Dissolving sorafenib in cola, instead of water, did not improve sorafenib exposure. Clinical benefit with stable disease as the best response was observed in two patients. Conclusion Treatment with high-dose, once weekly sorafenib administration resulted in dose-limiting toxicity precluding dose escalation above the exposure cohort of 125–150 mg/L/h. Drug monitoring was a successful strategy to pursue a target exposure. |
| Databáze: | OpenAIRE |
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