Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma
| Autor: | Thomas Hundsberger, Dietrich Py, N. Dunkel, A. Ben Aissa, Maria Vargas, Andreas F. Hottinger, Karl Lothard Schaller, Vittoria Espeli, Nicolas Mach, D. Squiban, Damien C. Weber, A Bodmer |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Oncology
Male Cancer Research medicine.medical_treatment Pharmacology urologic and male genital diseases radiation therapy tyrosine kinase inhibitor Antineoplastic Combined Chemotherapy Protocols heterocyclic compounds ddc:616 Glioblastoma/mortality/therapy Brain Neoplasms Chemoradiotherapy Middle Aged Sorafenib Brain Neoplasms/mortality/therapy female genital diseases and pregnancy complications Phase i study Dacarbazine Treatment Outcome Female Corrigendum high-grade glioma medicine.drug Adult Niacinamide medicine.medical_specialty Niacinamide/administration & dosage/analogs & derivatives Maximum Tolerated Dose ddc:616.0757 pharmacokinetic study Disease-Free Survival Glioma Internal medicine medicine Temozolomide Humans neoplasms Aged business.industry Phenylurea Compounds medicine.disease digestive system diseases ddc:616.8 First line treatment Radiation therapy Phenylurea Compounds/administration & dosage Clinical Study Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics/therapeutic use/toxicity Dacarbazine/administration & dosage/analogs & derivatives business Glioblastoma |
| Zdroj: | British Journal of Cancer, vol. 110, no. 11, pp. 2655-2661 British Journal of Cancer British Journal of Cancer, Vol. 110, No 11 (2014) pp. 2655-2661 |
| ISSN: | 0007-0920 |
| Popis: | BACKGROUND: Sorafenib (Sb) is a multiple kinase inhibitor targeting both tumour cell proliferation and angiogenesis that may further act as a potent radiosensitizer by arresting cells in the most radiosensitive cell cycle phase. This phase I open-label, noncontrolled dose escalation study was performed to determine the safety and maximum tolerated dose (MTD) of Sb in combination with radiation therapy (RT) and temozolomide (TMZ) in 17 patients with newly diagnosed high-grade glioma. METHODS: Patients were treated with RT (60 Gy in 2 Gy fractions) combined with TMZ 75 mg m(-2) daily, and Sb administered at three dose levels (200 mg daily, 200 mg BID, and 400 mg BID) starting on day 8 of RT. Thirty days after the end of RT, patients received monthly TMZ (150-200 mg m(-2) D1-5/28) and Sb (400 mg BID). Pharmacokinetic (PK) analyses were performed on day 8 (TMZ) and on day 21 (TMZ&Sb) (Clinicaltrials ID: NCT00884416). RESULTS: The MTD of Sb was established at 200 mg BID. Dose-limiting toxicities included thrombocytopenia (two patients), diarrhoea (one patient) and hypercholesterolaemia (one patient). Sb administration did not affect the mean area under the curve(0-24) and mean Cmax of TMZ and its metabolite 5-amino-imidazole-4-carboxamide (AIC). Tmax of both TMZ and AIC was delayed from 0.75 (TMZ alone) to 1.5 h (combined TMZ/Sb). The median progression-free survival was 7.9 months (95% confidence interval (CI): 5.4-14.55), and the median overall survival was 17.8 months (95% CI: 14.7-25.6). CONCLUSIONS: Although Sb can be combined with RT and TMZ, significant side effects and moderate outcome results do not support further clinical development in malignant gliomas. The robust PK data of the TMZ/Sb combination could be useful in other cancer settings. |
| Databáze: | OpenAIRE |
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