Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma

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 deter...

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Bibliographic Details
Published in:British journal of cancer 2014-05, Vol.110 (11), p.2655-2661
Main Authors: HOTTINGER, A. F, AISSA, A. B, BODMER, A, DIETRICH, P.-Y, ESPELI, V, SQUIBAN, D, DUNKEL, N, VARGAS, M. I, HUNDSBERGER, T, MACH, N, SCHALLER, K, WEBER, D. C
Format: Article
Language:English
Subjects:
Adult
Aged
Angiogenesis
Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Antineoplastic Combined Chemotherapy Protocols - toxicity
Biological and medical sciences
Brain cancer
Brain Neoplasms - mortality
Brain Neoplasms - therapy
Cancer therapies
Cell cycle
Cell growth
Chemoradiotherapy
Clinical Study
Dacarbazine - administration & dosage
Dacarbazine - analogs & derivatives
Disease-Free Survival
Drug dosages
Female
Glioblastoma - mortality
Glioblastoma - therapy
Humans
Kinases
Male
Maximum Tolerated Dose
Medical prognosis
Medical research
Medical sciences
Middle Aged
Neurology
Niacinamide - administration & dosage
Niacinamide - analogs & derivatives
Oncology
Patients
Pharmacokinetics
Phenylurea Compounds - administration & dosage
Radiation therapy
Sorafenib
Temozolomide
Treatment Outcome
Tumors
Tumors of the nervous system. Phacomatoses
Vascular endothelial growth factor
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Summary: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. 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). 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). 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.
ISSN:0007-0920
1532-1827
DOI:10.1038/bjc.2014.209