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 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.
1] Clinical Research Unit of the Foundation Dr Henri Dubois Ferriére Dinu Lipatti & Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland [2] Department of Clinical Neurosciences & Oncology, CHUV University Hospital and University of Lausanne, Lausanne, Switzerland.
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Hottinger
Clinical Research Unit of the Foundation Dr Henri Dubois Ferriére Dinu Lipatti & Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
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Ben Aissa
Clinical Research Unit of the Foundation Dr Henri Dubois Ferriére Dinu Lipatti & Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
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Espeli
Clinical Research Unit of the Foundation Dr Henri Dubois Ferriére Dinu Lipatti & Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
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Squiban
Clinical Research Unit of the Foundation Dr Henri Dubois Ferriére Dinu Lipatti & Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
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Dunkel
Department of Neuroradiology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
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Vargas
Department of Neurology and hematology/oncology, Cantonal Hospital St Gallen, St Gallen, Switzerland.
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Hundsberger
Clinical Research Unit of the Foundation Dr Henri Dubois Ferriére Dinu Lipatti & Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
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Mach
Department of Neurosurgery Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
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Schaller
1] Clinical Research Unit of the Foundation Dr Henri Dubois Ferriére Dinu Lipatti & Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland [2] Department of Radio-oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
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Weber
Clinical Research Unit of the Foundation Dr Henri Dubois Ferriére Dinu Lipatti & Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
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Bodmer
Clinical Research Unit of the Foundation Dr Henri Dubois Ferriére Dinu Lipatti & Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
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Dietrich
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D001932:Brain Neoplasms / Q000401:mortality / Q000628:therapy*; D059248:Chemoradiotherapy; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000401:mortality / Q000628:therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D000077157:Sorafenib; D000077204:Temozolomide; D016896:Treatment Outcome
D010671:Phenylurea Compounds; D009536:Niacinamide; D003606:Dacarbazine; D000077157:Sorafenib; D000077204:Temozolomide