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

摘要

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: {"type":"clinical-trial","attrs":{"text":"NCT00884416","term_id":"NCT00884416"}}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 C _(max) of TMZ and its metabolite 5-amino-imidazole-4-carboxamide (AIC). T _(max) 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.