A phase I trial of concurrent sorafenib and stereotactic radiosurgery for patients with brain metastases

We hypothesized that sorafenib (BAY 43-9006), an oral multi-kinase inhibitor, used in combination with SRS will improve overall intracranial control. This Phase I study assesses the safety, tolerability, and maximal tolerated dose of sorafenib administered with SRS to treat 1-4 brain metastases. This was an open label phase I dose escalation study with an expansion cohort. Eligible adults had 1-4 brain metastases from solid malignancies. Sorafenib was begun 5-7 days prior to SRS and continued for 14 days thereafter. Dose escalation of sorafenib was conducted via a "3 + 3" dose escalation design. Dose limiting toxicities (DLT) were determined 1 month after SRS and defined as ≥grade 3 neurologic toxicities. Twenty-three patients were enrolled. There were no DLTs at dose level 1 (400 mg per day) or dose level 2 (400 mg twice per day). An expansion cohort of 17 patients was treated at dose level 2. There were six grade 3 toxicities: hypertension (n = 2), rash (n = 1), lymphopenia (n = 1), hypokalemia (n = 1), fatigue (n = 1) and hand-foot syndrome (n = 1). All of these were attributable to sorafenib and not to the combination with SRS. The median time to CNS progression was 10 months, 1 year CNS progression-free survival was 46%, the median overall survival was 11.6 months and the 1 year overall survival was 46%. The use of sorafenib concurrent with SRS for the treatment of 1-4 brain metastases is safe and well tolerated at 400 mg twice a day. Our recommended phase II dose of concurrent sorafenib with SRS would be 400 mg twice daily.