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.