A phase I trial of mFOLFOX6 combined with the oral PI3K inhibitor BKM120 in patients with advanced refractory solid tumors.

PURPOSE: The oral PI3K inhibitor BKM120 has been reported as safe and well tolerated in early phase clinical trials of advanced cancer patients. We performed a phase I trial of BKM120 plus mFOLFOX6 (5-FU/LV + oxaliplatin), a common chemotherapeutic backbone in GI malignancies, to establish the maximum tolerated dose (MTD) and characterize the safety and tolerability of the combination.
METHODS: Patients with advanced solid tumors received oral BKM120 daily combined with standard doses of mFOLFOX6 every 2 weeks of a 28 day cycle. The study utilized a standard 3 + 3 dose escalation schema.
RESULTS: A total of 17 patients received treatment with BKM120, 13 of which were evaluate for dose limited toxicity (DLT). The most common tumor types were colorectal cancer, cholangiocarcinoma, pancreatic cancer and hepatocellular carcinoma. DLT included grade 3 hyperglycemia, grade 3 AST/ALT elevation, grade 4 neutropenia and grade 4 thrombocytopenia. A total of 76 % of patients experienced treatment related grade 3/4 adverse events (AEs), the most common of which were neutropenia, fatigue, leukopenia, hyperglycemia and thrombocytopenia. One patient demonstrated an unconfirmed partial response and three patients had stable disease. DISCUSSION: The MTD of BKM120 in combination with standard doses of mFOLFOX6 was 40 mg daily, which is well below the 100 mg daily dose proven effective and tolerable both as a single agent and in combination with other chemotherapeutics. In addition, the regimen of BKM120 with mFOLFOX6 in patients with refractory solid tumors resulted in increased toxicity than would be expected from either the PI3K inhibitor or the chemotherapy backbone alone.