The inhibitor of apoptosis (IAP) family of anti-apoptotic proteins has been identified as a target for small molecule inhibitors in cancer. SMAC (Second Mitochondrial-derived Activator of Caspases) efficiently and naturally antagonizes IAPs, and preclinical studies have determined that SMAC mimetics have potent anti-cancer properties. Here we report a first-in-human trial designed to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics/pharmacodynamics (PK/PD) of birinapant, a novel SMAC mimetic. Patients with advanced solid tumors or lymphoma were enrolled in a 3+3 dose escalation design with birinapant administered intravenously from 0.18 to 63 mg/m2 once weekly every three of four weeks. Fifty patients were enrolled to 12 dose cohorts. Birinapant 47 mg/m2 was determined to be the maximum tolerated dose (MTD). At 63 mg/m2 dose limiting toxicities (DLT) included headache, nausea, and vomiting. Two cases of Bell's palsy (Grade 2) also occurred at 63 mg/m2. Birinapant had a plasma half-life of 30-35 hours and accumulated in tumor tissue. Birinapant suppressed cIAP1, and increased apoptosis in PBMC and tumor tissue. Prolonged stable disease was observed in 3 patients :non-small cell lung cancer (5 months), colorectal cancer (5 months), and liposarcoma (9 months). Two patients with colorectal cancer had radiographic evidence of tumor shrinkage. In conclusion, birinapant was well-tolerated with MTD of 47 mg/m2 and exhibited favorable PK and PD properties. Several patients demonstrated stable disease and evidence of anti-tumor activity. These results support the ongoing clinical trials of birinapant in patients with cancer.
- Received June 8, 2015.
- Revision received August 5, 2015.
- Accepted August 18, 2015.
- Copyright © 2015, American Association for Cancer Research.