Amaravadi et al, 2015 Molecular Cancer Therapeutics
Phase 1 study of Birinapant, a novel SMAC mimetic. Inhibitors of apoptosis (IAP) proteins suppress apoptosis and activate TNF. Overexpression of IAP contributes to tumor chemotherapy resistance. SMAC binds to IAP causing them to degrade and apoptosis to occur in tumor cells.
This is the first human study of birinapant. In 50 adults this drug was well tolerated with main side effects of headache, nausea and vomiting. These were patients with relapsed or refractory colorectal, head and neck, lung, and pancreatic cancers, soft tissue sarcomas and melanomas aged 31-58. The regimen was given iv q 3 weeks, with good PK and PD profile. Transient cytokine release syndrome seen at doses which exceeded the MTD. Stable disease and anti-tumor activity was noted.
*Further studies will look at combination with other chemotherapy (particularly as it can overcome resistance), and is in phase 2 trials for MDS and ovarian cancer.