Phase I dose-escalation study with extended daily administration of Debio1143, an oral inhibitor of apoptosis protein inhibitor, in patients with solid tumors.

Abstract

2531 Background: Inhibitors of apoptosis proteins (IAPs) play a critical role in modulating multiple processes, including caspases activation and NF-κB signaling. Because high expression of IAPs represent a frequent oncogenic event in human cancers, therapeutic targeting of IAPs is considered as a promising approach. The small molecule Debio 1143 is a potent orally-active IAP antagonist able to promote apoptosis in tumour cells by restoring caspase activity, and modulating NF-κB signaling and TNFα effects in various preclinical models. A shorter schedule of Debio1143 (daily x 5, every 21 days) was well tolerated in cancer patients up to 900 mg QD. Methods: Oral Debio1143 was administered to patients with advanced solid tumors according to a novel extended schedule: daily x 14, every 21 days. The starting dose was 200 mg QD. The MTD was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). Serial blood samples and urine were collect on cycle 1 for PK and PD assessm...