Phase I study evaluating the safety, tolerability, and pharmacokinetics (PK) of HGS1029, a small-molecule inhibitor of apoptosis protein (IAP), in patients (pts) with advanced solid tumors.

Abstract

2580 Background: Overexpression of IAPs confers protection against a number of proapoptotic stimuli in a variety of tumors. XIAP, the best characterized IAP family member, binds to and inhibits the activation of caspase 9, so targeting caspase activation through the inhibition of IAP function may be an anticancer strategy. HGS1029 is an IAP inhibitor designed to directly kill tumor cells. XIAP inhibition by small molecules has been associated with loss of cIAP-1, a potential pharmacodynamic (PD) marker. Methods: To evaluate the safety, tolerability, and PK profile of HGS1029, given as a 15 min IV infusion on days 1, 8, and 15 of a 28-day cycle, in pts with relapsed or refractory advanced solid malignancies. Results: 27 pts (12 females, 15 males) with a median age of 63 years (range: 42-79 years) have been enrolled in 7 cohorts (0.1, 0.2, 0.4, 0.6, 0.9, 1.4, and 2.1 mg/m2). At 1.4 mg/m2, 1 pt experienced DLTs of grade (Gr) 3 AST, Gr3 amylase, Gr4 lipase, and Gr3 fatigue after receiving the first dose of HGS1029. All events recovered quickly without clinical sequelae and no further DLTs were observed. The most frequent Gr1 to Gr2 adverse events (AEs), judged to be at least possibly related to HGS1029, include nausea (37%), diarrhea (22%), anorexia (19%), vomiting (19%), fatigue (15%), and pyrexia (7%). HGS1029 produced a dose-dependent short-lived lymphocytopenia and possibly a transient neutrophilia. In addition to the DLTs described above, 2 Gr3 AEs were considered to be at least possibly related to HGS1029: elevated INR and supraventricular tachycardia. Preliminary PK analysis indicates that PK are linear over the dose range tested with a similar profile between single vs. multiple dosing. At 1.4 mg/m2, the elimination of HGS1029 follows a three-compartment model with a terminal half life of 4.8 hrs and no apparent accumulation of HGS1029 in the plasma between the doses. cIAP-1 loss in PBMC's occurred rapidly at each dose level. The decrease in cIAP-1 levels was related to the dose. Conclusions: The administration of HGS1029 has been well tolerated in pts with advanced malignancies and the MTD has not been reached. Accrual to this study continues. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Human Genome Sciences Human Genome Sciences Human Genome Sciences