Dogs are more sensitive to antagonists of inhibitor of apoptosis proteins than rats and humans: a translational toxicokinetic/toxicodynamic analysis.
3008 Background: IAPs are key regulators of cancer cell survival, which makes them appealing targets for cancer therapy. HGS1029 is a small molecule IAP inhibitor which directly kills tumor cells as a single-agent or in combination. METHODS The safety, PK and PD (various cytokines and apoptotic markers) of HGS1029, given as a 15 min IV infusion with Schedule (Sch) A (Day 1, 8 and 15 every 28D) and then Sch B (continuous weekly) were evaluated in pts with advanced solid tumors. RESULTS 44 pts (20 females, 24 males) with a median age of 62 years (range: 41-88) have been enrolled in 10 cohorts (Sch A: 0.1, 0.2, 0.4, 0.6, 0.9, 1.4, 2.1 and 3.2 mg/m2; Sch B: 3.2 and 4.8 mg/m2). Dose-limiting toxicities (DLTs) were observed in 1/9 pts at 1.4 mg/m2 (Grade (G) 3 AST, G3 amylase, G4 lipase, and G3 fatigue) and in 2/6 pts at 4.8 mg/m2 (G3 fatigue, prolonged asymptomatic G4 amylase and lipase). The most frequent adverse events (typically mild to moderate in severity), reported to be at least possibly related to HGS1029, include nausea (33%), anorexia (21%), pyrexia (21%), vomiting (19%), diarrhea (17%), fatigue (17%), and rash (12%). HGS1029 produced a dose-dependent short-lived lymphocytopenia and a transient neutrophilia. Confirmed tumor regression has been observed in a pretreated pt with colon cancer and 2 pts (NSCLC, adrenocortical carcinoma) had stable disease for > 6 months. Plasma HGS1029 concentration-time profiles suggest a linear PK across the dose range. At ≥ 1.4 mg/m2, the disposition of HGS1029 follows a 3 compartment model with a terminal half life ≥ 4.8 hrs. The levels of cIAP-1, an IAP family member, were profoundly reduced in PBMC's after a single administration of HGS1029. The greatest elevations of the cytokine MCP-1 were observed in the highest dose cohorts. Two-fold increases in baseline M30 levels, indicating a possible apoptotic response, were also observed in the serum of several pts. CONCLUSIONS HGS1029 has been well tolerated in pts with advanced solid malignancies. DLTs include severe fatigue, elevated amylase and lipase. Based on this favorable safety profile, combination studies with mapatumumab and chemotherapies are warranted.