NKTR-102, a novel PEGylated-irinotecan, has a superior acute safety and tolerability profile compared to irinotecan in rats and dogs

5742 Purpose: NKTR-102, a novel PEGylated-irinotecan, is currently in Phase 2 clinical development as a second-line colorectal cancer therapy. Prior non-clinical studies demonstrate that adding a PEG moiety to irinotecan results in sustained tumor growth inhibition that is associated with an increase in SN38 exposure secondary to extended disposition and metabolism of NKTR-102. The purpose of these studies was to evaluate the acute single dose toxicity of NKTR 102 compared to irinotecan in rats and dogs.
 Methods: Groups of 6 to 12 rats were administered 30-minute intravenous infusions of either NKTR-102 (PEG-irinotecan) or irinotecan at a target dose range of 30 to 120 mg/kg. Endpoints included mortality, clinical observations, clinical chemistry, hematology and histopathology. Groups of 2 dogs were given 30- to 60-minute intravenous infusions at target dose ranges from 6 to 60 mg/kg NKTR-102 (irinotecan equivalents) or 6 to 30 mg/kg irinotecan.
 Results: In rats, the maximum tolerated dose (MTD) was 90 mg/kg for NKTR-102 and 60 mg/kg for irinotecan. Within the dose ranges evaluated, no neutropenia was noted for either NTKR-102 or irinotecan. Diarrhea was not observed for NKTR-102, whereas diarrhea occurred in 50% of rats receiving irinotecan at 90 or 120 m/kg. In dogs, the MTD was 40 mg/kg for NKTR-102 and 20 mg/kg for irinotecan. Leukopenia occurred at 6 mg/kg irinotecan, but only at doses of 30 mg/kg and greater of NKTR-102. Severe (bloody) diarrhea occurred at 30 mg/kg irinotecan, but only at doses of 60 mg/kg and greater of NKTR-102.
 Conclusions: The MTD of NKTR-102 was 33% and 50% greater than that of irinotecan in rats and dogs, respectively. In dogs, the onset of neutropenia was at a five-fold higher dose of NKTR-102 relative to irinotecan. Similarly, the onset of severe diarrhea in dogs was at a two-fold higher dose of NKTR-102 relative to irinotecan. The findings in rats were consistent with the improved acute safety profile for NKTR-102 relative to irinotecan observed in dogs.