NKTR-102, a novel PEGylated-irinotecan, demonstrates reduced gastrointestinal and hematopoietic toxicity compared to irinotecan with repeat dosing in dogs

5741 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 this study was to evaluate the repeat dose toxicity of NKTR-102 compared to irinotecan in dogs, and to determine the pharmacokinetic profile of the active metabolite SN38 upon repeat dosing. Methods: Groups of 6 dogs were administered doses of 20 or 25 mg/kg irinotecan-equivalent doses of either NKTR-102 or irinotecan as 1-hour intravenous infusions on Days 1, 8, 15, and 22. Clinical pathology and histopathology were performed and animals were observed for clinical signs of toxicity. Serial pharmacokinetic blood samples were collected and analyzed for the parent compound and metabolites including SN38. Routine non-compartmental analysis was used to estimate pharmacokinetic parameters. Results: At 20 mg/kg NKTR-102, neutropenia was absent. At 25 mg/kg NKTR-102, minimal neutropenia was observed 11 days after dosing in 50% of animals, with spontaneous resolution by Day 22. In both irinotecan dose groups, marked neutropenia was observed as early as 4 days in greater than 50% of animals with no apparent resolution by Day 22. At 20 mg/kg, diarrhea was less frequent in NKTR-102-treated (33%) relative to irinotecan-treated dogs (83%). At 25 mg/kg, the frequency of diarrhea (87.5%) was the same between test articles, but dogs treated with irinotecan exhibited bloody diarrhea (29%) and diarrhea lasting greater than three days (72%) while dogs treated with NKTR-102 did not. Hematopoietic hypocellularity in the bone marrow was minimal in 3/6 dogs treated with 25 mg/kg NKTR-102 but moderate to severe in 4/6 dogs treated with an equivalent dose of irinotecan. The maximum tolerated dose (MTD) for repeated doses of NKTR-102 was 25 mg/kg and less than 20 mg/kg for irinotecan. Pharmacokinetic estimates of SN38 AUC were approximately four fold greater in dogs treated with NKTR-102 when compared to dogs treated with equivalent irinotecan doses at both 20 and 25 mg/kg. Conversely, SN38 Cmax values were approximately one fifth lower in dogs treated with NKTR-102 when compared to dogs treated with equivalent irinotecan doses.
 Conclusions: NKTR-102 exhibits a 25% increase in MTD relative to irinotecan. At 20 mg/kg NKTR-102, no neutropenia and a 60% decrease in incidence of diarrhea were observed relative to the same dose of irinotecan. Compared to similar doses of irinotecan, NKTR-102 achieved a five-fold lower SN38 Cmax, and was associated with lower gastrointestinal and hematopoietic toxicities with a concurrent four-fold increase in exposure (AUC).