NKTR-102, a novel PEGylated irinotecan, results in sustained tumor growth suppression in mouse models of human colorectal and lung tumors that correlates with increased and sustained tumor SN38 exposure Free

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Purpose NKTR-102, a novel polyethylene glycol (PEG)-irinotecan conjugate, is in Phase I clinical development. During preclinical development, the relationship between drug and metabolite pharmacokinetics and tumor growth was investigated in xenograft mouse models of HT29 human colorectal tumor, which is moderately resistant to irinotecan treatment, and NCI-H460 human lung tumor.
 Methods In separate studies, mice implanted subcutaneously with either cell line received 40 mg/kg irinotecan (Irino)-equivalent IV doses of Irino or NKTR-102 every 4 days for 3 doses after measurable tumors had developed. Tumor size was measured and plasma and tumor tissue were sampled serially at planned times for 60 and 30 days in HT-29 and H460 cell lines, respectively. Plasma and tumor samples were assayed for NKTR-102, Irino, and SN38 (the principal active metabolite of Irino) using a sensitive, selective, and validated LC/MS-MS method.
 Results NKTR-102 caused marked, statistically significant decreases in both HT-29 and H460 tumor growth, whereas Irino at the same dose and schedule resulted in only modest suppression of tumor growth that was short lived.
 Median HT-29 tumor weights (mg) at end of study were 3553 for Irino and 674 for NKTR-102 (p<0.0001 less than Irino by ANOVA), with a NKTR-102/Irino ratio of 0.19. Median H460 tumor weights (mg) at end of study were 3579 for Irino and 1601 for NKTR-102 (p<0.0001 less than Irino by ANOVA), with a NKTR-102/Irino ratio of 0.44. The 2- to 5-fold greater suppression of tumor growth after NKTR-102 was attributable to substantially greater and prolonged tumor exposure to SN38.
 Day-1 SN38 AUC values (ug/g*d or ug/mL*d) in mice implanted with HT-29 cells were 0.01 and 0.03 for Irino in plasma and tumor, respectively, and 5.8 and 11.7 for NKTR-102 in plasma and tumor, respectively. Day-1 SN38 AUC values (ug/g*d or ug/mL*d) in mice implanted with H460 cells were 0.2 and 0.18 for Irino in plasma and tumor, respectively, and 2.6 and 10.5 for NKTR-102 in plasma and tumor, respectively. NKTR-102/Irino AUC ratios in plasma and tumor were 580 and 390, respectively, for the HT-29 cell line, and 13 and 58, respectively, for the H460 cell line.
 NKTR-102 SN38 tumor AUC values were 2- to 4-fold greater than those in plasma, indicating accumulation in tumor tissue. Ratios of NKTR-102/Irino AUC values indicate that clearance of SN38 from both cell line tumors is significantly reduced compared to that of Irino, resulting in greater SN38 exposure at the site of action.
 PK/PD models relating tumor SN38 conc-time data to relative tumor weight for both cell lines were developed and used as an aide to selecting doses and dosing frequency for Phase I.
 Conclusions NKTR-102 results in greatly suppressed tumor growth in mouse models of human colorectal and lung tumors that correlates with increased and sustained tumor SN38 exposure compared to Irino at equivalent dose and schedule. The potential benefit of this profile for NKTR-102 is being investigated in clinical studies.