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Abstract 5151: Nanoliposomal irinotecan (nal-IRI, MM-398) has greater anti-tumor activity than topotecan and irinotecan in mouse models of small cell lung cancer

伊立替康 拓扑替康 医学 喜树碱 药理学 活性代谢物 序号38 拓扑异构酶 药代动力学 癌症 内科学 化疗 化学 生物化学 结直肠癌 有机化学
作者
Shannon C. Leonard,Daniel F. Gaddy,Helen Lee,Stephan G. Klinz,Jonathan B. Fitzgerald,Bart S. Hendriks
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:77 (13_Supplement): 5151-5151
标识
DOI:10.1158/1538-7445.am2017-5151
摘要

Abstract Nal-IRI, a liposomal formulation of irinotecan, is designed for extended circulation relative to non-liposomal irinotecan and to exploit leaky tumor vasculature for enhanced drug delivery to tumors. Following tumor deposition, nal-IRI is taken up by phagocytic cells followed by irinotecan release and conversion to its active metabolite, SN-38. Sustained inhibition of topoisomerase 1 (TOP1) by extended SN-38 exposure is hypothesized to enable superior anti-tumor activity compared to traditional TOP1 inhibitors. Topotecan, another TOP1 inhibitor, is an approved second-line treatment option for small cell lung cancer (SCLC). Here, we evaluate the anti-tumor activity of nal-IRI compared to irinotecan and topotecan in preclinical models of SCLC including those that have been pre-treated with therapeutics used clinically to treat SCLC. Anti-tumor activity of nal-IRI, irinotecan, or topotecan was evaluated based on tumor volume assessments in DMS-53, DMS-114 and NCI-H1048 subcutaneous xenograft models in NOD-SCID mice, as well as in a patient-derived xenograft (PDX) model in nu/nu mice. To approximate clinical dosing: Nal-IRI was dosed at 16 mg/kg (irinotecan HCl basis), q1w, equivalent to a proposed clinical dose of 90 mg/m2 free base, q2w; irinotecan was dosed at 33 mg/kg q1w, equivalent to a clinical dose of 180 mg/m2 q2w; and topotecan was dosed at 0.83 mg/kg/week, day 1-2 every 7 days, which approximates a clinical dose intensity of 1.5 mg/m2 (days 1-5 every 21 days). Additionally, the activity of these agents was evaluated after tumors progressed following prior treatment with either topotecan, irinotecan or the combination of weekly carboplatin (30 mg/kg) plus etoposide (25 mg/kg), a standard first line regimen. Nal-IRI demonstrated anti-tumor activity in xenograft models of SCLC at clinically relevant dose levels, and resulted in complete or partial responses in DMS-53, DMS-114, NCI-H1048 and a PDX model in comparison with irinotecan or topotecan, which each had limited tumor growth control. Furthermore, Nal-IRI demonstrated anti-tumor activity in tumors that progressed following treatment with topotecan, and demonstrated significantly greater anti-tumor activity than both topotecan (p<0.0001) and irinotecan (p<0.0001) in NCI-H1048 tumors (8/8 complete responses) that had progressed on prior carboplatin plus etoposide treatment. These results support the further clinical development of nal-IRI versus IV topotecan in patients with SCLC that progressed on or after prior platinum containing therapy. Citation Format: Shannon C. Leonard, Daniel Gaddy, Helen Lee, Stephan Klinz, Jonathan Fitzgerald, Bart Hendriks. Nanoliposomal irinotecan (nal-IRI, MM-398) has greater anti-tumor activity than topotecan and irinotecan in mouse models of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5151. doi:10.1158/1538-7445.AM2017-5151

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