Abstract 4626: Evaluating the pharmacodynamics and pharmacokinetic effects of MM-398, a nanoliposomal irinotecan (nal-IRI) in subcutaneous xenograft tumor models of human squamous cell carcinoma and small cell lung cancers
Authors: Chan Daniel C. , Kalra Ashish , Zhang Zhiyong , Paz Nancy , Kirpotin Dmitri , Drummond Daryl , Nielsen Ulrik , Bunn Paul A. , Fitzgerald Jonathan 
Published: May 2015

Background: MM-398 is a novel nanoliposomal encapsulation of irinotecan (nal-IRI), a topoisomerase I inhibitor. In preclinical studies, nal-IRI has been shown to greatly modify the pharmacokinetics and biodistribution of CPT-11 and its active metabolite, SN-38, thereby improving its activity. In this report, we evaluate the in vivo activity of nal-IRI in the two xenograft models of lung cancer. A pharmacodynamics (PD) study was performed to measure the drug activation and deposition parameters in these tumor models. In addition we investigated the effects of nal-IRI on tumor growth, tumor-associated macrophages (TAM's), vasculature, cell proliferation, and apoptosis.

Methods: Xenograft models of subcutaneous H157 squamous cell carcinoma (SCC) and H841 small cell lung cancer (SCLC) were established in mice. A short pharmacodynamics (PD) study was performed, wherein, 24 hours after a single dose, animals were euthanized and tumors collected. PD analysis included profiling for carboxylesterase (CES) levels, vasculature (CD31), macrophage (F4/80), and metabolite (CPT-11 and SN-38) levels. For the tumor activity study, animals (5 per group) were treated by weekly i.v. injections with placebo liposome, free irinotecan at 25 mg/kg/wk, or nal-IRI at 30 and 50 mg/kg/wk for three weeks. Tumor volumes were measured with digital calipers. IHC analysis was performed for TAM content, tumor proliferation (Ki67), apoptosis, and vasculature.

Results: (1) The carboxylesterase enzyme (activation) and CPT-11 (deposition) tumor levels resulted in extended intratumor SN38 duration, as predicted by the model simulation; (2) nal-IRI suppressed H157 tumor growth in a dose dependent manner, much more efficiently than free irinotecan. On day 25, nal-IRI, at 30 and 50 mg/kg/wk, inhibited tumor growth by 92.6% and 96.3%, respectively, when compared with placebo liposome. In contrast, free irinotecan inhibited tumor growth by 55.7%; (3) For the SCLC H841 xenograft, on day 35, nal-IRI at 30 and 50 mg/kg/wk, also inhibited tumor growth by 84.9% and 93.4% respectively, greater than free irinotecan by 32.7%, when compared with placebo liposome. No obvious toxicities or weight loss were noted in the nal-IRI treated groups; (4) TAM levels were significantly (p&lt;0.05) higher in tumors treated with nal-IRI (30mg/kg and 50mg/kg), as compared to control or free irinotecan treated tumors.

Conclusion: nal-IRI inhibited tumor growth in lung tumor xenograft models, suggesting the treatment of human SCC and SCLC, in which there are high unmet medical needs, as a potential target for clinical investigation.

Citation Format: Daniel CF Chan, Ashish Kalra, Zhiyong Zhang, Nancy Paz, Dmitri Kirpotin, Daryl Drummond, Ulrik Nielsen, Paul A. Bunn, Jonathan Fitzgerald. Evaluating the pharmacodynamics and pharmacokinetic effects of MM-398, a nanoliposomal irinotecan (nal-IRI) in subcutaneous xenograft tumor models of human squamous cell carcinoma and small cell lung cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4626. doi:10.1158/1538-7445.AM2014-4626