Abstract 1715: Anti-cancer activity of a SN-38 nanoparticle, DEP® irinotecan, in human colon cancer xenograft models
Authors: Brian D. Kelly, Victoria McLeod, Rachael Walker, Jeannette Schreuders, Susan Jackson, Michael Giannis, Christine Dietinger, Shirley Xia, Anne Cargill, Aynaz Seta, Richard Hufton, Graham Heery, Carleen Cullinane, David J. Owen
Journal: Cancer Research (2020)

Abstract Irinotecan (Camptosar®) is a water-soluble prodrug of the potent topoisomerase I inhibitor SN-38 used clinically to treat multiple cancers. Irinotecan must be metabolized to its active metabolite SN-38 by carboxylesterases in hepatic and tumor cells. This metabolism in humans is inefficient with significant interpatient variability and leads to serious toxicities, notably diarrhea and myelosuppression. The narrow therapeutic window of irinotecan makes it an ideal candidate for improvement using dendrimer nanomedicine delivery. Starpharma's novel dendrimer nanoparticle DEP® platform has broad applicability in drug delivery, enhancing the therapeutic utility of drugs through improved solubility, efficacy and pharmacokinetics, reductions in certain toxicities (e.g. bone marrow toxicity) and providing novel intellectual property. The DEP platform has shown reproducible advantages across a wide range of drug classes including small molecule, peptides and proteins. Starpharma's DEP irinotecan is a PEGylated polylysine dendrimer with SN-38 conjugated to the surface via a hydrolytically labile linker. The incorporation of the active metabolite, SN-38 avoids the need for hepatic conversion and thereby minimizes variability in SN-38 levels. In preclinical studies, DEP irinotecan has shown to be well tolerated in animals. Efficacy assessments have been conducted, using a range of xenograft cancer models [SW620 (colon), HT-29 (colon), MDA-MB-231 (Breast) and CAPAN-1 (pancreatic)]. These studies demonstrated significant efficacy and survival benefits of DEP irinotecan compared to standard irinotecan. DEP irinotecan also showed significant benefit when dosed in combination with current standard of care therapies such as the anti-EGFR antibody, cetuximab, and the PARP inhibitor, olaparib. DEP irinotecan in combination with olaparib, significantly improved anti-tumor efficacy leading to tumor regression and extended median survival by 28 days compared to DEP irinotecan alone (P&amp;lt;0.0001, Mantel Cox Log rank test) whereas olaparib alone had minimal activity. This result highlights the synergistic combination benefits that can be achieved using DEP technology. DEP irinotecan is Starpharma's third internal DEP candidate to enter the clinic. The fourth DEP candidate, AZD0466 is a promising Bcl-2/Bcl-xL inhibitor and is partnered with AstraZeneca. AZD0466, is currently transitioning into clinical trials in the US. In summary, DEP irinotecan is well tolerated and allows for the delivery of SN-38 by successfully utilizing dendrimer drug delivery technology. The dendrimer nanoparticle shows significant efficacy and survival benefits compared to current standard of care therapies when used either as a monotherapy or in combination. DEP irinotecan is currently in a phase 1 / 2 adaptive trial at leading UK hospitals; The Christie, The Royal Marsden and The Newcastle Upon Tyne. Citation Format: Brian D. Kelly, Victoria McLeod, Rachael Walker, Jeannette Schreuders, Susan Jackson, Michael Giannis, Christine Dietinger, Shirley Xia, Anne Cargill, Aynaz Seta, Richard Hufton, Graham Heery, Carleen Cullinane, David J. Owen. Anti-cancer activity of a SN-38 nanoparticle, DEP® irinotecan, in human colon cancer xenograft models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1715.