Abstract 3972: Activity of MM-398, nanoliposomal irinotecan (nal-IRI), in Ewings family tumor xenografts is associated with high exposure of tumor to drug and high SLFN11 expression

Introduction: Pharmacokinetic properties of irinotecan limit tumor exposure to the active metabolite SN-38. MM-398, a nanoliposomal irinotecan (nal-IRI) developed to attempt to enhance delivery of irinotecan and SN-38 to tumor cells is being tested in clinical trials. We assessed the pharmacokinetics and anti-tumor activity of nal-IRI in comparison to the current clinical formulation of irinotecan (free irinotecan) in preclinical models of pediatric cancer in relationship to expression of the putative DNA/RNA helicase SLFN11. Experimental Design: Plasma and tissue samples were analyzed by liquid chromatography-tandem mass spectrometry for irinotecan and SN-38. In vivo activity of free irinotecan and nal-IRI was compared in subcutaneous xenograft models (3 each) of Ewing's sarcoma family of tumors (EFT), neuroblastoma (NB), and rhabdomyosarcoma (RMS). SLFN11 mRNA expression (real-time RT-PCR) was correlated to in vitro cytotoxicity of SN-38 (by DIMSCAN) in 20 EWS, 13 RMS, and 20 NB cell lines. SLFN11 mRNA expression in primary tumors (10 EFT, 10 NB, and 39 RMS) was assessed by Affymetrix HuEx microarrays. Results: Plasma and tumor concentrations of irinotecan and SN-38 were ∼ 10-fold higher for nal-IRI than for free irinotecan at 4h, 6h, and 24h post-intravenous injection (p 100 days (88% EFS on day 120). EFS for mice with RMS (median 39 days) and NB (median 81 days) was significantly shorter (P 100-fold higher in EFT cell lines and > 10-fold in EFT primary tumors compared with NB or RMS cell lines or primary tumors (P