Abstract 2493: Enhanced activity of fenretinide/-LYM-X-SORBTM (4-HPR/LXS) oral powder in combination with ketoconazole and vincristine against recurrent neuroblastoma xenografts

Abstract

Abstract Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. Survival from relapsed NB is low and novel therapies are needed against recurrent NB, which often manifest loss of p53 function and multidrug resistance. Fenretinide (4-HPR) is a synthetic retinoid that achieved multiple complete responses in minimal disease in a phase I clinical trial in recurrent neuroblastoma when formulated as an oral powder using the LYM-X-SORBTM (LXS) organized lipid matrix (4-HPR/LXS). We recently showed that ketoconazole (keto) increased 4-HPR plasma concentrations in mice by > 2-fold over 4-HPR alone (P<0.02) (Br J Pharmacol 163:1263-75, 2011). To explore the anti-neuroblastoma activity in vivo of 4-HPR/LXS given with keto, we tested three human neuroblastoma xenografts established from patients with progressive disease, CHLA-119 and CHLA-90 (both TP53-mutant, multidrug-resistant cell lines) and COG-N-415x (from a progressive disease patient). 4-HPR/LXS was dosed at 240 mg/kg/day, keto at 38 mg/kg/day (both by oral gavagex5d/wk). 4-HPR and metabolite (4-oxo-4-HPR and 4-MPR) tumor concentrations were determined 4 h after last treatment and were quantified by HPLC. In the CHLA-119 xenograft, keto increased the complete response (CR) rate of 4-HPR/LXS from 1/10 mice to 5/10 mice. Survival >350 days with 4-HPR/LXS alone was 10% compared to 50% of mice treated with 4-HPR/LXS+keto (P< 0.005). 4-HPR/LXS+keto increased 4-HPR and 4-oxo-4-HPR tumor concentrations by > 2-fold over 4-HPR alone (P<0.02) and (P<0.04) respectively. We then added intravenous (i.v.) vincristine (VCR) at 0.5 mg/kg given twice a week every other week to the 4-HPR/LXS+keto regimen. In CHLA-119 xenografts, VCR increased the CR rate to 5/10 mice compared to 3/8 with 4-HPR/LXS+keto and 1/10 with VCR alone. Mouse survival for >300 days with 4-HPR/LXS+keto+VCR was 50% vs 38% with 4-HPR/LXS+keto (P<0.01) and 10% for VCR alone (P<0.003). COG-N-415x and CHLA-90 xenografts failed to achieve responses to 4-HPR/LXS or in combination with keto. Addition of VCR to 4-HPR/LXS+keto achieved CR's in 2/9 COG-415x mice compared to 0/9 and 0/8 for 4-HPR/LXS+keto and VCR alone, respectively. Survival of COG-415x mice was >90 days with 4-HPR+keto+VCR for 2/9 mice (22%) vs 0% for the other treatments (P<0.001). In CHLA-90 xenografts, 4-HPR/LXS+keto+VCR achieved 1 CR and 1 stable disease compared to no responses with 4-HPR/LXS+keto or VCR alone. CHLA-90 xenograft mouse survival for >60 days with 4-HPR/LXS+keto+VCR was 2/5 (40%) vs 0% for VCR or 4-HPR/LXS+keto alone. Toxicity of the combination regimens in mice (assessed by body weight) was negligible. These data suggest that if an ongoing phase I study of 4-HPR/LXS+keto is well-tolerated that a subsequent clinical trial exploring that combination+VCR should be undertaken in patients with recurrent NB. Supported by CPRIT RP10072. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2493. doi:1538-7445.AM2012-2493