Abstract 1615: Initial testing (stage 1) of the Curaxin, CBL0137, by the Pediatric Preclinical Testing Program (PPTP)

Abstract

Abstract The Curaxin, CBL0137, is a member of a new class of small molecules that simultaneously activate p53 and inhibit cancer-associated stress response pathways such as NFκB and Heat Shock Factor 1. CBL0137 sequesters the FACT (FAcilitates Chromatin Transcription) complex on chromatin, inhibiting its function. CBL0137 has shown antitumor activity against a broad range of tumor models. Because of its novel mechanism of action CBL0137 was evaluated for its antitumor activity against the PPTP in vitro and in vivo models. Methods: CBL0137 was tested against the PPTP's in vitro cell line panel (n = 23) at concentrations ranging from 1.0 nM to 10.0 μM using the PPTP's standard 96 hour exposure period. CBL0137 was tested against the PPTP solid tumor xenografts using a dose of 50 mg/kg administered by the intravenous route weekly for 4 weeks. Standard PPTP time to event and objective response metrics were used to assess CBL0137 in vivo activity. Results: The median relative IC50 (rIC50) value for the PPTP cell lines was 0.28 μM, with a range from 0.13 μM to 0.80 μM. There were no significant differences in rIC50 values by histotype. The median rIC50 for the neuroblastoma cell lines exceeded that of the non-neuroblastoma cell lines (0.51 μM vs 0.26 μM, respectively, p = 0.16), while the median rIC50 for the ALL cell lines was less than that of the non-ALL cell lines (0.20 μM vs 0.31 μM, respectively, p = 0.06). All PPTP cell lines showed a pronounced cytotoxic effect, with T/C Ymin% values approaching 0% and with Relative I/O% values approaching -100% for all cell lines at the higher concentrations tested. CBL0137 was generally well tolerated in vivo with a 3.1% toxicity rate in the treated groups compared to a 0.8% rate for control animals. CBL0137 induced significant differences in EFS distribution compared to control in 9 of 30 (30%) of the solid tumor xenografts evaluable for this measure and in 8 of 8 (100%) evaluable ALL xenografts. Significance differences in EFS distributon were observed in 4 of 6 osteosarcoma lines, 2 of 2 rhabdoid tumor lines, and 2 of 6 rhabdomyosarcoma lines. No objective responses were observed among the 30 solid tumor xenografts. For the ALL panel, 1 xenograft achieved CR and 4 achieved PR. In summary, CBL0137 showed potent cytotoxic activity in vitro without clear histotype selectivity. In vivo the most consistent activity for CBL0137 was observed against the ALL xenografts, with most solid tumor xenograft lines showing limited response to single agent CBL0137. In considering clinical translation of these testing results, it will be important to relate the drug levels in SCID (soid tumor models) or NOD/SCID (ALL models) mice at 50 mg/kg to those tolerated in humans at the CBL0137 recommended phase 2 dose. Citation Format: Malcolm A. Smith, Min Kang, Patrick C. Reynolds, Richard B. Lock, Hernan Carol, Richard Gorlick, Anders E. Kolb, John M. Maris, Stephen T. Keir, Catherine A. Billups, Raushan Kurmasheva, Peter J. Houghton. Initial testing (stage 1) of the Curaxin, CBL0137, by the Pediatric Preclinical Testing Program (PPTP). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1615. doi:10.1158/1538-7445.AM2015-1615