Abstract LB-354: Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of the XPO1/CRM1 inhibitor KPT-330.
Authors: Houghton Peter , Kang Min , Reynolds Patrick , Gorlick Richard , Kolb Anders , Maris John , Keir Stephen , Carol Hernan , Lock Richard , Billups Catherine , Kurmasheva Raushan , Landesman Yosef , Shacham Sharon , Kauffman Michael , Smith Malcolm A. 
Published: August 2014

Abstract
Introduction: KPT-330 is an oral Selective Inhibitor of Nuclear Export (SINE) that binds covalently to XPO1 at Cys528 resulting in its irreversible inactivation. The nuclear export of over 200 proteins with specific nuclear export sequences (NES) is mediated via XPO1. Amongst the client proteins are many tumor suppressor and growth regulatory proteins (e.g., FOXO, IκB, pRb, p53, p73, p21, and p27).
Methods: KPT-330 was tested against the PPTP's in vitro cell line panel at concentrations ranging from 1.0 nM to 10.0 μM using the PPTP's standard 96 hour exposure period. It was tested against the PPTP solid tumor xenografts using a dose of 10 mg/kg administered by the oral route thrice weekly (M-W-F) for 4 weeks with a total treatment/observation period of 6 weeks.
Results: The median relative IC50 (rIC50) value for the PPTP cell lines was 125 nM, with a range from 13 nM to greater than 10 μM. There were no significant differences in rIC50 values by histotype, although there was a trend for greater sensitivity for the Ewing sarcoma cell lines (median rIC50 = 57 nM) and lesser sensitvity for the neuroblastoma cell lines (median rIC50 = 235 nM). Most cell lines showed Relative I/O% values between -75% and -100%, consistent with a prominent cytotoxic effect for KPT-330.
KPT-330 was well tolerated in vivo. It induced significant differences in EFS distribution compared to control in 29 of 37 (78%) solid tumor xenografts and in 5 of 8 (63%) ALL xenografts. For those xenografts with a significant difference in EFS distribution between treated and control groups, an EFS T/C value of greater than 2.0 indicates a substantial agent effect in slowing tumor growth. KPT-330 induced this level of effect in 11 of 32 (34%) solid tumor xenografts, most frequently for the Wilms tumor (2 of 3) and the Ewing sarcoma (4 of 5) panels. Objective responses were observed in 3 of 38 (4%) solid tumor xenografts, including a maintained complete response (MCR) for a Wilms tumor xenograft, a CR for a medulloblastoma xenograft, and a CR for a slow-growing ependymoma xenograft. For the ALL panel, 2 of 8 (25%) xenografts achieved either CR (ALL-8, T-cell ALL) or MCR (ALL-19, B-precursor ALL).
Conclusions: KPT-330 shows potent in vitro activity against many PPTP cell lines, consistent with the activation of multiple tumor suppressor proteins across diverse tumor genotypes. KPT-330 shows tumor regressing activity against selected PPTP solid tumor and ALL xenografts, and shows tumor growth inhibition for a larger number of models. Defining the relationship between KPT-330 systemic exposure in mice and humans will be important in assessing the clinical relevance of the PPTP in vivo results. Planned PD testing may identify biomarkers associated with response of pediatric preclinical models to KPT-330. KPT-330 is in phase 1 clinical trials in adults with advanced solid or hematological malignancies (NCT01607905 and NCT01607892). (Supported by NCI NO1-CM-42216)
Citation Format: Peter Houghton, Min Kang, Patrick Reynolds, Richard Gorlick, Anders Kolb, John Maris, Stephen Keir, Hernan Carol, Richard Lock, Catherine Billups, Raushan Kurmasheva, Yosef Landesman, Sharon Shacham, Michael Kauffman, Malcolm A. Smith. Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of the XPO1/CRM1 inhibitor KPT-330. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-354. doi:10.1158/1538-7445.AM2013-LB-354