Pediatric Preclinical Testing Consortium Evaluation Of The Second-Generation Selective Inhibitor Of Nuclear Export (Sine) Compound Kpt-8602

Introduction: KPT-8602 is a second-generation SINE compound that specifically blocks exportin-1 (XPO1) cargo interactions. XPO1 is a nuclear export receptor, a critical regulator of cell proliferation and survival, that is characterized as the sole transporter of several tumor suppressor and growth regulatory proteins, including p53, p21, p27, BCR-ABL, FOXO and STAT3. Overexpression of XPO1 has been correlated with high-risk disease and poor survival in multiple pediatric cancers, including leukemia and neuroblastoma (NB). Our prior work demonstrated that selinexor, a closely-related SINE compound, induced complete remission (CR) or maintained CR (MCR) in 2 of 8 ALL patient-derived xenografts (PDXs) tested while it did not induce tumor regressions in 6 neuroblastoma models (Attiyeh EF, et al. Pediatr Blood Cancer. 2016;63:276-86). While selinexor has shown activity in a variety of adult malignancies and is being tested in pediatric phase 1 trials, KPT-8602 shows similar pharmacokinetic properties to selinexor and improved tolerability in preclinical models, and thus it was tested against ALL and NB models by the PPTC. Methods: KPT-8602 was tested against 6 NB and 12 ALL pediatric PDX models using 10 and 8 mice/arm, respectively. Based on tolerability, a dose of 12.5 mg/kg was selected and administered once daily via oral gavage 5 days per week for 4 weeks. Events were defined as quadrupling of tumor volume from day 0 (for NB) or as the proportion of human CD45 + cells in the peripheral blood (%huCD45 + ) ≥25% (for ALL). The Kaplan-Meier method was used to compare time-to-event between treated and control groups. Objective response categories were assigned as progressive disease (PD, which is subdivided into progressive disease without or with growth delay, PD1 or PD2, respectively), stable disease (SD), partial response (PR), CR, and MCR [Houghton PJ, et al. Pediatr Blood Cancer, 2007]. KPT-8602 was developed and provided for testing by Karyopharm Therapeutics, Inc. Results: KPT-8602 was generally well tolerated, but with weight loss during treatment of approximately 15% and 2% for the neuroblastoma and ALL models, respectively. KPT-8602 induced significant differences in event free survival (EFS) distribution compared to control in 16 of the 18 (88.9%) evaluable xenograft lines studied. Four NB and 10 ALL PDX models showed a u003e2-fold extension in median EFS for treated compared to control animals. For the 6 NB PDX models, 3 had a minimum relative tumor volume (minRTV) of Citation Format: Kateryna Krytska, Kathryn Evans, Tara Pritchard, Matthew Tsang, Raymond Yung, Yael P. Mosse, Stephen W. Erickson, Yuelong Guo, Erkan Baloglu, Yosef Landesman, Kyle A. Jensen, William Senapedis, Beverly A. Teicher, Malcolm A. Smith, Richard B. Lock, John M. Maris. Pediatric Preclinical Testing Consortium evaluation of the second-generation selective inhibitor of nuclear export (SINE) compound KPT-8602 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B14.