Abstract LB-232: Preliminary results of a phase I study of the novel CRM1 inhibitors KPT-276 and KPT-335 in dogs with spontaneous cancer

Abstract

Abstract Introduction: KPT-276 and KPT-335 are irreversible inhibitors of CRM1/XPO1, the major nuclear export protein in cells, forcing nuclear retention of key tumor suppressor and growth regulatory proteins ultimately resulting in tumor cell death. KPT-276 and KPT-335 demonstrate potent anti-tumor activity against tumor cells in vitro at nanomolar concentrations (IC50 < 500 nM) and in multiple mouse xenograft models at doses 5-25 mg/kg with minimal effects on normal cells in vitro (IC50 > 5 μM). In normal laboratory dogs, both KPT-276 and KPT-335 are well tolerated with mild reversible transaminase and bilirubin elevations and mild to moderate anorexia. The purpose of this Phase I study was to evaluate the clinical toxicities, establish the maximum tolerated dose and dosing regimen, and provide a preliminary assessment of biologic activity in dogs with spontaneous cancers that receive KPT-276 and KPT-335 Methods: Dogs with Non-Hodgkins lymphoma (NHL), metastatic osteosarcoma (OSA), melanoma (MEL) and mast cell tumor (MCT) were eligible for enrollment. Drug was administered at a starting dose of 30 mg/kg orally on a Monday/Wednesday/Thursday schedule for KPT-276 and at 3 mg/kg orally on a Monday/Thursday schedule for KPT-335. Complete blood count, serum chemistries, clotting times, drug peak plasma level and response to therapy were assessed at each visit. Results: The first four of dogs entered (MCT n=3 and NHL n=1) received KPT-276; the 3 dogs with MCT experienced progressive disease (PD, n=2) and stable disease (SD, n=1). The dog with NHL experienced a cytologic complete response (CR) of approximately 3 months duration despite having failed chemotherapy induction and prednisone treatment. Adverse events included vomiting, diarrhea, and anorexia (all grade 1-2) and elevations in liver function tests (LFTs, grade 1-3) and bilirubin (grade 1-2), as well as neutrophilic leukocytosis. Pharmacokinetic (PK) analysis indicated wide variation in oral bioavailability among dogs so the closely related analog, KPT-335, that is more potent and has better canine bioavailability was subsequently used. To date, 7 dogs have received KPT-335 (NHL, n=6, OSA, n=1) with responses consisting of PR (NHL n=2), SD (NHL n=2), and PD (NLH n=2 and OSA n=1). Adverse events included anorexia and weight loss (grade 1-3) and LFT elevations (grade 1-3) necessitating dpse reductions to 1-1.5 mg/kg on the M/Th schedule. PK analysis indicated more consistent drug absorption among dogs receiving KPT-335. Conclusions: The novel oral SINE CRM1 inhibitors KPT-276 and KPT-335 exhibit biologic activity in a relevant spontaneous large animal model of cancer. Adverse events associated with drug administration are tolerable and reversible with drug holiday. Enrollment in this clinical trial is ongoing. 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 LB-232. doi:1538-7445.AM2012-LB-232