Mount Sinai School of Medicine, New York, NY
John Martignetti , Albiruni R.A. Razak , Ying Chen , Nashat Y. Gabrail , John F. Gerecitano , Catalina Camacho , Elena Pereira , Peter Remsen Dottino , Sharon Shacham , Dilara McCauley , Tami Rashal , Jean-Richard Saint-Martin , Eran Shacham , Darcy Vincett , Michael Kauffman , Mansoor Raza Mirza , Morten Sorensen
Background: Increased XPO1 expression has been linked to progression of OvCa and is an independent poor prognostic for survival. Most tumor suppressor proteins (TSP) are transported out of the nucleus exclusively by XPO1 and thereby rendered non-functional. KPT-330 is a slowly reversible inhibitor of XPO1, and forces the nuclear retention and activation of over 10 TSP resulting in OvCa cell death while sparing normal cells. Methods: SINE compounds were tested for their ability to localize OvCa-relevant TSP to the nucleus and induce apoptosis in platinum sensitive and resistant cell lines in vitro. Combination with cisplatin was assessed in vitro and in patient-derived xenograft models (30 mg/m2 po, 3 times/week). As part of an on-going Phase 1 (KCP-330-002) in pts with solid tumors, oral KPT-330 (8-10 doses/4-weeks cycle) was administered to pts with heavily pre-treated OvCa that were progressing on study entry. Pharmacokinetic (PK) analyses were performed. Response was evaluated every 2 cycles (RECIST 1.1). Results: SINE potently induced OvCa cell death in platinum sensitive and resistant cell lines (IC50s < 0.12 µM). Nuclear accumulation and functional activation of p53 and other TSP was demonstrated. Synergy between SINE and cisplatin was shown in vitro and in vivo in OvCa models with diverse genetic backgrounds, and increased overall survival. Seven OvCa pts resistant/refractory to platinums and other agents (median age 55 yrs; ECOG PS 0/1: 3/4; median number of prior therapies 5) were treated with 30-35 mg/m2 oral KPT-330 (300 mg/cycle or 280 mg/cycle). No grade 4 AEs were reported. The most common AEs were fatigue, nausea, diarrhea, and vomiting; manageable with supportive care. PK analysis showed Cmax of 0.5-1 mM and AUC0-inf 2800-4000 ng*h/mL, which exceed levels in vitro and in animal models. RECIST response was evaluable in 5 pts: 1 PR (5 months), 2 SD (4 and 7+ months) and 2 PD. Conclusions: KPT-330 treatment is generally well tolerated and shows preliminary antitumor activity in pts with platinum resistant or refractory OvCa. Additional single agent and combination studies are planned. Clinical trial information: NCT01607905.
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Abstract Disclosures
2015 ASCO Annual Meeting
First Author: Ulrik Niels Lassen
2013 ASCO Annual Meeting
First Author: Albiruni R A Razak
2023 ASCO Annual Meeting
First Author: Ignace Vergote
2014 ASCO Annual Meeting
First Author: Morten Mau-Soerensen